A gene linked to sleep deprivation
Chronic fatigue syndrome affects millions worldwide. Istock

Scientists have found new clues that inflammation is a driver of chronic fatigue syndrome, a still mysterious condition that affects about 250,000 people in Britain. They have identified novel biomarkers of the disease in patients' blood – 17 immune-system signalling proteins known as cytokines.

The causes of chronic fatigue syndrome (ME/CFS) are still uncertain, despite more and more scientists dedicating time to studying the condition. It has attracted a lot of controversy in recent years, as scientists and people in the general public wondered whether the condition could be classified as a physical illness at all.

Now, influential institutions such as the World Health Organization and the Royal College of Physicians in the UK have said that chronic fatigue syndrome is real, but they do not know why it develops in some people, women in particular, nor how to improve diagnosis and treatment.

Signs of inflammation have previously been documented in chronic fatigue syndrome patients, pointing to potential causes, but the data was limited and contradictory at times. In a study now published in PNAS, scientists have worked with more patients to identify markers of inflammation at an unprecedented scale.

"There's been a great deal of controversy and confusion surrounding ME/CFS - even whether it is an actual disease," said senior author Mark Davis of Stanford University in a statement. "Our findings show clearly that it's an inflammatory disease and provide a solid basis for a diagnostic blood test."

Cytokines in the blood

The scientists collected and analysed blood samples from 192 patients as well as from 392 healthy control subjects. The average age of patients and controls was about 50, and most patients had had symptoms of the condition for more than 10 years.

The researchers identified what cytokines were present in the blood of patients. They found that some cytokine levels were lower in patients with mild forms of the condition than in control subjects. However, they were much more elevated in patients with severe symptoms.

A total of 17 cytokines in particular were associated with severe manifestations of the disease, 13 of which were proteins that promote inflammation - the immune system's normal response to injuries. These cytokines likely contribute to the flu-like symptoms reported by patients, which are characteristic of inflammation-driven diseases.

These findings suggest that the immune system plays a crucial role in development of the disease and confirms what scientists previously suspected - that inflammation is central to the symptoms of of chronic fatigue syndrome.

The scientists believe that the different levels of cytokines may reflect different genetic predispositions among patients to progress to mild versus severe disease.

Improving the diagnosis

At present, the difficulty to diagnose chronic fatigue syndrome is a major problem, as it means that many patients are not identified, or are caught very late. This study could form the basis for the development of new blood tests to diagnose people more accurately and to assess the severity of their condition.

"There's been a great deal of controversy and confusion surrounding ME/CFS - even whether it is an actual disease," Davis said. "Our findings show clearly that it's an inflammatory disease and provide a solid basis for a diagnostic blood test."

But it looks like the debate is set to continue as some researchers think more evidence is needed before the condition can be described as an inflammatory disease.

"Contrary to the authors' assertions, the study provides no evidence that inflammation actually causes CFS/ME. Just two out of 51 measures of inflammation were increased in patients, but this could just as easily be a consequence of the illness and its effects on people's lives," said Anthony Cleare, Professor of Psychopharmacology & Affective Disorders, King's College London's Institute of Psychiatry, Psychology & Neuroscience, who was not involved with the study.

"For example, CFS/ME sufferers may have sleep problems or depression, both of which can cause elevated inflammation, and neither of which were measured in this study. They may also take medication that can alter the cytokines measured in the study, and the authors do not state if this was examined. Thus, it is premature to assert that CFS is an inflammatory disease. There remains no basis to use cytokines as a diagnostic test."

Chronic fatigue syndrome

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) devastates the lives of millions of people around the world. In the UK, about 250,000 people are infected although figures may be higher since there are no specific diagnostic tests.

It has remained a mystery illness despite decades of research and there has been a lot of debate as whether it was a physical condition or if it was primarily psychological. It is much more common in women, and tends to develop when people are in their mid-20s or mid-40s.

Symptoms include extreme tiredness but also sleep problems, muscle or joint pain, headaches and generally, flu-like symptoms. Since the condition is so poorly understood, there is no cure for it, but some treatments can help relieve the symptoms, and include cognitive behavioural therapy (CBT), a structured exercise programme called graded exercise therapy (GET) or drugs to control pain, nausea and sleeping problems.

The article was updated to include comments by Professor Anthony Cleare.