Medical practice

Immune changes found in people with CFS/ME

"Distinct stages to chronic fatigue syndrome identified," reports BBC News online.

People with chronic fatigue syndrome (CFS), sometimes called myalgic encephalopathy (ME), can have debilitating exhaustion affecting their everyday life that does not go away with sleep or rest.

The authors of this study say there are no laboratory tests to diagnose or manage the condition, despite efforts to find biological markers of the disease.

They aimed to address this by looking for differences in immune system signalling chemicals (cytokines) between people with CFS/ME and healthy controls.

Comparing all CFS/ME participants with controls found few differences. However, differences were found when the CFS/ME group was divided into those with short- (three years or less) and long-term (more than three years) disease.

These results suggest that people with CFS/ME may have higher levels of some cytokines until around the three-year mark, at which point the differences disappear. 

The study is not reliable enough on its own to prove that the disease has distinct stages, and it doesn't give us any more clues as to how or why these particular cytokines might be involved in the condition.

Other studies, and study types, are needed to build on these initial findings.

Find out more about CFS/ME.

Where did the story come from?

The study was led by researchers from Columbia University Mailman School of Public Health in New York, and was funded by the CFI/Hutchins Family Foundation and the US National Institutes of Health.

It was published in the peer-reviewed journal Science Advances.

The BBC reported the story accurately, and included useful quotes from independent experts who commented on this research.

What kind of research was this?

This case-control study used data from two cohort studies to investigate biological makers of CFS/ME.
This type of study is an effective way of finding out the ways in which people with a disease – in this case, CFS/ME – differ from those without.

However, the links established usually mean that the two things are found together, not that one causes the other.

What did the research involve?

The study used disease diagnostic information and blood samples taken from two recent large multicentre US cohort studies of people with CFS/ME.

The researchers analysed the relationship of 51 immune system chemical messengers called cytokines with diagnosis of CFS/ME and other clinical variables, such as the duration and severity of the disease.

People without CFS/ME (the controls) were matched with people with CFS/ME based on key variables known to affect immune status, including the season of sampling, geographic site, age and sex.

The main analysis looked for statistically significant differences in the 51 immune system markers in people with and without CFS/ME.

What were the basic results?

All CFS/ME versus all controls

Comparing all 298 people with CFS/ME with all 348 controls led to few statistically significant results. In rare instances where there were differences, levels of cytokines were lower in people with CFS/ME.

Short- and long-duration CFS/ME versus controls

In a sub-analysis, the researchers looked at the effect of grouping CFS/ME into short-duration (having the condition for three years or less) and long-duration (more than three years) disease.

They found significant differences in more than half the 51 immune system markers tested in the group of 52 people early on in the course of the disease, relative to the healthy controls. These differences were not present in the 246 people with longer-duration illness.

Cytokine levels, which differed between short- and long-duration groups, were correlated with duration of illness.

The two most prominent cytokines associated with short-duration CFS/ME were interferon-gamma and interleukin-12p40, both known to be important for an effective immune system.

How did the researchers interpret the results?

On the BBC website, lead author Dr Mady Hornig said: "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 … this shows there are distinct stages to the disease."

In their research paper, the researchers suggested that their findings "have critical implications for the discovery of interventional strategies and early diagnosis of ME/CFS".


This case-control study found cytokine differences in people diagnosed with CFS/ME for three years or less, compared with healthy controls. The same was not found for people with CFS/ME of more than three years' duration.

The study authors interpreted this as a sign that CFS/ME might have two stages. The implications are that this may one day help researchers better understand the disease, and potentially develop new ways of testing and diagnosing the condition.

Optimism notwithstanding, there are significant limitations to this study design, meaning it cannot say anything reliable or solid on its own. Further research needs to repeat, confirm and build on its findings.

Professor Michael Sharpe, professor of psychological medicine at the University of Oxford, said: "Whilst this finding that some patients with CFS/ME have an immune abnormality is potentially interesting, we should treat it with great caution … This type of study [a case-control study] is notorious for producing findings that other researchers subsequently fail to replicate."

He added: "Everyone who has worked clinically with patients with CFS/ME knows this is a real illness; this study neither proves nor disproves that observation."

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