A new study strengthens the findings that ME/CFS is a disease with a highly unusual feature. Analysis of survey data on patients across Europe found there are two peak ages for getting ME/CFS, around 16 and the late 30s – a rare bimodal pattern. There are differences between people in the two peaks. Those in the early peak are more likely to report an infectious onset, be more severely ill, and have close relatives with ME/CFS. That combination of age peaks is unique, even amongst those diseases that do have two peaks, and this could be a clue to the biology behind ME/CFS

The biology of ME/CFS is hard to pin down, with few unique features. But a 2014 study of medical records in Norway suggested a striking one: two different ages when people are most likely to get ill. Two onset age-peaks is unusual in disease biology, but it is seen in a few cancers and some autoimmune diseases.

It started with a tweet

This unusual pattern seemed to me back then as though it might help unravel the biology behind ME/CFS, but, over the years, the clue wasn’t pursued. Perhaps no one thought the finding was real: the study was limited to one country, and data were for age at diagnosis – which can be very different from age at onset.

Last year, I decided to see if we could get stronger evidence by focusing on age at onset rather than diagnosis, and by looking in more countries. An initial trawl of data sources found nothing, so I tweeted to ask if anyone had something like this. And struck gold.

Trude Schei, Head of the ME Norwegian ME Association, replied to say that she had led the 2021 European ME Association (EMEA) survey, and had a database of over 10,000 responses with onset age, year, suspected trigger and other invaluable data from countries across Europe. She and her co-lead, Professor Arild Angelsen, were willing to share the data. Suddenly, a study was on.

We formed a team consisting mostly of people who live with ME/CFS: having it, or being close to someone who does. Dr Audrey Ryback at the University of Edinburgh led the study, joined by Charlie Hillier, a scientist with severe ME/CFS, along with Dr Joshua Dibble, also based at the University of Edinburgh, Schei, Angelsen and myself.

Two onset age peaks

We looked at ten European countries with the largest number of responses to provide us with enough data to get a reliable picture from each country. One third of the 9,380 responses came from Norway, which had the largest number of responses by far, and for Norway two age peaks were visible with the naked eye:

For all other countries – both combined (shown above) and individually – the two peaks were less obvious and we turned to statistical techniques to robustly identify whether there were peaks in the data.

First we used a ‘dip’ test, which tells us whether we have evidence for more than one peak in our data. This produced results for Norway and all other countries combined that were highly significant, both having a p value well below the statistical significance threshold of p ≤ 0.05, at p < 0.0000000000000002 (that is, p < 2 x10^-16).

Six of the nine other countries were also individually statistically significant, though Switzerland and France (which had the smallest sample sizes), and the Netherlands, were not.

Next we wanted to work out where the peaks were and describe their features. We used a technique called a Gaussian Mixture Model to do this, and the results were striking, as you can see below.

Countries with very different looking profiles had consistent early and late peak ages

The model had no problem finding an early peak, shown by the orange line, and a late peak, shown in blue. You can see considerable differences in the relative size of these peaks (the early peak contains only 9% of respondents in Spain and it ranges  up to 38%, as seen in Germany), which makes the overall profiles look very different.

Consistency of peak ages suggest they are a core feature of ME/CFS

But what struck us was how consistent the ages (and standard deviations) of these peaks were between countries: around age 16 for the early peak and age 37 for the late peak for almost all countries (Germany was significantly higher for both).

Replication of these findings

We wanted to further confirm the findings by attempting to replicate them on an independent dataset – DecodeME. This had data on illness length but only in year-bands of varying size. This limited us to a less precise analysis of 6,455 respondents who reported having ME/CFS for under ten years. We approximated their age at onset (which could have a maximum error of 2.5 years).

The dip test gave almost identical results as for Norway and all other countries for the EMEA data with p < 2×10^-16.

The estimated age for the two peaks was a little older than for the EMEA data: 18.8 years for the early peak and 40.1 years for the late one. The higher figures might in part be because we could only estimate onset age and because DecodeME participants had to be 16 years or older to participate in the study.

Summary – strong evidence for two onset age peaks in ME/CFS

• Highly significant dip test results .
• Consistent peak ages and standard deviations between countries.
• Replication of findings in the DecodeME subset.

Differences between people with early and late onset

We looked to see if there were difference between patients in the early and late peaks that might point to differences in the underlying biology, as it does in other illnesses, such as in inflammatory bowel disease.

Triggers for ME/CFS

Patients reported similar triggers for their illness in most countries, with infection dominating. There were large differences in the triggers between early and late peaks (p < 2.2 x 10^-16), with higher rates for infection in particular in the early peak (57% vs 47% in the late peak).

We found a similar pattern for DecodeME data, where infectious mononucleosis (also known as glandular fever, and recorded separately from other infections) had a much younger onset peak.

Infectious onset, particularly infectious mononucleosis, was particularly prominent in the early peak.

Having a close relative with ME/CFS was associated with early onset

Thirteen per cent of people reported having a first-degree relative with the illness, and those with such relatives were more likely to have early onset:

Put another way, having an affected relative was more common in the early peak (22.5% vs 14.9% in the late peak) with an odds ratio of 1.43. This could indicate a genetic risk of early onset although it could also be explained by shared exposure risks in families.

Early onset cases were more likely to be severely affected

Perhaps surprisingly, we also found that early onset cases were significantly more likely to be severe. Early cases were more than twice as likely to be severe or very severe (compared to moderate or mild) than late onset cases (odds ratio 2.1, p  < 2×10^-16).

Mild cases have about a 50% reduction on pre-illness activity and moderate cases are mostly housebound. Severe are mostly bedbound; very severe are totally bedbound and need help with basic functions.

We checked if early cases were more severe simply because they had been ill for longer, but surprisingly there was very little association between duration and severity. This indicates a direct association between severity and early onset.

Strengths and weaknesses

Our study has confirmed two onset peaks in multiple ways and used onset age rather than age at diagnosis used in earlier studies. In combination with the original Norwegian findings, we now have strong evidence that ME/CFS has two onset age peaks.

But a significant weakness is that we relied on self-report data. Although it is probably the best source of data on onset age, self-report data isn’t always entirely accurate. And only those with n a diagnosis were likely to find the survey, which was promoted by national ME organisations.

Among diseases with two onset age peaks, the adolescent and early middle age peaks in ME/CFS are unique. This very unusual pattern could be an important clue to the biology behind ME/CFS. See the examples of other illnesses below. It is possible in ME/CFS that the two peaks are due to some biological process that changes at particular ages and makes people more likely to develop the disease at those ages.

Subgrouping cases into early and late onset in future studies could make it easier to detect any different biological mechanisms underlying the two peaks. And that could lead to treatments. Vaccinations are also a potential way to reduce ME/CFS triggered by specific infections, and these are already in development.

Extra: Illnesses where two peaks is linked to different causes

Autoimmune vitiligo is an interesting example of a disease with bimodal onset where the age at onset has provided clues into the mechanisms of the disease. A specific genetic association related to the immune system has been demonstrated in the early onset peak, which has an odds ratio of >8 – a very large genetic risk.

Another disease with two age peaks is Inflammatory bowel disease, which includes Crohn’s disease and ulcerative colitis, is another example. Early and late onset disease have been proposed to even constitute different diseases (read more in this Nature article).