ME/CFS onset has two peaks, which may be a clue to causes
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 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).
21 thoughts on “ME/CFS onset has two peaks, which may be a clue to causes”
This is very interesting. I had glandular fever as a 17 year old this is when I became very unwell. I finally got my mecfs diagnosis in my late 50s. My consultants is convinced that the onset was around the age of 17.
That’s a long wait for diagnosis, even by the lousy standards of ME. Did having a diagnosis help?
Yes I think it did. I finally had validation that it wasn’t all in my head. After so many years of not knowing what was really going on it was almost a relief to be diagnosed even though I knew there was no cure. Everything fell into place and made sense.
That’s good to hear. I think for many people (and not just for this illness
), simply knowing what it is provides some respite.
Great blog, thank you that was enlightening!
Thank you.
Yes! Fits my ME profile. Onset at 38. Managed having a life with moderate ME.
I had TB in my teens, IBS in my 20s, but ME stopped my active life. Housebound at 77 now.
I hope for other’s sake that you continue to look at this illness in new ways and make progress. Thank you.
Have any genetic studies been done into vitiligo and Crohn’s? It would be interesting to see how they compare with DecodeME and SequenceME.
Yes, and if you click through those links at the end of the blog, you can find more information there. Certainly for vertigo, the genetic research was done first. But they did capture onset age, I’m back to allowed them to do a subgroup analysis comparing early and late onset. In vertigo, that proved an incredibly strong genetic association with early onset, which has an odd ratio of over 8 to 1 for particular HLA variants. (HLA is a large group of immune – related to genes).
In New Zealand I have seen two main groups of patients in my studies corresponding to the so called pediatric form .(teenagers at onset ) and the 30-40s age group. Interestingly those from the teenage group often report their best years with ME/CFS during pregnancy and breastfeeding ( my own daughter’s experience too ) and so hormonal state/changes seem critical for this group ( ie likely at onset). How that relates to the adult women in the 30’s is not so clear to me as it should be a period of relative hormonal stability albeit with cycling -but is this a post child birth hormonal change back to a cycling state ie the reverse of the teenagers – instead of going from the stability of a child to change in a young woman, going from a hormone stabilising period of pregnancy and breast feeding to back to the more cyclical state. The ‘teenager group’ do seem to revert back to their previous debilitating state of their condition once breast feeding stops. This gives hope that if the debilitating nature of the conditions can be modulated significantly by ‘natural events’ it should be possible to find a way of mimicking this and give those affected a much better quality of life.
Age of change in severity for those with a pre-existing diagnosis would be interesting to look at for this as well.
I had the onset of ME/CFS in my early 40’s (I’m now in my 50’s). My daughter had the onset of ME/CFS when she was 16. She is now 20 and has severe ME/CFS. This fits our situation perfectly but sadly.
Thanks for your post. Yes, a good fit and also very sad.
Anecdotally it does seem like most of those who die from ME have the early onset kind. I wonder how much the increased severity of people who got ME in their teens is exacerbated by their being told they’re too young to be ill, and therefore over-exerting, with young people being more active in general.
Thank you very nuch for this very interesting study. I have come right in the centre of the second peak as I got sick after an apparent 2 week virus from which I couldn’t recover. I was 41 at the time and I live in the UK. I gave all my data in the very early stage of the Decode Study fyi. I am now 78 and finding things increasingly difficult.
That’s a long time ill. And I can imagine that increasing years makes this illness so much harder to handle, sorry to hear it.
For the late onset, there’s probably a sociological element to it. For example, it is often the age where young children bring home strings of mild viruses. In this group, it might not be one single virus like EBV that triggers ME/CFS, but the combined load of repeated (minor) immune activation, more interrupted sleep, more career pressure/ worklife balance, etc., finally pushing the system into a maladaptive, self perpetuating state
Thanks for that idea, I think figuring out why they are two peaks could be very important in understanding ME/CFS. Young school kids bringing home viruses with something I looked at a couple of years ago. But the timing isn’t quite right because the age of first child in Europe’s late 20s, and has been for some time there should be before that it was earlier So late 30s is probably a bit late for that. A friend of mine who was head of biology at a secondary school pointed out that secondary schools are much bigger than primary schools and draw people from a much bigger area. So people starting secondary school are probably exposed to s much wide range of viruses. But maybe that would be a bit late for the late 30s peak, particularly for people with two children.. but maybe schools and sociological factors are driving this, even if we’re not quite clear how
Although it wasn’t in the paper, we also saw an early and late peak for people reporting they had specific types of non-infectious onset.
Another possibility is that this is something to do with the host, us, a vulnerability in our immune system at particular ages. But there isn’t a good explanation for how that would work yet.
I think identifying some kind of self perpetuating mechanism, which you suggest, is probably the central of challenge for trying to understand the illness.
.
Thank you for being willing to take on this thorny question. I agree that it may really help in figuring out what is going on. Is it possible that some of the later group actually got ME/CFS at a younger age but it wasn’t severe enough to impact their lives initially. Then at an older age something triggered a severe crash that resulted in diagnosis. This possibility would also fit with those getting a later diagnosis not remembering a specific illness right before onset.
This is really interesting and fits my experience too. I was not quite right from about 16 but didn’t get my ultimate trigger virus until I was 22. My sister got ill at 11. Interestingly our illness trajectories and experiences have been quite different though we are both severe now, 30+ years on. We also both have hypermobility. I would love to know how many of the early group also were hypermobile. It seems that it is a strong predisposing factor for Long Covid?
Also re covid, what are your thoughts on how the pandemic affects ME research? It seems to me there is no pure dataset any more? All these patterns may be disrupted by repeat and frequent covid infections and the long term negative impact they are having on the immune system population-wide might change the pattern dramatically? The almost complete inability to diagnose ME from other triggers going forward (due to no effort to test us when we get any common virus) will be a loss? Perhaps it will provide new information but it feels like a bit of a mess?
Also it strikes me how important it is to identify those young people who seem vulnerable to ME. I was “TATT” but told to struggle on, in my teens. If I had known and been supported to rest when I needed to, and to protect myself from infection (we now know a lot more about how to do that!) things could have been less life-devastating.
The EBV vaccine etc could also be really valuable tools for at least some prevention/delay.
In the meantime, having health professionals that can recognise both PEM type reactions and hypermobility and other risk factors such as IBS symptoms, and intervene with advice and guidance is critical.