Incidence age is bimodal for [ME/CFS], with higher severity burden for early onset disease, 2026, McGrath et al

[Nightsong]

Abstract:
Myalgic Encephalomyelitis, or Chronic Fatigue Syndrome (ME/CFS), is a disease of uncertain origin. Studies of Norwegian health records have suggested that ME/CFS incidence across age groups is bimodal–a characteristic that could provide insight into the aetiology of the disease. Here, we analysed survey data from over 9,000 respondents with ME/CFS from 10 European countries, and observe an early onset peak with a mean of 16.0 years old (standard deviation [sd]: 4.3) and a late onset peak at 36.6 years old (sd: 10.5).

Statistical support for multimodal onset age was evident in 7 of the 10 countries examined. Infection as a trigger for ME/CFS is 10 percentage points higher among early compared to late onset disease (P = 2.1 × 10−13). Early onset ME/CFS was associated with greater odds of being severely or very severely affected (OR = 2.15, 95% CI [1.84—2.51], p < 2 × 10−16). Those with first degree relatives with ME/CFS had greater odds of early than late onset ME/CFS (OR = 1.43, 95% CI [1.25—1.63], P = 4.4 × 10−07).

We further validated our findings in a UK dataset where we replicated bimodal onset age and observed significantly greater odds of glandular fever/infectious mononucleosis as a trigger in early onset cases (OR = 2.32, 95% CI [1.99—2.71], P = 2.4 × 10−24). Our findings suggest that incidence of ME/CFS peaks in adolescence and in early middle-age and that early onset ME/CFS is more common in those with affected relatives, more often triggered by infection, and associated with more severe disease.

Link | PDF (Oxford Open Immunology, March 2026, open access)

 

[Sasha]

@Nightsong, isn't that more properly our very own McGrath et al.?

 

[Nightsong]

This is fascinating. A few quotes:

Infection was the dominant trigger in both the early (57%) and late onset ME/CFS groups (47%). The frequency of trigger types was significantly different between the early and late onset groups (Chi-squared = 117.6, df = 6, p-value < 2.2x10-16). Examining the residuals, there was a larger relative frequency of respondents in the early onset ME/CFS group who reported an infectious trigger than in the late onset group (Bonferroni-adjusted p = 2.1x10-13)

Across all countries, about half of all respondents reported moderate ME/CFS (range: 40.6%-58.7%) (Figure 4A). This was the majority severity category, except for Finland where slightly more respondents had mild than moderate ME/CFS (42.2% vs 40.6%). The percentage of severely affected individuals varied by country with Sweden and Spain having the highest (23.7% and 23.3%) and Finland the lowest percentage of severely affected respondents (9.4%).

Testing the association between ME/CFS severity and onset group using a non-proportional odds ordinal logistic regression revealed that early onset ME/CFS was associated with more severe disease, while the late onset group was more strongly associated with moderate and mild disease (Figure 4B, Supplementary Table 1). The odds of being moderate, severe or very severely affected compared to mild, better than mild or recovered were greater for the early onset group with an odds ratio of 1.4 (95% CI [1.20 - 1.63], p = 1.83x10-5).

Bakken et al (2014), reported a higher proportion of females diagnosed in the second age peak. We therefore hypothesised that the gender composition of the early and late onset peaks may differ by gender. Nevertheless, gender proportions were consistent across countries, at 78%-86% female (Figure 5A, B). There was no significant difference in the probability-weighted frequencies of male and female genders in the early and late onset groups (Chi-squared = 1.59, df = 1, p-value = 0.21)

On average 13.0% of respondents had a first degree relative with ME/CFS, with Norway reporting the highest percentage of relatives (17.9%), and France the lowest (7.7%) (Figure 6A). A larger percentage of respondents in the early onset group had one or more first degree relatives with ME/CFS (22.5%) relative to the later onset group (14.9%) (Figure 6B-D). Those with relatives with ME/CFS were more likely to belong to the early onset group, with an odds ratio of 1.43 (95% CI [1.25 - 1.63], p = 4.4x10-07), which is considered a moderate effect size

 

[Utsikt]

The odds of being moderate, severe or very severely affected compared to mild, better than mild or recovered were greater for the early onset group with an odds ratio of 1.4 (95% CI [1.20 - 1.63], p = 1.83x10-5).

Can this be somewhat influenced by survivorship bias?

We often hear that the prognosis is better if you get ME/CFS when you’re younger. Perhaps the people that end up staying sick on average are the ones that are more severely affected?

The alternative is that the prognosis is worse if you get ME/CFS while young.

Perhaps both are true. Genetic susceptibility makes the younger ones more likely to be severe, but the immunological shifts during/after puberty makes you more likely to recover/improve?

This is why we need long term tracking studies of e.g. EBV-infected youth.

 

[BrightCandle]

Its missing a critical piece here that could impact remaining severity quite a lot, death. Death is a big part of living with this condition, I have lost many friends with ME/CFS over the years. Any prognosis paper that isn't trying to determine fatality rate can't really say much about the other severities because I suspect that more severe people die more often, and hence their numbers are reduced. Prognosis absolutely needs to include death, we have 17 confirmed coroner deaths in the UK already with 2 prevention of deaths orders and anyone serious about asking the question is going to find a lot more where the disease was removed or left off the death certificate. Giiven so few patients receive a diagnosis deaths are also not recorded attributed correctly to the disease. Any prognosis paper not including fatal outcomes has missed a common result of the disease and one that biases the other severities and likely depletes the severe/very severe end the most.

 

[Trish]

A question about severity and its association with age of onset. Many pwME experience a wide range of severities over the course of their illness. How was that dealt with in the data? Is it severity at the date of recording the information, or at onset?

 

[Murph]

Pleasing to see the name McGrath in press. A brilliant mind in the field. Tremendous respect for the et als as well!

@Simon M @chillier @trudeschei @audrey_ryback