Typing myalgic encephalomyelitis by infection at onset: A DecodeME study, 2023, Bretherick et al

[dratalanta]

There’s a difference between sickness behaviour and health-help-seeking (to use the awful jargon).

Women often push through minor illnesses in their daily lives (hiding symptoms) but there’s a lot of evidence that women generally go to the doctor more than men (seeking help).

Hence the phenomenon of men reporting symptoms at home to their wives but suppressing them in front of the doctor. When my stepfather’s achilles was tearing I knew two months before the doctor did: he was open about his symptoms at home but minimised them in front of the GP and physio.

The sex / gender differences in ME are so substantial though that they must surely be related to biological sex.

 

[Saz94]

There’s a difference between sickness behaviour and health-help-seeking (to use the awful jargon).

Women often push through minor illnesses in their daily lives (hiding symptoms) but there’s a lot of evidence that women generally go to the doctor more than men (seeking help).

Hence the phenomenon of men reporting symptoms at home to their wives but suppressing them in front of the doctor. When my stepfather’s achilles was tearing I knew two months before the doctor did: he was open about his symptoms at home but minimised them in front of the GP and physio.

The sex / gender differences in ME are so substantial though that they must surely be related to biological sex.

Yes, that’s what I was trying to express, that men often seek help from doctors less than women. Thanks for putting my brain foggy post into better words!

I wouldn’t be so sure about “biological sex”. I know of a person whose ME/CFS symptoms improved (though weren’t cured) after he started medical transition FtM.

 

[JemPD]

H @Sarah94 nice to see you, it seems like ages, perhaps i just missed your posts. I hope you're as well as you can be

I know of a person whose ME/CFS symptoms improved (though weren’t cured) after he started medical transition FtM.

the key word there being 'after'. I'm pleased for him but as you know, it doesnt mean that transtioning was the cause of the improvement, with such a fluctuating and unpredictable disease it could be pure coincidence. Intriguing though... is he taking hormones? (If you/he doesnt mind my asking).

I always wondered why research into hormonal effects/mechanisms isnt explored more

Edited to correct pronouns

 

[Saz94]

H @Sarah94 nice to see you, it seems like ages, perhaps i just missed your posts. I hope you're as well as you can be

Yeah I haven't been around much, just prefer to spend my energy on non-ME related things, especially since acquiring a girlfriend (!!) (If you missed that post, you won't have to scroll far down my recent to find it)

the key word there being 'after'. I'm pleased for him but as you know, it doesnt mean that transtioning was the cause of the improvement, with such a fluctuating and unpredictable disease it could be pure coincidence. Intriguing though... is he taking hormones? (If you/he dont mind my asking).

I always wondered why research into hormonal effects/mechanisms isnt explored more

I said "after he started medical transition", by which I meant "shortly after he started taking testosterone".

I don't want to get into a debate about one anecdote. I just wanted to make the point that it's not as simple as biological/birth sex, as someone else had brought that up. People taking cross-sex hormones cannot simply be put into the category of their birth sex, scientifically.

 

[JemPD]

I don't want to get into a debate about one anecdote. I just wanted to make the point that it's not as simple as biological/birth sex, as someone else had brought that up. People taking cross-sex hormones cannot simply be put into the category of their birth sex, scientifically.

yes absolutely agree. I was clearly not awake enough to be posting this morning as i see now my post was unnecessary & your point was clear, i didnt take in the context given by prior posts fully enough. Sorry

Edited: for clarity, & to add that i so pleased the reason i've not seen you is because you've been doing other more enjoyable stuff, congrats on the girlfriend so pleased for you

 

[Simon M]

Just remember that there is societal pressure on men to be manly (i.e. not ill) and to under-report their symptoms.

I can see that as a reason for men to be slower in seeking diagnosis (if it’s true). But most case definitions of ME requires a 50% reduction in functional capacity. If that has happened, which usually means losing your job or reducing hours with huge financial impact, as well as massive impact on the rest of your life, then would I find it almost impossible to think that people wouldn’t eventually go to the doctor. Not in a country where healthcare is free and almost everybody is registered with a GP practice.

In any case, the same argument applies to every chronic illness, but the very high female ratio seen in ME is way ahead of almost all chronic illnesses.

It’s interesting that in the Norwegian study of 2014, looking at new cases, which includes a lot of children, the higher rate for females emerges at roughly the age that puberty starts.

Added, I think I saw similar data in an old Esther Crawley study, but I can’t find it now.

 

[horton6]

I always wondered why research into hormonal effects/mechanisms isnt explored more

There's some people (usually AFAB, I think) who report some improvement when taking progesterone, but I don't know if that's been studied.

I'm a trans man (assigned female at birth, taking testosterone) and if testosterone affects my illness, it must take weeks or months because I've never been able to tie a change in symptoms to starting or stopping testosterone.

 

[JemPD]

There's some people (usually AFAB, I think) who report some improvement when taking progesterone, but I don't know if that's been studied.

I'm a trans man (assigned female at birth, taking testosterone) and if testosterone affects my illness, it must take weeks or months because I've never been able to tie a change in symptoms to starting or stopping testosterone.

Interesting, thanks for sharing your experience.

What/who is 'AFAB'?

I started taking progesterone about 10yrs into my ME & didnt notice any difference. Am just coming off it now after 13yrs so we will see what happens. It was the progesterone only pill - desogesterel though, so perhaps as a synthetic progesterone thats not the smae & perhaps the dose is different.

 

[horton6]

What/who is 'AFAB'?

Sorry, AFAB = Assigned Female At Birth

A fair number of transfeminine people (i.e. those assigned male at birth) are also prescribed progesterone, but given the sex differences in incidence of CFS, I don't know that there are many who would be able to speak to this question. They do often take progesterone capsules rectally to avoid some of the filtering done by the liver.

The doses I've seen people report anecdotally have been big - well into the hundreds of milligrams per day. These seem to usually be people who have experienced remission during pregnancy and are able to convince a doctor to prescribe on that basis, so maybe that's why (to mimic the levels during pregnancy rather than what's required for contraception? I'm not certain, it's been a long time since I had to consider hormonal contraception).

 

[JemPD]

Sorry, AFAB = Assigned Female At Birth

A fair number of transfeminine people (i.e. those assigned male at birth) are also prescribed progesterone, but given the sex differences in incidence of CFS, I don't know that there are many who would be able to speak to this question. They do often take progesterone capsules rectally to avoid some of the filtering done by the liver.

The doses I've seen people report anecdotally have been big - well into the hundreds of milligrams per day. These seem to usually be people who have experienced remission during pregnancy and are able to convince a doctor to prescribe on that basis, so maybe that's why (to mimic the levels during pregnancy rather than what's required for contraception? I'm not certain, it's been a long time since I had to consider hormonal contraception).

thats interesting horton6 thanks. yeah desogesterel is only 75micrograms so pretty low anyway.

 

[Simon M]

There's some people (usually AFAB, I think) who report some improvement when taking progesterone, but I don't know if that's been studied.

I'm a trans man (assigned female at birth, taking testosterone) and if testosterone affects my illness, it must take weeks or months because I've never been able to tie a change in symptoms to starting or stopping testosterone.

That's very interesting, thanks for sharing.

I'd also say that any effect of sex hormones is most likely seen on risk (whether or not you get ME), not symptoms for the illness. DecodeME found women had more symptoms (a bigger effect) and were more severe (smaller effect) than men (not sure if that is sex at birth) - but these effects were both small compared with the very large effect on sex ratio overall.

 

[SNT Gatchaman]

@horton6 you might be interested in Akiko Iwasaki's comment on Twitter. (She might be interested in yours above too.)

There is a fascinating backstory to this study I wish to share (with permission). In August of 2022, @tarazupancic DM me about a profound improvement in the long COVID symptoms of her child after receiving testosterone for gender-affirming care. I discussed this at our weekly long COVID lab science meeting. This is how it all started. So grateful to Tara for sharing this key insight with us

 

[Hutan]

On the question 'is ME/CFS more severe in men, or in women, or can we not say?'

Study lead Prof Chris Ponting, from the University of Edinburgh’s Institute of Genetics and Cancer, said: “ME/CFS is a devastating disease affecting a UK population the size of Derby. We discovered that the disease is worse for women, in older people, and many years after their ME/CFS started.”"

"Not only are women far more likely to suffer from ME, but they're also more likely to have more symptoms, and co-occurring conditions that are more severe, according to early results of the largest-ever study into the disease.

Study shows women more severely affected by ME/CFS
https://www.ukri.org/news/study-shows-women-more-severely-affected-by-me-cfs/

I'd also say that any effect of sex hormones is most likely seen on risk (whether or not you get ME), not symptoms for the illness. DecodeME found women had more symptoms (a bigger effect) and were more severe (smaller effect) than men (not sure if that is sex at birth) - but these effects were both small compared with the very large effect on sex ratio overall.

Moreover, being female, being older and being over 10 years from ME/CFS onset are significantly associated with greater severity.

Figure 5



I'm wondering about the reports about severity coming out of the paper. I understand that several things are being reported here, differences in:

• overall severity (mild versus the more severe categories)
• number of symptoms
• number of diagnoses of co-occurring conditions and the severity of them.

Figure 5 shows that being male is associated in this sample with being more likely to be in a severity category that is moderate or worse.

Male participants tended to be older than females (median 52y [IQR=40y-63y] and 48y [IQR=37y-59y] respectively; p< 2.2×10 -16, Wilcoxon rank sum test).

Worse severity was also associated with increased age, and the men in the DecodeME sample are reported as being older than the women. But, the difference in age is not very big. I'd be surprised if adjusting for age changed the finding that being male is associated with having a severity that is worse than mild.

The substantial number of males participating in DecodeME ( n=2,827) allowed the study to reveal previously unreported sex-biases in comorbidities or symptoms. Females with ME/CFS reported more comorbidities and symptoms than males in the DecodeME questionnaire. Two-thirds (66.7%; n= 9,507) of females, but a half (52.7%; n=1,489) of males, reported at least one active comorbidity; similarly 39.2% ( n=5,588) of females and 28.6% ( n=809) of males reported at least one inactive comorbidity. Female participants reported, on average, more symptoms than males (42 versus 36).

I said it before and I think others did too: I'm pretty sure that women are more likely to be diagnosed with comorbidities such as depression, anxiety and fibromyalgia. The DecodeME asked people about what they had been diagnosed with. Women being diagnosed with more co-morbidities doesn't mean that their health is substantially worse than someone with ME/CFS who has not been given those diagnoses.

Being female, increasing age and being over 10y from ME/CFS onset are each separately associated with severity in the DecodeME cohort (sex: p=4.5×10 -4; age: p<2.2×10 -16; years since ME/CFS onset: p=1.6×10 -6). These results are from a comparison of those with mild ME/CFS (34%; n=5,779) against the remaining 66% ( n=11,295) with moderate, severe or very severe illness.

The paper doesn't really address the difference between Figure 5 where being male was associated with high severity and later claims that being female is associated with high severity. Can anyone shed some light on this?

 

[Kitty]

I said it before and I think others did too: I'm pretty sure that women are more likely to be diagnosed with comorbidities such as depression, anxiety and fibromyalgia. The DecodeME asked people about what they had been diagnosed with. Women being diagnosed with more co-morbidities doesn't mean that their health is more substantially worse than someone with ME/CFS who has not been given those diagnoses.

True, but women are also much more likely to be diagnosed with autoimmune diseases, endometriosis and adenomyosis.

The paper doesn't really address the difference between Figure 5 where being male was associated with high severity and later claims that being female is associated with high severity. Can anyone shed some light in this?

Well spotted! I'm not sure about the answer, though. Unless—as you say—one is based on ME/CFS severity and the other on overall symptom burden (including ME/CFS, comorbidities, and the effect of ME/CFS on women with difficult menstrual symptoms).

 

[Hutan]

I find the paper frustratingly light on details, skimming over lots of issues. I think there could have been a few good papers in the DecodeME questionnaire results- maybe there still could be. Less is usually more in terms of the scope of papers, I reckon.

50.6% ( n= 8,637) of participants (all with self-reported ME/CFS diagnosed by a health professional) reported two or more comorbid conditions, most commonly irritable bowel syndrome (IBS; 41.3%; n=7,052), clinical depression (32.4%; n=5,537) and fibromyalgia (29.5%; n=5,043), anaemia (14.1%; n=2,402) and hypothyroidism (12.8%; n=2,178) (Figure 2).

True, but women are also much more likely to be diagnosed with autoimmune diseases, endometriosis and adenomyosis.

Yes. Possibly those conditions actually explain the symptoms being attributed to ME/CFS and some of the women don't have ME/CFS.

The paper tells us that 34 conditions were considered as co-morbidities. But Figure 7 only tells us about five:

Thirty-four comorbidities were considered in a logistic regression model of the form OnsetType ~ age + sex + comorbidities and an intercept. A covariate is only shown if it survived Bonferroni multiple testing correction ( p<0.05) for one or more onset type. Active and inactive comorbidities were considered independently: Active, if the condition has given symptoms in the past 6 months, or Inactive, if the condition has not given symptoms in the past 6 months, either because it has died down or treatment has controlled it. The z-score (Y-axis) is the effect-size estimate in standard deviation units.

They were MCAS active, Lyme disease active, clinical depression active, fibromyalgia active, and shingles not active. ('Active' being the disease was reported as causing symptoms in the last 6 months.)

The four active 'co-morbidities' could easily just be diagnostic constructs. By that I mean that they aren't really reflecting a unique additional pathology but are actually just ideas that a doctor has made up and convinced the person about.

For example, MCAS. That is reported as being associated with a Covid-19 onset. I suspect many of the doctors that would diagnose a person presenting with post-covid-19 symptoms as having ME/CFS also diagnose the person with MCAS at the same time. Whereas, a person presenting with ME/CFS symptoms 10 or more years ago probably would not have got that extra MCAS diagnosis.

A diagnosis of Lyme disease was associated with an ME/CFS onset caused by an infection other than Covid-19 and EBV. A diagnosis of clinical depression and the person reporting it as 'active' was associated with the ME/CFS onset being reported as not caused by an infection trigger. That makes sense as the person's diagnostic odyssey was probably longer and more difficult. Their doctors were probably more likely to suggest that their disease was depression than if the person's illness had clearly started with, for example, glandular fever.

My point is, being diagnosed with these co-morbidities doesn't necessarily line up well with having more severe ME/CFS. The diagnoses are a reflection of the beliefs of the doctors the people have seen. And, given the questionnaire seemed to ask the participants to endorse the co-morbidity diagnoses by only calling them 'active' if the person attributed symptoms to them in the last six months, they also reflect the willingness of the person to accept the diagnoses as true.

 

[Hutan]

The reason that I'm picking through this is that an editor of wikipedia is quoting this paper as suggesting that women are more likely to have more severe ME/CFS than men. Figure 5 suggests the opposite, with being male being associated with worse severity (although the analysis of worse severity of Mild versus All the other severity categories is pretty coarse).

Testing all symptoms simultaneously with sex and age, showed strong association between ME/CFS severity and 18 factors including fatigue, age, difficulty remaining standing, and sleep problems ( Figure 5).

But there is the suggestion in the text that an analysis found that being female was associated with worse severity. Maybe that was after confounders such as men in the sample being on average very slightly older than females and age being associated with worse severity were taken into account? I can't tell if confounders were taken into account in the analysis presented in Figure 5.

(4) greater disease severity for those who are female, older and/or have had ME/CFS for >10y.

And then there is all the noise around the number and severity of co-morbidities. I think that is probably best ignored when trying to answer the question 'is there an association between ME /CFS severity and sex'.

 

[forestglip]

But there is the suggestion in the text that an analysis found that being female was associated with worse severity. Maybe that was after confounders such as men in the sample being on average very slightly older than females and age being associated with worse severity were taken into account? I can't tell if confounders were taken into account in the analysis presented in Figure 5.

It's confusing to me too. But I think female associated with severe is without any covariates, and figure 5 showing the opposite is after adjusting for everything.

Being female, increasing age and being over 10y from ME/CFS onset are each separately associated with severity in the DecodeME cohort (sex: p=4.5×10-4; age: p<2.2×10-16; years since ME/CFS onset: p=1.6×10-6).

Testing all symptoms simultaneously with sex and age, showed strong association between ME/CFS severity and 18 factors including fatigue, age, difficulty remaining standing, and sleep problems (Figure 5).

Edit: So the way I understand it, is if you found a random male and female and asked them only about sex and severity, the female would be more likely be more severe. But if you found two people where everything was identical (age, comorbid conditions, answers to symptom questions, etc) except sex and severity, then the male would be more likely to be more severe.

 

[forestglip]

I'm really foggy right now from a car alarm waking me up at 4 AM, so I might be misunderstanding something.

It seems "severity" is self-identified.

Respondents were asked: “How severe is your illness?” with answer options matching severity definitions from the UK’s National Institute for Health and Care Excellence (NICE) guidelines (2021). Severity categories were consistent with participants’ reports of their comorbidities and symptoms (Results).

And in figure 5, they're adjusting for answers about specific symptoms ("fatigue is disabling", "fatigue worse when active", etc). So they're saying if you took age matched people who described their symptoms exactly the same, the males would be more likely to say they are severe?

Is this actually useful?

Edit: Apart from age and sex, the other symptom associations in figure 5 seem more useful. Showing what specific symptoms play the biggest part in someone's self identified severity.

Which in this case is "Fatigue is disabling" followed by "Fatigue >50% of the time" then "Difficulty remaining standing" which makes sense to me.

Maybe that's why they didn't mention the males being more severe association in the text.

 

[Hutan]

Edit: So the way I understand it, is if you found a random male and female and asked them only about sex and severity, the female would be more likely be more severe. But if you found two people where everything was identical (age, comorbid conditions, answers to symptom questions, etc) except sex and severity, then the male would be more likely to be more severe.

Yes, I think that is likely. And, I don't think you need everything other than sex to be identical, just age and time since onset.

In which case, it is misleading to say that this study proves that ME/CFS is more severe in females. It actually appears to be evidence for the opposite, that being male is associated with increased severity. Not that I would claim that to be proven, but I don't think we should be claiming that the opposite is true, that being female is associated with increased severity.

The reason it matters is that if the sample of males in the DecodeME sample tends to be more severe than the sample of females, it could be that for cultural reasons, there's a bias towards males with mild ME/CFS not getting diagnosed as having it and/or not accepting that diagnosis and/or not participating in research.

And in figure 5, they're adjusting for answers about specific symptoms ("fatigue is disabling", "fatigue worse when active", etc). So they're saying if you took age matched people who described their symptoms exactly the same, the males would be more likely to say they are severe?

Is this actually useful? It sounds like it's saying males who are experiencing the exact same thing are more likely to say they are more "severe" than females.

No. They are just testing individual answers on the questionnaire against the likelihood of a self-report of 'moderate, severe or very severe ME/CFS' (as opposed to a self report of 'mild' ME/CFS. So, is someone who says 'fatigue is disabling' more likely to report that their ME/CFS is not mild? Yes, much more likely. Is someone who says that they are male more likely to report that their ME/CFS is not mild? Also yes. We don't know if the males are, on average, interpreting the severity categories differently, but there were definitions of mild, moderate and so on, so they probably aren't.

 

[Yann04]

Subjective data is obviously to take with grains of salt, but even if we had activity level counters or something (think smartwatch data) it still would be vulnerable to selection biases. The most severe likely won’t have the energy or capability to sign up to any study — as they can’t use their phones at all. (and that isn’t even thinking of the myriad biases possible on the milder ends of the spectrum, as @Hutan briefly mentioned.)