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

[LarsSG]

They also report:

"Participants reporting an infectious onset (when compared to those who did not) were also significantly more likely to report: improving symptoms, relapsing/remitting, or recovered (relative to ‘Fluctuating’) symptoms, and less likely to report worsening symptoms (again, relative to ‘Fluctuating’). They were more likely, among other things, to report viral infections with long recovery periods, fewer viral infections than they used to get, and having a pale face." (The association between infectious onset and viral infections with long recovery periods is quite strong.)

Does that mean that people with infectious onset ME have something that differs from those that don't or that people who believe they had an infectious onset are more likely to believe they have viral infections with long recovery periods? Hard to know.

And younger people were significantly more likely to report a non-infectious onset. I wonder why?

 

[LarsSG]

Does anyone have a plausible explanation for this? Might it point to more ME/CFS-outbreaks in the past (more than 10 years ago) than in recent years?

10y+ duration was also associated with severity, as was age and being female. Is it possible that it has become easier to get an ME diagnosis in the UK in the past decade (or even two decades)?

If that were the case, I can see two possibilities:

• severity is associated with infectious onset and milder patients are more likely to be diagnosed than they were in the past (but the paper doesn't report this correlation, not sure if that is because it isn't in the data or they just didn't report it) or
• recently, more people who have something else other than ME have been given an ME diagnosis, and those people are less likely to report an infectious onset (correlations of non-infectious or unknown onset with co-morbid depression and FM might make sense in this case).
  
  EDIT: It could also be the case that people who are diagnosed with ME but actually have something else are more likely to recover in less than 10 years, which might make the most sense of these options.

 

[Peter T]

It is important to remember that DecodeME subjects are self selected, and though I don’t have any functional logical circuits at this time of night, so am unable to come up with a plausible hypothesis, it could be that the reasons people with long standing ME participated are different from the reasons people more recently diagnosed participated meaning for some reason the entire group is not homogeneous.

Though the size of the DecodeME sample hopefully means the results are more reliable we can not rule out some sort of selection bias that differentially impacts on people with different patterns of ME.

 

[duncan]

This relative paucity of participants not reporting an infection around the time of onset of their ME/CFS over 10y ago is unexpected, and not easily explained by historic variation in ME/CFS triggers because association with age was not significant in this analysis (p > 0.05)."
Does anyone have a plausible explanation for this? Might it point to more ME/CFS-outbreaks in the past (more than 10 years ago) than in recent years?

Perhaps more individuals being told more recently they test negative to a wider array of pathogens, as more are being tested for? Since many diagnostics flat out suck, some of those reporting no infectious onset, or they do not know, may simply have been incorrectly informed - which would change a lot of things by itself. Compound that with the import of asymptomatic infections, and 20-minute exam limits.

If the tandem-insult theory proves true, the second trigger insult could have been unnoticed. Patients would report no infection -or they do not know - at time of onset.

 

[Simon M]

Does that mean that people with infectious onset ME have something that differs from those that don't

That is the intriguing prospect, though this is a cross-sectional study.

Does that mean that...people who believe they had an infectious onset are more likely to believe they have viral infections with long recovery periods? Hard to know.

I would say the former as my instinct is to believe the patient, particularly when they have a 'don't know' alternative. Plus there is good evidence this is a often a post-infectious illness:

Spoiler: boring detail

glandular fever, Ross River virus and Q-fever are all infections shown to trigger MEcfs with fairly good evidence for Giardia (Scandinavian outbreak). Researchers and clinicians in the field often refer to MEcfs as a post-infectious illness, the ICD diagnostic code is post-infectious (currently 93.32) and multiple studies find a large majority of pwme report an infectious onset (forum thread somewhere!)

10y+ duration was also associated with severity, as was age and being female. Is it possible that it has become easier to get an ME diagnosis in the UK in the past decade (or even two decades)?

[If so]

• severity is associated with infectious onset and milder patients are more likely to be diagnosed than they were in the pas...
• recently, more people who have something else other than ME have been given an ME diagnosis, and those people are less likely to report an infectious onset (correlations of non-infectious or unknown onset with co-morbid depression and FM might make sense in this case).
  
  EDIT: It could also be the case that people who are diagnosed with ME but actually have something else are more likely to recover in less than 10 years, which might make the most sense of these options.

Agree that the final option [higher recovery rates for non-infectious onset] makes the most sense and ties in with your earlier point about "something different", and also this from @JemPD:

ouldnt the explanation be that perhaps infectious onset ME is a different biological/pathological beast, than non infectious onset..... ie look similar but actually not, and non infection onset is less long lasting/easier to recover or improve from. Could be 2 completely different entities that only appear same/similar??

It could be a different route to the same illness, or a different illness. I look forward to seeing if the infectious/non-infectious split shows up anything in the genetic analysis.

And younger people were significantly more likely to report a non-infectious onset. I wonder why?

Good point. Could be a higher chance of non-infectious when younger combined with higher recovery rates for non-infectious combining to mean older folk with an active illness (required by the study) are less likely to have a non- onset.

Of course, all this is speculation, but the genetic analysis might throw light on things.

 

[Solstice]

Perhaps more individuals being told more recently they test negative to a wider array of pathogens, as more are being tested for? Since many diagnostics flat out suck, some of those reporting no infectious onset, or they do not know, may simply have been incorrectly informed - which would change a lot of things by itself. Compound that with the import of asymptomatic infections, and 20-minute exam limits.

If the tandem-insult theory proves true, the second trigger insult could have been unnoticed. Patients would report no infection -or they do not know - at time of onset.

If you'd asked me at age 20 or 21 whether I'd had an infectious onset I would've flat-out said no. But the more I learn about the disease, the more I feel pieces are falling into place. Dr. Karl Morten in a recent talk hinted towards an infection at a very young age. My parents told me I was very sick at age 2/2,5 or something like that, my dad was afraid I might die as I was sitting on my little tricycle outside with barely any movement. Something I only learned later in life.

Then at age 10-12(I don't know exactly) I had a big lump on my arm that probably was an infection of sorts, it got sliced open at hospital and slowly drained. Something I hadn't thought about, but starting the Dutch version of high school at age 12 I turned inwards even more. I was a very lively 2-yo, that'd talk to basically anyone. After I'd been sick my personality changed to the degree that kindergarten-teachers questioned if I could even talk. I think it took one of them making a house visit to quickly be convinced that I could very well. At about age 12 this worsened, post-lump on my arm.

At age 18 I got sicker still, but it might've just been a slow burn from 12 to 18 tbh. The hospital doctor that examined me found traces of EBV. Later tests showed active bartonella and lyme. And again at age 20/21 I probably would've answered the question about previous infections as no, based on poor understanding.

Now I'm relatively sure I had several infections. Roll back the years though and I wouldn't even consider it as an option.

 

[Sean]

Huge problem here is that an infectious onset/trigger isn't necessarily obvious. Non-symptomatic Covid being a recent example.

It is possible that all ME has an infectious onset/trigger. But we just don't have the technical capacity to determine that in an individual case, at this stage at least, and maybe ever. Particularly if common infections, like colds, can do it. Finding a control group that has never had a common cold is practically impossible.

Also an issue is whether infectious insults are a cumulative risk for ME. That would complicate assessing onset a whole lot more.

This whole question is a methodological minefield.

 

[JemPD]

Huge problem here is that an infectious onset/trigger isn't necessarily obvious. Non-symptomatic Covid being a recent example.

absolutely.

Also an issue is whether infectious insults are a cumulative risk for ME. That would complicate assessing onset a whole lot more.

havent i read that the more times you get infected with covid the more likely you are to get LC?

Another issue is getting an infection, feeling a bit crap after it, snd experiencing mild forms of PEM after cumulative 'overdoing it' over a few wks. Repeatedly pushing through because you're brushing it off as 'need to eat more green veg/do more exercise & you're a big believer in the whole 'think positive thing' so dont even really notice anything is significantly wrong.... leading to gradual worsening of health until it cant be ignored any more when you collapse & seek help.

Collapse, but by then it appears as if this collapse has come out of the blue with no obvious trigger

 

[SNT Gatchaman]

It is possible that all ME has an infectious onset/trigger. But we just don't have the technical capacity to determine that in an individual case, at this stage at least, and maybe ever.

There is the possibility that we already do have the technical capability - we just have to apply it. Eg we can read the T cell history, so I think it could be possible to separate groups by viral history. This is a much greater step than simply showing that in fact yes, people who "merely" thought they had Covid but tested negative on PCR and serology actually did have T cell evidence of Covid infection.

See John Wherry's comments from the beginning of the year: "You take that same blood back to any number of research labs that are working in these areas and in an afternoon you can have several hundred million pieces of information about the immune system."

 

[LarsSG]

There is the possibility that we already do have the technical capability - we just have to apply it. Eg we can read the T cell history, so I think it could be possible to separate groups by viral history.

That sounds pretty neat. Does a pathogen-specific T-cell detection array exist or is this something someone needs to build?

Somewhat relatedly, I've been thinking that maybe we just need to sequence patients' blood (RNA and DNA) and see if any known pathogens comes up in patients more than controls (in my mind, with people who live in the same household as controls). Like environmental DNA or microbiome studies, but in blood. I'm sure it would be expensive, but then yesterday I saw that Morten Group have done something along these lines in chronic Lyme, on a very small scale:

 

[NelliePledge]

Yeah gradual onset definitely doesn’t mean non infectious just that any infections didn’t cause a level of acute illness and seemed unexceptional so hard or impossible to pinpoint in the same way as a severe infection.

 

[Simon M]

This whole question is a methodological minefield.

It’s certainly a challenge, but I think we can get somewhere.

I don’t know how much T cell, history approach will help if common infections are a trigger (as they appear to be), because most people will have a history of many common infections. Though the T cell work is amazingly cool. And it will be very informative if they are specific triggers – we know particular pathogens are more likely to trigger the illness.

I understand that it is possible to have long Covid following asymptomatic Covid – is there any date on this? I had the impression that long Covid is much less likely if you have an asymptomatic infection.

Also, there is evidence from prospective studies (Dubbo and Peter White’s.) that the severity of the initial infection is a predictor of developing CFS after glandular, fever,(EBV) Ross, river virus and Q fever).

We also shouldn’t rule out the possibility that people do have non-infectious onset.

what I found so interesting about the data presented here is that there do seem to be significant differences between the infectious and non-infectious groups. Also, the “don’t know” group is somewhere between the two.

I said earlier, I think the genetic data will be really interesting, because that might point to genetic differences between infectious versus not.

and that could point to different pathology and/or different treatments.

 

[Simon M]

Somewhat relatedly, I've been thinking that maybe we just need to sequence patients' blood (RNA and DNA) and see if any known pathogens comes up in patients more than controls (in my mind, with people who live in the same household as controls)

that was done quite a few years back by both Ron Davis and Ian Lipkin. Null result in both cases, which is probably why neither group public published the work, though the results were shared publicly.

 

[duncan]

that was done quite a few years back by both Ron Davis and Ian Lipkin. Null result in both cases,

If they said they found no evidence of pathogens (sorry for my memory lapse), this would logically border on the absurd given the samples were from the U.S.

 

[Hutan]

Also, there is evidence from prospective studies (Dubbo and Peter White’s.) that the severity of the initial infection is a predictor of developing CFS after glandular, fever,(EBV) Ross, river virus and Q fever).

In the case of the Dubbo study, I recall that there were issues with the assessment of severity. From memory, they only assessed people a bit after the infection, so people with the beginning of persistent symptoms might have been assessed as more severe. I'd have to go back and look at the papers - I've forgotten the detail, but I think it's worth checking it before assuming that stated association between severity and chance of persistence is reliable.

We also shouldn’t rule out the possibility that people do have non-infectious onset.

Not least because we've seen people with Gulf War Illness have symptoms that, as far as I know, are compliant with an ME/CFS diagnosis and were probably caused by exposure to a neurotoxin. And also a proportion of people who have ciguatera poisoning (from a marine neurotoxin) go on to experience persistent symptoms that sound rather like ME/CFS. Perhaps both share a pathology with infectious-onset ME/CFS. Or perhaps some of what is called ME/CFS is actually the result of exposure to various neurotoxins.

 

[Kitty]

symptoms that, as far as I know, are compliant with an ME/CFS diagnosis and were probably caused by exposure to a neurotoxin

Ditto Lady Mar, whose illness appears to have been caused by exposure to sheep dip.

 

[LarsSG]

that was done quite a few years back by both Ron Davis and Ian Lipkin. Null result in both cases, which is probably why neither group public published the work, though the results were shared publicly.

I think they did report the results recently. Does anyone have a PDF? Would like to see what specifically they sequenced and looked for.

 

[Binkie4]

If the severity of the initial infection is a predictor of the development of ME/CFS, it fits my illness although there was a significant time delay. I had a really severe infection in March 1986 ( labelled as something akin to glandular fever) but I wasn't diagnosed with ME until 2008.

It was interesting in that three of us ( members of staff) teaching the same subject in the same college sharing the same work space became ill at the same time in 1986. It was also the time of the Incline Village outbreak but I was on the other side of the world, in south east England. In fact I was called to cover for one of the others staff members who had had to go home and then I felt ill within a couple of hours. It wasn't psychosomatic. My GP had my blood tested and I had reactive lymphocytes ++.

All 3 of us were quite severely ill. The most severe had to be hospitalised every 3 weeks for an infusion of antibodies, another was absent from college for the whole of the summer term so didn't return until September and I (who was doing a post grad cert) staggered through the summer term. I had a very understanding tutor who suggested a reduced attendance and I visited my mother for a week to write my extended essay in bed.

I continued to have blood tests weekly then alt weeks until July at which point I was called in for a spinal tap which I was told threw up nothing of significance. Dr Google wasn't around then so I know nothing more. I began to feel better but was not well enough to take up an A level teaching job in September so I resigned before I started the job. It took another couple of months before I could teach two x half days a week and it was probably about 2 years before I could teach two - 3 days a week.edit: I was given a diagnosis of PVFS by my GP during this time.

I never recovered fitness to work full time. Whenever I really started to put my foot down, I just didn't have the energy. I started a Ph. D but had to suspend after two years and I never resumed, and I had to retire on health grounds in my early 50s. I did some quite challenging voluntary work after that but again, could never extend real effort.


It was in 2008 when I woke up one day completely unable to move from my bed. 2007 had been a physically stressful year. I had had two surgeries one of which was a hip replacement and both required heavy doses of antibiotics. There were also emotional stresses.

I stayed there unmoving for 2 weeks then consulted an endocrinologist who I was seeing for hormone issues. He did some tests including a short synacthen test which made me very ill. I didn't recover my energy and he could offer no help so I consulted another endocrinologist assuming it had something to do with the hormone issue. He just listened very carefully for about an hour to what I said including what the lack of energy felt like and then diagnosed me with ME. On hearing this, my other endocrinologist said there was no such thing as ME. The diagnosis was confirmed at Dr Bansal's NHS clinic when I was seen there and I have remained ill with ME ever since. My view is that I never entirely recovered from my 1986 infection and when my body was severely stressed, I couldn't continue to function. I wish I knew more about the tests that were carried out in 1986 and what they indicated.

 

[Saz94]

In the DecodeME cohort, females outnumber males by over five-to-one (83.5% females; 16.5% males). This is among the highest female-bias among those with ME/CFS yet reported internationally3,9,21,23–27. Despite this strong bias, 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%) of females, but a half (52.7%) of males, reported at least one active comorbidity; similarly 39.2% of females and 28.6% of males reported at least one inactive comorbidity. Female participants reported, on average, more symptoms than males (42 versus 36).

To test more formally for an association between age and sex and each symptom we used logistic regression using the Bonferroni correction to adjust for multiple tests (Methods). This identified 62 of 80 symptoms as significantly female-biased, and 61 as biased towards younger age (Figure 4). Female-bias is evident across all symptom types (Figure 4). Females were significantly more likely to report fatigue ‘often, repeatedly, or all the time’ (p=6×10-4; age p=1.1×10-13), and more likely to report post-exertional malaise after physical or mental activity (p=3×10-4; age p=4.2×10-7).

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

 

[Trish]

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

I wonder if that's really the case. My impression from some of the men I know is that they run to the doctor for every minor symptom and take sick leave for a cold, whereas the women I know, being accustomed to having to hide things like severe period pains and act well, only take to their beds if they can't get out of tnem, especially so for mothers, again from my experience.