A logistic regression analysis of risk factors in ME/CFS pathogenesis. Lacerda et al. 2019

[John Mac]

Abstract

Background

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease, whose exact cause remains unclear. A wide range of risk factors has been proposed that helps understanding potential disease pathogenesis. However, there is little consistency for many risk factor associations, thus we undertook an exploratory study of risk factors using data from the UK ME/CFS Biobank participants. We report on risk factor associations in ME/CFS compared with multiple sclerosis participants and healthy controls.

Methods
This was a cross-sectional study of 269 people with ME/CFS, including 214 with mild/moderate and 55 with severe symptoms, 74 people with multiple sclerosis (MS), and 134 healthy controls, who were recruited from primary and secondary health services. Data were collected from participants using a standardised written questionnaire. Data analyses consisted of univariate and multivariable regression analysis (by levels of proximity to disease onset).

Results
A history of frequent colds (OR = 8.26, P <= 0.001) and infections (OR = 25.5, P = 0.015) before onset were the strongest factors associated with a higher risk of ME/CFS compared to healthy controls.
Being single (OR = 4.41, P <= 0.001), having lower income (OR = 3.71, P <= 0.001), and a family history of anxiety is associated with a higher risk of ME/CFS compared to healthy controls only (OR = 3.77, P < 0.001). History of frequent colds (OR = 6.31, P < 0.001) and infections before disease onset (OR = 5.12, P = 0.005), being single (OR = 3.66, P = 0.003) and having lower income (OR = 3.48, P = 0.001), are associated with a higher risk of ME/CFS than MS.
Severe ME/CFS cases were associated with lower age of ME/CFS onset (OR = 0.63, P = 0.022) and a family history of neurological illness (OR = 6.1, P = 0.001).

Conclusions
Notable differences in risk profiles were found between ME/CFS and healthy controls, ME/CFS and MS, and mild-moderate and severe ME/CFS.
However, we found some commensurate overlap in risk associations between all cohorts.
The most notable difference between ME/CFS and MS in our study is a history of recent infection prior to disease onset.
Even recognising that our results are limited by the choice of factors we selected to investigate, our findings are consistent with the increasing body of evidence that has been published about the potential role of infections in the pathogenesis of ME/CFS, including common colds/flu.

https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-019-1468-2

 

[Cheshire]

A history of frequent colds (OR = 8.26, P <= 0.001) and infections (OR = 25.5, P = 0.015) before onset were the strongest factors associated with a higher risk of ME/CFS compared to healthy controls.

I've spent my life getting cold after cold since the age of 7/8. During winter, the years prior to te onset, it was often a kind of long, uninterrupted cold.

 

[rvallee]

I was curious about what "frequent colds" means since it's hard to assess for a whole life, memory being unreliable and all that, and it's:

frequent colds and coughs, and infections in the 6 months prior to disease onset

Which makes more sense. That was my experience but I'm not sure if they were actually regular colds or flus, they seemed a bit different but not being able to say otherwise I would agree that it's close enough. Could be a prodromal phase of ME, however.

There is an additional variable for "History of frequent colds/flu" but "within the 6 months prior to disease onset" is 3x more significant. I have no idea what is a normal history of colds/flus and where I stand on this.

Young age being a risk factor to disease severity really, really makes a strong case for a full stop on all behavioral experiments that are based on a belief that there is no disease and using ignoring symptoms as treatment. This needs to be replicated and validated ASAP considering that there is a growing effort by Chalder, Crawley and the like at exposing children and teens to their nonsense, a more pliable and captive population that can't complain.

Despite the fact that younger people seem to have better prognostic, it looks to be a risk factor in developing severe ME:

Participants with more severe ME/CFS in our cohort were younger by an average of 4.5 years at disease onset and were more likely to report a family history of neurological problems.

Norris et al. report a large-scale follow-up of adolescents with suspected chronic fatigue syndrome (age 13–18); 75% spontaneously recover within 2–3 years [45], with a quarter with persistent disease.

Could be significant to check whether this is a result of bad advice, of pushing through, for those who did not recover.

Family history of neurological disease seems pretty significant, those numbers are way above the norm, although hard to tell with a small sample:

Those with severe ME/CFS were more likely to be younger; 15 (out of 55) of these participants reported a family history of neurological problems, of which the most commonly reported were stroke (4) and Parkinson’s disease (3/15); 9/15 reported that their father was affected and 4/15, their mother. Of the 9 people with mild-moderate ME/CFS who reported neurological family problems, 4 of those reported had a family history of dementia, 5 reported that it was their mother who was affected.

My maternal grandmother had Parkinson's and neuropathy while my paternal grandmother had Alzheimer's. Pretty much everyone else died of cancer rather young so it's impossible to say what would have developed.

This refers to a 2008 study (Chia JK, Chia AY. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. J Clin Pathol. 2008;61(1):43–8.):

Chia and Chia proposed a link between ME/CFS and enterovirus infection after the biopsies from 135/165 CFS patients (82%) stained positive for VP1 within parietal cells, versus just 7/34 (20%) of healthy controls

Still impressively high that 20% have those viral proteins.

About the "association" with psychiatric co-mobordities, people who don't cherry-pick oddly don't find cherries:

In a study of 279 patients referred to a Belgium clinic with suspected chronic fatigue syndrome, 45.2% were diagnosed with a mood or anxiety disorder, yet only 23.3% of the entire cohort eventually received an unequivocal CFS diagnosis [42]. In a UK study of referrals to a specialist CFS treatment centre, out of 260 patient referrals examined, 40% of these did not have CFS but other medical and psychiatric illnesses [43].

 

[Michelle]

I had frequent cold/flu from 10 years old onward -- enough so that I usually missed about 20+ days of school each year. Looking back now, I can't tell if I was getting the flu or a cold that often or was just experiencing PEM. My flu-like days were just that, flu-like. Chills, prostration, icky-sick feeling, loose stools, and maybe a low-grade fever and/or sore throat--basically, what I feel now except then it was only a day or two every few weeks. Colds did have the usual sinus congestion, post-nasal drip, cough (in fact, they usual followed a distinct pattern starting with nasal congestion and then ending with chest congestion). When the chest congestion hit, I'd take some NyQuil so I could sleep and wake up miraculously cured the next morning. I have no idea why.

 

[Snow Leopard]

Keep in mind that studies of this kind are of 'suggestive' quality evidence only. Retrospective studies of risk factors that rely on what is still basically a convenience sample, despite claims of it being cross-sectional are not conclusive.

Recruitment for the UKMEB cohort included the invitation of potential participants by collaborating NHS Services (primary and secondary care), who used their databases to identify people diagnosed with ME/CFS, people diagnosed with MS, and potential healthy controls, aged between 18 and 60 years. The NHS Services sent out invitation packs provided by the research team containing an invitation letter from the health service with information about the study (with specific information sheets for cases and controls), a consent form, a questionnaire to assess symptoms, and a refusal form.

We invited 2430 individuals identified by our collaborating NHS services (942 with ME/CFS, 278 with MS and 1210 healthy), in addition to 112 people with a confirmed medical diagnosis of ME/CFS invited by ME/CFS support groups, of whom 84 invited healthy individuals to act as controls. Of the total potential participants invited, 138 declined to participate (45 had a possible diagnosis of ME/CFS, 26 MS, 48 healthy controls; 19 received refusal forms were incomplete) and 1828 were non-respondents.

 

[Forbin]

A history of frequent colds (OR = 8.26, P <= 0.001) and infections (OR = 25.5, P = 0.015) before onset were the strongest factors associated with a higher risk of ME/CFS compared to healthy controls.

I'd suspect that the connection between frequent colds and infections and the risk of ME/CFS is indirect; that is, there's probably not a shared "weakness" that results in both frequent cold/infections and ME/CFS, but rather that ME/CFS is often triggered by colds and infections. The more colds and infections you have, the greater the chance that one of them will be severe enough to trigger ME/CFS.

 

[ME/CFS Skeptic]

It seems that ME/CFS patients reported a little more of most things but that nothing really stood out.

I suspect that these kinds of retrospective studies are mostly useful to exclude hypotheses and indicate that some things aren't important. Otherwise one would expect a much clearer difference in (recent) exposures such as living on a farm, radiation, flooding, head injury or major operations etc.

Only 10% said they had a family history of ME/CFS (compared to 5.7% in the healthy controls). ME/CFS patients seemed to have less alcohol consumption than controls but it's difficult to interpret how significant this difference was.

 

[Mij]

I never got a cold or flu before I became ill with M.E. at age 28. Perhaps slow onset patients experienced more colds and flu? I had a sudden onset, I know the exact time I got ill one morning.

 

[adambeyoncelowe]

I never got a cold or flu before I became ill with M.E. at age 28. Perhaps slow onset patients experienced more colds and flu? I had a sudden onset, I know the exact time I got ill one morning.

My experience is that I *thought* I was getting colds and flu all the time. Then I realised this really wasn't normal and my flu seemed to follow about two to four days after 'big' days. It was really just PEM but I didn't know any better.

 

[NelliePledge]

My experience is that I *thought* I was getting colds and flu all the time. Then I realised this really wasn't normal and my flu seemed to follow about two to four days after 'big' days. It was really just PEM but I didn't know any better.

This I think too. I had bad throats all the time and colds and flu but likely to be PEM episodes.

 

[chrisb]

It seems to me that a possible flaw in this paper is a failure to distinguish between cases of acute and insidious onset.

Those with acute onset know the occasion of onset, and the rest don't. How does one determine the timing of a latent onset and thus say whether any frequent colds/flu pre-date or post-date that onset? Are they a predisposing or a precipitating factor EDIT or a symptom of the illness?

 

[Mithriel]

This may be a step forward from a similar study done years ago using GP records. They found that people with ME had more GP visits in the previous year with the commonest reason to see the doctor being "illegible"

 

[beverlyhills]

It seems to me that a possible flaw in this paper is a failure to distinguish between cases of acute and insidious onset.

Those with acute onset know the occasion of onset, and the rest don't. How does one determine the timing of a latent onset and thus say whether any frequent colds/flu pre-date or post-date that onset? Are they a predisposing or a precipitating factor EDIT or a symptom of the illness?

Why do that when you can do this?

No means, no standard deviations, deliberate data opacity, improper stratification, publish known information as new information.

On the other hand, I definitely like they included BCG.

 

[Amw66]

My experience is that I *thought* I was getting colds and flu all the time. Then I realised this really wasn't normal and my flu seemed to follow about two to four days after 'big' days. It was really just PEM but I didn't know any better.

This

 

[Ravn]

My experience is that I *thought* I was getting colds and flu all the time. Then I realised this really wasn't normal and my flu seemed to follow about two to four days after 'big' days. It was really just PEM but I didn't know any better.

This.
I wonder how common that confusion between a cold and mild PEM is?

I spent years thinking I had a particularly strong immune system because whenever I caught a 'bug' I got that 'off' feeling and a sore throat but it never went on to develop into a runny nose. And I explained away the fact that I was catching 'bugs' all the time with temporarily lowered immunity after a big day. With hindsight....

I actually hardly ever got any real colds. And I never had any of the usual childhood illnesses (so I'm told anyway). But on the rare occasion I got the real flu or similar, bang: ME.

So, a link between infection and ME - yes. A link between frequent infection and ME - in my case no.

 

[Snow Leopard]

I know the difference between a cold and PEM - mild cough for a few days can be PEM, cough or runny nose that doesn't go away for weeks is an infection. I seem to catch at least one per year, more when I was attending uni and caught pretty much everything going around.

 

[Andy]

My experience is that I *thought* I was getting colds and flu all the time. Then I realised this really wasn't normal and my flu seemed to follow about two to four days after 'big' days. It was really just PEM but I didn't know any better.

Yes, me too. The individual days off I had to take when I was working full-time to deal with what, in hindsight, was PEM my best description at the time was it was a 24-hour heavy cold.

 

[Nellie]

I used to get frightful, mostly one-sided, sore throats and expected colds to hit the next morning but they didn't. It took an age for me to realise that they were chemical hits from gardening or household products.

 

[Mij]

@Nellie the "chemical hits" symptoms (one sided sore gland under my ear) started 15 years into the illness. In the last few years I find that dust/allergens are causing the exact same symptoms. Kind of hard to avoid those!

 

[chrisb]

Why do that when you can do this?

No means, no standard deviations, deliberate data opacity, improper stratification, publish known information as new information.

On the other hand, I definitely like they included BCG

Because unless you know when the pathogenesis occurred you cannot hope to identify the risk factors for it.