Making Invisible Illnesses Visible: Recognizing and Responding to Infection Associated Chronic Conditions 2026 Iskander and Haridopolos

[Jonathan Edwards]

It's what I've generally seen from ME/CFS clinicians and researchers on Twitter and from talking to multiple ME/CFS specialists I have seen (again, they may have different ideas about how non-infectious triggers lead to ME/CFS - e.g. resulting in reactivating pathogens). It seems like many review/hypothesis-type articles on ME/CFS acknowledge non-infectious triggers too, but I don't have them all sitting in front of me.

I wouldn't put much store by any of those to be honest. ME/CFS is disinformation central, as you know. I don't think we have any meaningful data papers that address non-infective triggers.

 

[Jonathan Edwards]

I think I might have asked this question years ago but if causation is stochastic, why are there risk factors for diseases such as RA? For example, why would people in northern latitudes be more likely to get MS?

The risk factors just increase the level of chance occurrence at any time. Just as the number of units of alcohol you drink or the number of days of sunbathing raises the chance of a mutation occurring in a cell that leads to cancer. There is no temporal trigger for that, which is what we are talking about.

 

[Peter T]

I think part of the problem may be that a lot of people assume that there must be a trigger. People always look for causes. But a lot of disease causation is stochastic - there may be no trigger. The disease process may have a natural tendency to engage at random times. That is almost certainly a predominant factor for autoimmune disease. It used to be taught that physical trauma could trigger RA but it looks very unlikely in the context of what we know now.

Thank you for expressing this more clearly than I could. We must maintain a degree of scepticism about individuals’ self reported causation of any medical condition including in relation to ourselves. How many people attribute their cancer say to stress or to trauma? Though I hope patients’ experience should always be taken seriously, it also should be remembered that we don’t necessarily have privileged access to underlying biological processes.

 

[nataliezzz]

I wouldn't put much store by any of those to be honest. ME/CFS is disinformation central, as you know. I don't think we have any meaningful data papers that address non-infective triggers.

You don't put much store in what ME/CFS clinicians who actually see these patients day in and out have observed? Or all these patients themselves reporting non-infectious triggers?

Is there any meaningful data on many/most of the things we just accept as likely true about ME/CFS because enough patients report them? I'm not sure there's any prospective studies showing that emotional stress can trigger PEM e.g. (are there any prospective studies on any PEM triggers at all?), but we generally accept that emotional stress can trigger PEM because enough (perhaps not even the majority of) ME/CFS patients report having that experience at some point.

 

[Jonathan Edwards]

You don't put much store in what ME/CFS clinicians who actually see these patients day in and out have observed?

No. Having read what a lot of these 'ME/CFS clinicians' write I have very little faith in them knowing what they are talking about. I worked in an area of medicine where ideas on pathogenesis and treatment were based on careful research and evidence gathering. When I got interested in ME/CFS it was immediately clear to me that the same did not apply. Most of what gets claimed is folklore - very similar to the biospychosocial folklore and often overlapping, even if it is dressed up as 'biomedical'.

Or all these patients themselves reporting non-infectious triggers?

I have made this point a hundred times now, I think. I believe patients' accounts of their symptoms. I do not rely on their attributions of cause of symptoms because there is a huge body of evidence indicating that people are very unreliable on that. Patients I have known with other diseases have often attributed their problems to thiings suggested by this or that guru. We are all very suggestible.

Is there any meaningful data on many/most of the things we just accept as likely true about ME/CFS because enough patients report them?

Same again. We should accept what people report as experience. We should not accept what they report as their belief on causation.

I'm not sure there's any prospective studies showing that emotional stress can trigger PEM e.g. (are there any prospective studies on any PEM triggers at all?), but we generally accept that emotional stress can trigger PEM because enough (perhaps not even the majority of) ME/CFS patients report having that experience at some point.

I have no reason to think that 'stress' triggers PEM. I don't even have a clear idea of what 'stress' is supposed to be. It has no clearly defined biological meaning - there is a long-standing confusion between stress as defined by Selye and stress as defined by a psychotherapist.

To me this is all in the realm of folklore. For conditions like EBV and Covid infection we have data, and such things are easier to interpret because they have a degree of homogeneity and are clearly separable from other life events. Beyond that I don't think we have anything reliable.

 

[nataliezzz]

No. Having read what a lot of these 'ME/CFS clinicians' write I have very little faith in them knowing what they are talking about. I worked in an area of medicine where ideas on pathogenesis and treatment were based on careful research and evidence gathering. When I got interested in ME/CFS it was immediately clear to me that the same did not apply. Most of what gets claimed is folklore - very similar to the biospychosocial folklore and often overlapping, even if it is dressed up as 'biomedical'.


I have made this point a hundred times now, I think. I believe patients' accounts of their symptoms. I do not rely on their attributions of cause of symptoms because there is a huge body of evidence indicating that people are very unreliable on that. Patients I have known with other diseases have often attributed their problems to thiings suggested by this or that guru. We are all very suggestible.


Same again. We should accept what people report as experience. We should not accept what they report as their belief on causation.

Ok, thanks for your reply.

I have no reason to think that 'stress' triggers PEM. I don't even have a clear idea of what 'stress' is supposed to be. It has no clearly defined biological meaning - there is a long-standing confusion between stress as defined by Selye and stress as defined by a psychotherapist.

You may have no reason to, but plenty of patients do. Maybe I should have said "emotional distress" rather than "emotional stress," although perhaps that wouldn't change anything about your take on it (ETA: although now that I think about it, it doesn’t actually have to be distress. I’ve heard plenty of severe patients say they crash from happiness / strong positive emotions too).

To me this is all in the realm of folklore. For conditions like EBV and Covid infection we have data, and such things are easier to interpret because they have a degree of homogeneity and are clearly separable from other life events. Beyond that I don't think we have anything reliable.

There's gotta be a middle ground between folklore and confirmed by large scale prospective studies. I've heard from enough people like Scott Daniska (who reported feeling ill immediately following hydrazine exposure and never felt well again, meets criteria for ME/CFS, etc. -- of course the trigger varies: for another person I talked to it was a spiked drink, etc...) to say that this isn't just folklore (as have all of the doctors who see ME/CFS patients for a living).

Here is a study that used Fukuda criteria (so I'm guessing the response will be it counts for nothing):

Onset Patterns and Course of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2019)

From March 2010 to August 2011, 200 ME/CFS subjects were recruited as part of our GESID (Genetic Expression and Immune System Dynamics) study examining the interactions among pathogen presence and load, human leukocyte antigen (HLA) types, and the immune system in ME/CFS. Some subjects originated from Stanford University's ME/CFS Clinic or the Clinic wait list while others were recruited via local support groups and electronic patient forums. All subjects were screened using a standardized telephone interview and included if they fitted Fukuda 1994 CFS criteria, lived in the San Francisco Bay area, were at least 14 years old, were non-pregnant, and had not been exposed to more than 2 weeks of antimicrobials recently. Subjects were excluded from the study if they were affected by an alternative medical or psychiatric condition that could explain their symptoms, suffered from certain immunological conditions, struggled with substance abuse issues in the last year (not including nicotine/caffeine), received an influenza vaccination within the past 4 weeks, or had limited ability communicating in English.

Most subjects (90%, n = 135) could remember a time before they were sick and 85% (n = 123) noted a specific time their illness began. When asked if they believed a specific factor precipitated their illness, 88% (n = 132) answered affirmatively or possibly.

Although we offered 14 different factors that could be associated with onset, 61% of subjects selected only one or two factors. We chose to group subjects who responded “yes” or “not sure” (vs. a clear “no”) together as illness onset has not been examined in detail and we wanted to include all possibilities. The top five factors selected were infectious illnesses (64%), stress/ major life events (39%, primarily work- or family-related), exposure to chemical/ environmental toxins (20%), recent international travel (19%), and recent domestic travel (17%)

Also... Precipitating factors for the chronic fatigue syndrome (1997) (not sure what criteria this one used - older CDC definition? ETA: yes, it was the 1988 Holmes CDC criteria)

We investigated precipitating factors in 134 CFS patients through the use of a questionnaire, interview, clinical examination and serology for infecting agents; 35 healthy controls completed a similar questionnaire. CFS started with an apparently infectious illness in 96 (72%) but a definite infection was only found in seven of these 96 (7%). Thirty-eight (28%) had no apparent infectious onset: 15/38 (40%) had noninfectious precipitants (trauma, allergy, surgery). There was no apparent precipitating event in 23/38 (61%). Immunization was not a significant precipitant. Stressful events were very common in the year preceding the onset of CFS (114/134, 85%) but these occurred in only 2/35 (6%) of the controls (p < .0001). The onset of CFS may bec associated with preceding stressful events and multiple other precipitants. An infectious illness is not uniformly present at the onset and no single infectious agent has been found; CFS is most likely multifactorial in origin.

 

[DMissa]

For conditions like EBV and Covid infection we have data, and such things are easier to interpret because they have a degree of homogeneity and are clearly separable from other life events. Beyond that I don't think we have anything reliable.

I really know nothing about it but Gulf War Illness comes to mind as involving another possible synchronised life event. Is consensus here that ME/CFS as we currently define and understand it here occurs in GWI or is it considered an unreliable muddle when ME/CFS and GWI are conflated in literature?

 

[ScoutB]

Is consensus here that ME/CFS as we currently define and understand it here occurs in GWI or is it considered an unreliable muddle when ME/CFS and GWI are conflated in literature?

Yeah I also thought of GWI here. I don't think we have a consensus, but some of us are interested in GWI exactly for this reason. @forestglip has posted a few studies (like this one) trying to figure out if some people with GWI would meet our current criteria for ME/CFS.

I wonder, if ME/CFS does turn out to be somewhat neurological, if that would make it more plausible for it to be caused by a single event or exposure in some cases? Individual neurons stick around our entire lives, so it seems easier to imagine one event causing lasting problems. (e.g. as may be the case in parkinson's)

 

[Jonathan Edwards]

There's gotta be a middle ground between folklore and confirmed by large scale prospective studies.

It is not a question of middle ground. There are three sorts of proposal:
1. Folklore
2. Individual observations that we have to treat as unproven
3. Factors for which we have reasonably strong evidence from large studies

ME/CFS occurring immediately after hydrazine exposure is probably 2. It isn't folklore.
Stress is very definitely part of the general population folklore - for every disease from stomach ulcers to cancer - and for nearly all of them the real evidence is close to zilch.

Fukuda studies are probably fine. That is quite an interesting set of answers, but it doesn't change my view. It supports the evidence for infection being relevant. Travel is often associated with picking up infection too. Chemical/environmental toxins are a key part of folklore but may also fall under 2.

My guess is that whatever the trigger, some degree of psychologically induced 'emotional stress' is very likely to have been around at the event. It is unquantifiable and such an easy cop-out for health professionals and neighbours alike. Effectively it makes ME/CFS a truly 'psychological' illness and one thing I am sure of is that coming to that conclusion takes us nowhere useful.

 

[PageofME]

for all these people who reported infectious onsets who did not actually get a laboratory confirmed diagnosis of an infection, how can you be sure that you actually had an infection since many of the symptoms of ME/CFS overlap with those of an infection? People report symptoms like fevers, congestion/sneezing, sore throats, etc. during PEM so how can you be sure that it was not just your first episode of PEM?

Thanks for pointing that out. This is a very important feature of my ME flares too and it is often overlooked. PEM and exhaustion are the most discussed symptoms. But to understand the full picture the flu like symptoms mustn't be omitted.

 

[PageofME]

I think it is sound to say that ME is infection-associated because EBV or Covid are so potential triggers of the disease. But I would add that the triggers aren't really important because not matter what the trigger the main features in ME/CFS look then the same in every one. So, yes, when these people say that it is important to look beyond persistent infection with viral triggers that's 100% what's needed.

The triggers are not what's important to understand the pathomechanism of ME. I am glad that the leading ME researchers have all understood that and I think that the Long Covid-ME researchers will understand that too with time.

I intuit that persistent viral infection has such a huge following among Long Covid-ME-patients because they feel that they have persistent viral infection but are not aware that there might be a better explanation for that – viral reactivation, namely HHV-6b.