Exercise does not cause post-exertional malaise Gulf War Illness: A randomized, controlled, dose–response, crossover study, 2024, Boruch et al.

[SNT Gatchaman]

Exercise does not cause post-exertional malaise in Veterans with Gulf War Illness: A randomized, controlled, dose–response, crossover study
Boruch; Barhorst; Rayne; Roberge; Brukardt; Leitel; Coe; Fleshner; Falvo; Cook; Lindheimer

ABSTRACT
Chronic multisymptom illnesses (CMI) such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, long-COVID, and Gulf War Illness (GWI) are associated with an elevated risk of postexertional malaise (PEM), an acute exacerbation of symptoms and other related outcomes following exercise. These individuals may benefit from personalized exercise prescriptions which prioritize risk minimization, necessitating a better understanding of dose-response effects of exercise intensity on PEM.

METHODS
Veterans with GWI (n=40) completed a randomized controlled crossover experiment comparing 20 minutes of seated rest to light-, moderate-, and vigorous-intensity cycling conditions over four separate study visits. Symptoms, pain sensitivity, cognitive performance, inflammatory markers (C-reactive protein and plasma cytokines) were measured before and within 1 hour after exercise and seated rest. Physical activity behavior was measured ≥7 days following each study visit via actigraphy. Linear mixed effects regression models tested the central hypothesis that higher intensity exercise would elicit greater exacerbation of negative outcomes, as indicated by a significant condition-by-time interaction for symptom, pain sensitivity, cognitive performance, and inflammatory marker models and a significant main effect of condition for physical activity models.

RESULTS
Significant condition-by-time interactions were not observed for primary or secondary measures of symptoms, pain sensitivity, cognitive performance, and a majority of inflammatory markers. Similarly, a significant effect of condition was not observed for primary or secondary measures of physical activity.

CONCLUSIONS
Undesirable effects such as symptom exacerbation were observed for some participants, but the group-level risk of PEM following light-, moderate-, or vigorous-intensity exercise was no greater than seated rest. These findings challenge several prior views about PEM and lend support to a broader body of literature showing that the benefits of exercise outweigh the risks.

Link | Paywall (Brain, Behavior, and Immunity)

 

[forestglip]

What was the point? Are they trying to show that not all people with gulf war illness have PEM?

What does this mean:

Undesirable effects such as symptom exacerbation were observed for some participants, but the group-level risk of PEM following light-, moderate-, or vigorous-intensity exercise was no greater than seated rest.

So some people in the study had PEM, but if you take the results of the group on average, then the average person in the group didn't? Is that was "group-level risk" means?

Link to PDF doesn't work, by the way.

 

[SNT Gatchaman]

Link to PDF doesn't work, by the way.

Paywall - corrected.

 

[SNT Gatchaman]

This study has several potential limitations and future research directions. First, unblinding participants and test administrators to condition assignment may have introduced bias into outcome measures. Nevertheless, non-significant changes in their expectations over the course of the study tempers this concern to some degree.

Second, while our findings may translate to exercise prescription for other CMI populations such as ME/CFS and Long-COVID, demographic, etiologic, and exercise-related physiological differences between Veterans with GWI and other CMIs may limit the generalizability of our findings.

Further, despite meeting case-definition criteria for GWI, the baseline characteristics of our sample reflected less severe symptoms than some prior studies. Prior studies of ME/CFS have reported associations between baseline symptom severity and PEM responses, suggesting that the most pronounced PEM responses occur in individuals with greater illness severity.

although linear mixed effects analysis indicated the group level effect of vigorous exercise on Kansas fatigue scores was not different from quiet rest, plotting individual responses shows that fatigue increased for 46% of participants after vigorous exercise versus 15% of participants after quiet rest (see Supplemental Fig S7).

Supplemental Fig S7. Individually reported changes in Kansas fatigue scores before and 10-min after exercise and seated rest

 

[forestglip]

Symptoms, pain sensitivity, cognitive performance, inflammatory markers (C-reactive protein and plasma cytokines) were measured before and within 1 hour after exercise and seated rest. Physical activity behavior was measured ≥7 days following each study visit via actigraphy.

Did they only test symptoms within one hour after exertion? So they missed any PEM that takes longer than one hour to appear?

@SNT Gatchaman Do you have the charts or any text about the "physical activity behavior"?

 

[SNT Gatchaman]

In the methods on at-home measures (i.e. the 7 days following), they write —

An ActiGraph GT3X+ triaxial accelerometer (ActiGraph, LLC, Pensacola, FL) was used to measure physical activity following Visits 2-5. The ActiGraph is a reliable device, with a mean intra-instrument coefficient of variation of 4.1% and a mean inter-instrument coefficient of variation of 4.9%. 45 Participants were instructed to wear the monitor on their hip via an elastic belt or belt clip during all waking hours except for bathing or swimming for ≥7 days. To facilitate data processing and interpretation, participants completed a daily physical activity log to indicate when they (1) woke up, (2) applied and removed the monitor, and (3) went to sleep. Participants were also encouraged to complete daily symptom questionnaires (Kansas VAS, POMS, MPQ) at approximately the same time of day when possible.

Accelerometer data were processed using in-house software to calculate time spent in sedentary, light, moderate, and vigorous activity levels. 46 Criteria for valid wear time was ≥ 10 hours for a minimum of 3 week days and 1 weekend day. 47 Moderate-to-vigorous activity (expressed as a percentage of total wear time) was treated as the primary outcome measure of physical activity. Secondary outcomes were percentage of wear time spent engaging in sedentary and light activity, steps per day, and transitions from a sitting to standing position.

The results subsection for physical activity states (in total) —

Descriptive statistics are provided in Supplemental Table S14. Overall missingness for accelerometry data was 10.3%. Significant between condition differences were not observed for moderate-to-vigorous activity (F3,100 = 0.14; p=.94) or secondary outcomes (Supplemental File 2).

 

[forestglip]

In the methods on at-home measures (i.e. the 7 days following), they write —





The results subsection for physical activity states (in total) —



View attachment 21888

Hmm, if they already spend 10% of their waking hours (~1.6 hours) doing "moderate-vigorous activity", it's not surprising that the exercise test wasn't very bad for them.

 

[SNT Gatchaman]

Also group mean of ~6700 steps/day and 58 sit-to-stand transitions/day.

 

[Maat]

Symptom criteria

From the Kansas GWI paper (Steele 2000) research criteria Prevalence and patterns of Gulf War illness in Kansas veterans: association of symptoms with characteristics of person, place, and time of military service - PubMed (nih.gov) which is referred in the 2024 study:

"Symptom groups and criteria. Several approaches to quantifying symptom criteria were considered, including exploratory factor analysis to identify latent constructs that might be used to define symptom groupings or illness subtypes. This approach provided general validation regarding the cooccurrence of symptoms within system-based categories (e.g., respiratory symptoms tended to occur together, as did gastrointestinal symptoms, and so on). The cooccurrence of symptoms in different categories, however, varied in veteran subgroups (e.g., PGW vs. non-PGW veterans, males vs. females, PGW veterans deployed to different areas). This method was therefore not considered a reliable way to define illness subtypes in this population. Instead, a more descriptive approach was taken, defining symptom groups based on measures of correlation and comparisons between PGW and non-PGW veterans. Veterans were asked about symptoms in several general categories (e.g., respiratory, gastrointestinal, neuropsychological, sleep disturbances, pain), as well as symptoms (e.g., fatigue, headache) for which no single category was apparent. Gulf War illness criteria symptoms must have persisted or recurred in the year prior to interview and first have been a problem for respondents in 1990 or later. The correlation of symptom scores was assessed among PGW veterans who did not report exclusionary conditions. The internal reliability of each symptom grouping was determined using Cronbach’s alpha (22)"

"One additional symptom group, skin symptoms, was identified. Veterans were asked specifically about only one skin symptom (rashes), disallowing correlation assessments. This symptom was frequently reported, strongly associated with deployment, and relatively independent of other symptom groups. Veterans also frequently reported other skin problems, about which they had not specifically been asked.

Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment - PMC (nih.gov) 2016

This paper also reports higher prevalence of light sensitivity and skin problems.

6.5. The bottom line
The research data to date on health in GW veterans converge to support these conclusions:

• Between one-fourth and one-third of deployed GW veterans are affected by a disorder characterized by chronic symptoms involving multiple body systems; this condition is best identified by the term GWI.
• This disorder was caused by toxicant exposures, individually or in combination, that occurred in the GW theater. At present, research most clearly and consistently links pesticide and PB exposures to GWI, while exposures to low-level nerve gas agents, contaminants from oil well fires, multiple vaccinations, and combinations of these exposures cannot be ruled out.
• In addition to GWI, deployed GW veterans suffer from a variety of neurological disorders, alone or in combination with GWI. ALS, brain cancer, stroke, migraine headaches, neuritis and neuralgia have all been reported as occurring at higher rates in this population. Rates of disorders such as MS and PD are unknown and further intensive research is needed to determine whether they are elevated in GW veterans. This should include studies focused on GW veteran subgroups classified by individual exposures or geographic locations in theater.
• Neurological disorders as well as alterations in brain structure and function have been linked to specific exposures in theater, including nerve gas agents, PB and oil well fires
• The state of knowledge on the health of deployed GW veterans supports the conclusion that they are suffering from persistent pathology due to chemical intoxication (sometimes referred to by veterans as “toxic wounds”).
• Further research into the mechanisms and etiology of the health problems of GW veterans is critical to developing biomarkers of exposure and illness and preventing similar problems for military personnel in future deployments; this information is also critical for developing new treatments for GWI and related neurological dysfunction.
• Given the similarity of the health problems of GW veterans and those of other occupational groups with OP exposures (e.g., insecticide applicators, farmers, sheep dippers, nursery workers, chemical plant workers), the identification of treatments for the GW veteran population will have far-reaching implications for treating other groups of ill patients for whom no effective treatments have been identified.

This paper is based on the 2014 report Gulf War illness and the health of Gulf War veterans: Research update and recommendations, 2009–2013 (RACGWI, 2014). The paper authors were also authors on the report.

Contrast and compare with this paper, and note the letters to the editor on publication of the paper.

Chaudhuri A, Behan WMH, Behan PO. Chronic Fatigue Syndrome. Journal of the Royal College of Physicians of Edinburgh. 1998;28(2):150-163. doi:10.1177/147827159802800203

Chronic Fatigue Syndrome - A. Chaudhuri, Wilhelmina M.H. Behan, P.O. Behan, 1998 (sagepub.com)

Chronic Fatigue Syndrome | Royal College of Physicians of Edinburgh (rcpe.ac.uk) pdf



Vol28_4.1.1 (rcpe.ac.uk) letters in response to research by Chaudhuri, Behan and Behan 1998 from Reilly, Wessely and Hotopf and Chaudhuri and Behan's response.

 

[rvallee]

So, one of the latest trends is clearly to argue that people who may or may not report PEM don't show PEM according to them. This are several studies doing the same bit.

These findings challenge several prior views about PEM and lend support to a broader body of literature showing that the benefits of exercise outweigh the risks.

"Views" such as widespread reports of PEM, which not everyone with GWI has, and this cohort was clearly highly active so would be unlikely to have PEM anyway. And what benefits of exercise? No benefits have been shown from exercise to people with chronic illness, or at best trivial. It's always generic benefits, but they're always said to improve symptoms.

This is obviously not a serious way of researching this. If you take a random group of people who mostly don't have allergies, if you take a group-level average and ignore the allergic reactions, this group doesn't appear to have significant problems with allergies.

Decade after decade of wasted lives. Eventually all GWI veterans will be dead, so the problem will have taken care of itself. Nevermind the lives of the patients, they clearly don't matter.

It's so hard to accept that my life is ruined by this mediocrity. I am furious with this bullshit.

 

[Jonathan Edwards]

The strange thing is that it seems that all these authors (pretty much) are students or very junior. Some involved in psychology, some sport.

Some of them have an interest in ME/CFS/. Maybe somebody hoped they could show GWI people had PEM. But why say exercise benefits outweigh risks?

It's like some sort of AI product. Barmy.

 

[poetinsf]

I wonder what the point is of labelling someone who can walk 6700 steps, with GWI. GWI should be about disability, and I don't see disability with someone who can take 6700 steps on average. Not a physical disability, anyway. The paper studied the non-disabled and then extrapolated the result to the disabled, it appears.

 

[forestglip]

I wonder what the point is of labelling someone who can walk 6700 steps, with GWI. GWI should be about disability, and I don't see disability with someone who can take 6700 steps on average. Not a physical disability, anyway. The paper studied the non-disabled and then extrapolated the result to the disabled, it appears.

"The paper studied the non-disabled and then extrapolated the result to the disabled" would be more accurate as "The paper studied people people diagnosed with GWI who walk a lot and extrapolated to people with GWI who do not/can not walk a lot."

Disability can come in a million different forms. Being able to walk a lot doesn't mean you aren't disabled. Even other physical disabilities, like missing arms, or even legs, don't necessarily prevent walking.

 

[bobbler]

The strange thing is that it seems that all these authors (pretty much) are students or very junior. Some involved in psychology, some sport.

Some of them have an interest in ME/CFS/. Maybe somebody hoped they could show GWI people had PEM. But why say exercise benefits outweigh risks?

It's like some sort of AI product. Barmy.

Yep

there’s the issue with most of the ME/CFs stuff - not just juniors, yet you’d hope the fresh blood might have spotted it or have been keen to fix it if the critical thinking and research design in their education was right:

to say that they needed to have design based around that research question if they wanted to make the claim of 'benefits vs disbenefits'

which almost certainly meant longitudinal and much longer term EDIT: and NOT retrospective so 'those who did more were more well' became the misnomer vs a trial seeing if more exercise/exertion (in total noting people cut back on other things often) = better or worse health.

now we do have better overall exertion monitors (which I’d hope could be programmed to output data that only covered what was needed detail wise so wasn’t such a privacy issue as doing the opposite aka in MEA proms list of all those activities which aren’t exhaustive vs measuring ‘exertion and impact’ ) this is surely possible

and with GWI injury if it was down to patient consent and willingness and researchers were honourable and transparent to build trust I can’t think of a more likely group to volunteer to do long term in the name of getting to the bottom of things ?

 

[bobbler]

"The paper studied the non-disabled and then extrapolated the result to the disabled" would be more accurate as "The paper studied people people diagnosed with GWI who walk a lot and extrapolated to people with GWI who do not/can not walk a lot."

Disability can come in a million different forms. Being able to walk a lot doesn't mean you aren't disabled. Even other physical disabilities, like missing arms, or even legs, don't necessarily prevent walking.

Indeed it’s 50% less than before - so a lot of very fit or able people often g eg hidden under that ‘but you still pass the tests so you can’t be ill’ nonsense giving the talented people no leeway

plus we don’t know when PeM hits fir all we know due to different cause or different fitness before it could be ‘cumulative’ and hit hugely after a week if they were used to 29mile daily marches and are now just doing one or ‘a bit more than normal’ etc


Who knows how this all calibrates if we aren’t listening and watching for these things?

 

[SNT Gatchaman]

Paywalled commentary by Wyller at Post-exertional malaise – A functional brain aberration? (2024, Brain, Behavior, and Immunity) which essentially concludes with a call for CBT and GET, claiming "evidence confirming that physical activity is not harmful in conditions characterised by PEM".

 

[Andy]

Trial By Error: Bogus Claims in Study of Exercise and PEM in Gulf War Illness

"A recent study investigated a question no one seems to have been asking. That can be a good thing—if it’s a question that’s worth investigating. But that’s not the case here.

The study, published in the journal Brain, Behavior, and Immunity and led by researchers at the University of Wisconsin, was called “Exercise does not cause post-exertional malaise in Veterans with Gulf War Illness: A randomized, controlled, dose–response, crossover study.” The title itself indicates a conceptual problem built into the study. I mean, has anyone seriously argued or raised concerns that exercise “causes” PEM among GWI patients even if they do not report having PEM as part of their GWI in the first place?"

https://virology.ws/2024/09/07/tria...tudy-of-exercise-and-pem-in-gulf-war-illness/

 

[Kalliope]

The tabloid newspaper Dagbladet with journalist Jorun Gaarder has an article about this study today titled: Tolerates exercise

Professor Wyller says this study suggests that people with fatigue syndromes as ME, long covid, fibromyalgia and so on tolerate exercise.

He says the feeling of pain and fatigue seems like a signal that something is wrong, but it's possible to feel pain without there being anything wrong in the body.

This means that the symptoms' origin is in the brain, rather than in the body.

Professor Tronstad says the study can't be transferred to other patient groups, as ME patients.

Wyller disagrees and thinks we have to do more research on the brain to find an explanation for these illnesses, rather than trying to find a physiological explanation.

Tronstad says there might have been a selection on beforehand of the participants of the study. That most people with PEM probably won't join such a study in the first place.

The article then refers to some other studies on varied patient groups with varied results. Wyller says that even if we can find changes in the immune system and with lactic acid production, that doesn't mean it's an explanation for the symptoms.

Tronstad ends with saying that PEM can be triggered by both physiological and cognitive activity and that they believe a failure in the cell metabolism may be behind. The brain is part of this as it uses 20% of the body's energy and it's important that the patient takes everything into consideration when trying to avoid PEM. Careful activity under the PEM threshold may still have a positive effect on the body.

https://www.dagbladet.no/nyheter/taler-a-trene/81904783

google translation
https://www-dagbladet-no.translate...._sl=no&_x_tr_tl=en&_x_tr_hl=en&_x_tr_pto=wapp

 

[dratalanta]

Presumably we can expect more of the same in relation to Long Covid: "Exercise does not cause PEM in a cohort of Long Covid patients most of whom never experience PEM."

Clearly these researchers do not understand the logic of the evidence review behind NICE 2021.

 

[rvallee]

Wyller disagrees and thinks we have to do more research on the brain to find an explanation for these illnesses, rather than trying to find a physiological explanation.

The brain, famously not physiological.

Not a dualist. You're the dualist.

See, the trick to cure diabetes is you take people who have normal insuline metabolism. Then, voilà, no more diabetes. It really is that simple.

You can apply the same with any other disease. Dementia? Just find a group of people with dementia who have perfectly normal cognitive function. From that you can, I don't know, decide that it also applies to post-concussion issues. It's really that simple if you don't care and don't mind making stuff up.