They understand the importance of PEM in definining ME/CFS, and spend a lot of the paper talking about it, which is nice:
Intolerance to even trivial increases in physical or mental activity above individual norms is the hallmark symptom of ME [
10–
12,
17,
18]. This intolerance manifests itself as marked worsening of symptoms that may be short lived or prolonged (sometimes weeks) but only rarely resulting in permanent disability [
10,
11].
The symptom simarities they list:
cross-sectionally there is a phenomenological overlap between sickness behavior and ME/CFS, both presenting with malaise, hyperalgesia, fatigue, exhaustion, sleepiness, failure to concentrate, and sometimes mood disturbances. PEM following mental and physical activities, a characteristic symptom of ME, may also occur during sickness behavior.
I'd love to see evidence of PEM in sickness behavior, but I don't see them cite anything. Though I may have missed it somewhere else in the paper.
One of the main reasons they give for the two conditions being different is that sickness behavior includes anorexia (decreased hunger) and pyrexia (fever), while ME/CFS, as a rule, doesn't.
gastrointestinal symptoms reminiscent of IBS [
10,
11] occur in many ME/CFS patients but not typically in sickness behavior. Anorexia and weight loss, typical symptoms of sickness, are not germane to ME/CFS unless there is comorbid depression. While pyrexia is a hallmark of the acute inflammation during sickness, mild fever may occur in a small proportion of ME/CFS patients.
This isn't satisfying to me. For a relatively short duration of acute infection, decreased food intake is totally fine and survivable for a person. Of course that couldn't continue forever or the person would starve, so if sickness behavior persisted for months, the body would have to override that feature of the response. I assume a similar reasoning would explain why fever doesn't persist for months. The cost to the body could be greater than the reward if it persists.
Not to mention, I don't think fever or anorexia is even always required in sickness behavior. At least for me, I don't remember the last time I got a fever from an infection. (Although I don't normally measure my temperature, but it doesn't feel like it.) And I don't stop being hungry when sick. (Sidenote: Is this lack of fever during acute sickness common in ME/CFS?)
Another reason they give seems to just be semantics, basically saying sickness behavior, by definition, describes a brief period, so it can not be involved in ME/CFS. I'm interested in whether the physiology is similar.
We have argued that attaching the terms prolonged, exaggerated or persistent to sickness behavior is unsatisfactory, primarily due to sickness behavior by definition, being a short-lasting, beneficial behavioral response that plays a role in the resolution of inflammation
Then there are some reasons given for physiological dissimilarities, such as the specifics of inflammation markers. Most of it is over my head, so I can't comment on it.
The objective of the sickness response from an evolutionary perspective is energy conservation
Wikipedia includes other objectives that I didn't see mentioned in this paper, though I might have missed them, including signalling to others that one is sick, and staying away to not infect them.
I haven't looked at these citations, but some of this looks interesting:
When reaching exhaustion, ME/CFS patients display diminished intracellular ATP and dysregulated oxidative metabolism, coupled to increased glycolysis in the exercising striated muscles [
12,
58]. ME/CFS patients display reduced rates of ATP resynthesis in the aftermath of exercise versus controls resulting from impaired oxidative phosphorylation [
56]. Patients with ME/CFS show prolonged elevations of lactate, returning extremely slowly to normal levels [
53,
59]. Behan
et al. [
55] found histopathological abnormalities in the mitochondria of skeletal muscles in ME/CFS. During exercise, the latter display decreased voluntary muscle contractions, which worsen subsequently [
59]. Thus, in ME/CFS patients reduced intracellular ATP, oxidative metabolism and accelerated glycolysis in skeletal muscles determine early exhaustion [
12,
58,
61]. Several studies report significantly increased levels of ventricular lactate in ME/CFS patients, suggesting central energy dysregulation [
62,
63]. [...]
Kennedy
et al. [
54] reported elevated surrogate biomarkers of O&NS [oxidative and nitrosative stress] in ME/CFS, which positively associated with symptom exacerbation following energy expenditure.
I personally think that it's most likely ME/CFS symptoms are caused by a live, replicating pathogen, and something similar to "sickness behavior" is causing the symptoms. The reasons being the profound symptom similarities between the two, which the paper listed above, as well as the obvious connection to infection that ME/CFS has. But most of all, I think a replicating pathogen is the most obvious explanation for PEM, as it explains the delayed onset (time for the pathogen to replicate), and I think that should be one of the first PEM mechanism theories to try to falsify. If the paper's claim is true that a PEM like symptom is seen in normal sickness behavior, I think that would strengthen the case even more.
One counterargument I can think of is the question, why don't we ever see the pathogen in ME/CFS replicate to high enough levels that it kills the person? One possible explanation could be that the sickness response is very overexaggerated in relation to the pathogen levels, and even in very severe ME/CFS, it is still nowhere near life threatening levels. Or maybe the body can keep it localized to a place where it can't actually do significant damage.
The reason I went looking for "sickness behavior" papers is that I thought I had heard or read that the body can basically "turn off" sickness behavior temporarily during an emergency, where the body feels pretty much normal for a time, so that the problem can be handled. I haven't found anything about that, so maybe I'm misremembering. But I was wondering if there might be some marker of that, like an adrenaline or cortisol pathway, which might also be able to be tested for in the brief "adrenaline"-like periods of ME/CFS where a person feels much more energetic if there's an important task or a lot of excitement.
