Spontaneous, persistent, T cell–dependent IFN-γ release in patients who progress to Long Covid, 2024, Krishna et al

[Jonathan Edwards]

What do you mean by ‘how specific it is’?

Whether gamma interferon production is unique to ME/CFS or a much more general phenomenon does not matter, as long as it is not normal physiology. Hypercalcaemia is not specific to hyperparathyroidism or myeloma but it is a crucial sign that there is disease.

 

[jnmaciuch]

I agree—I think that it actually is unlikely that the state of PEM is a completely unique biological phenomenon in itself. What seems to be ME/CFS-specific is the pattern of being triggered by exertion (as far as we know, we likely can’t confirm that until the mechanism is known).

So there’s:
1) the pathological state that exists when someone is actively in PEM (call it state ‘X’), and
2) the pathway that leads to state ‘X’ in response to overexertion (call it process ‘Y’), and
3) the underlying mechanism which causes a “normal” level of exertion for a healthy person to trigger process ‘Y’ in ME/CFS but not in healthy people

State X is, in all likelihood, not completely unique to ME/CFS. Most people probably experience (at least parts of) it when they have the flu, for example. But it would be useful to have a objective test that can indicate whether or not someone is in state X

 

[Utsikt]

But it would be useful to have a objective test that can indicate whether or not someone is in state X

Would it be enough to have a test to measure process Y if we can’t find X?

 

[Kitty]

But it would be useful to have a objective test that can indicate whether or not someone is in state X

People could tell you, though?

There are shades of grey, of course, but if you wanted to run an experiment, it's not difficult for moderately ill to people make sure they're actively in PEM on a particular day.

It's not only quicker than spending years and £££ looking for an objective test, it's potentially just as reliable.

 

[Jonathan Edwards]

People could tell you, though?

I think the idea is to have an objective test for a process. I think we may get into a muddle about terms here but my guess is that jnmaciuch is really suggesting that we need a test for the activity of Y, which will prove objectively that there is a biological cause for being in X when you say you are.

 

[jnmaciuch]

People could tell you, though?

I think the idea is to have an objective test for a process. I think we may get into a muddle about terms here but my guess is that jnmaciuch is really suggesting that we need a test for the activity of Y, which will prove objectively that there is a biological cause for being in X when you say you are.

I think tests for both X and Y-->X would be useful in their own regard.

A test for X alone would be useful for the reason that @Sasha already noted--proving that there is actually a biological phenomenon X that is happening when we claim PEM is happening. Ergo, it's not "all in our heads." As you already stated @Jonathan Edwards, if X happens to be similar (or the same, even) as something more societally "legitimate" like viral myalgia, all the better for us.

Primarily, this would be useful on its own for the purposes of any treatment trial. We don't want to rely on subjective reports of PEM because of the heightened susceptibility for confounders.

E.g. if someone just went through one of the "cognitive restructuring" trials which convinced them that PEM isn't real, and then were asked to rate their PEM after the treatment, that would be an invalid measure. But if there is a marker for X, then we could actually check if the participant is still in the state of X after that treatment (even if they claim not to be).

Added: I think this could even be useful as an objective comparative measure for placebo effect for a drug trial. If placebo actually has the power to change something on the relevant biological pathway wrt PEM, a test for X could effectively quantify that.

After that, yes, it would be useful to have a test for the activity of Y leading to X (and that would be where the bulk of useful research happens, in my opinion)

 

[Creekside]

What seems to be ME/CFS-specific is the pattern of being triggered by exertion

Add "reliably" to that. There may be people who trigger PEM, but only occasionally, so they don't link exertion with the symptoms. For that matter, maybe some of the symptoms of viral infection are actually from PEM's mechanism, triggered by the immune system's activation.

 

[forestglip]

In case it's useful to the IFN-γ discussion:

Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation (2024, Cell Reports Medicine)

In particular, gene sets associated with chemokine signaling, migration, and activation are expressed at elevated levels in patient classical monocytes (Figure 2D). Furthermore, we observed the suppression of genes associated with interferon gamma (IFN-γ) signaling in patient classical monocytes. These results suggest that classical monocytes from ME/CFS individuals are biased toward a profile that promotes migration of monocytes to tissue and increased progression toward a macrophage fate. However, we also observed the activation of genes associated with interleukin-10 (IL-10), an anti-inflammatory cytokine. Thus, monocytes in ME/CFS patients may undergo a combination of conflicting inputs.