Sickness behaviour – useful concept or psycho-humbug?

[EndME]

What would be considered as part of sickness response? Does it have to be feeling awful or does feeling just slightly worse but actually still quite fine and good enough to ride the Tour de France count? How does one a "sickness response in ME/CFS" which leaves people disabled compare to others that feel good enough?

Seems that this sort of condition hasn't been described or doesn't exist? It might fly under the radar as asymptomatic infection but there you have the problem that the infection might simply not be severe enough to cause sickness behavior.

That seems a bit circular to me: You only consider infections that already cause sickness behaviour and ignore those that don't. I think there are plenty of counterexamples in real life where the infections were in fact severe enough: Attend enough major amateur sporting events and you will often find someone that died as a result of participanting whilst being actually dealing with an infection but they clearly weren't desplaying much sickness behaviour, as they were competing. I also think that things like myocarditis can often go unnoticed. Weren't there also cases of organ damage in Covid that went fairly unnoticed, at least until a certain point? I'm also unsure why AIDS would not fit into the picture, why would that be considered too local when it can be measured in blood fairly simply and causes issues in many bodily systems whilst something like post-viral fatigue as of yet cannot be captured by any test at all, why should that not just be a local immune response?

There's also plenty of people that feel perfectly fine after getting a vaccination whilst others feel symptoms of malaise and infection, does that mean something was too weak if they develop antibodies ect appropriately? What about people who have a delay between viral infection and feel quite ok during it but develop symptoms of ME/CFS, how do you tie those 2 together? In the case of Covid don't we think most ME/CFS follows mild infections? Would one say that their infection was strong enough to cause a sickness response or not?

On the other hand I also wouldn't be suprised if there's people that feel little fatigue or malaise during/after infections and others that feel more for rather complicated genetic dynamics similar to those that don't feel pain. People with CIPA can apparently have a fever without nothing any symptoms and many die of hyperthermia, does that count? Maybe something similar applies to neuropathies?

 

[ME/CFS Science Blog]

What would be considered as part of sickness response? Does it have to be feeling awful or does feeling just slightly worse but actually still quite fine and good enough to ride the Tour de France count?

Yes, feeling terribly awful so that nobody in such condition would be able to ride a Tour stage. The more similar to ME/CFS the better.

That seems a bit circular to me: You only consider infections that already cause sickness behaviour and ignore those that don't.

Which immune responses cause sickness behavior and which don't is interesting, but a different question from the one I wanted to ask. Namely, if there are genetic defects or diseases where people don't experience sickness behavior in a situation where others do.

Sickness behavior after an infection involving e.g., type I interferons is one of the medical conditions that have notable similarity to ME/CFS. Because ME/CFS often starts after an infection there is a suspicion that it may involve a defect in this pathway that amplifies it or turns it on inappropriately. I was wondering if there is a known medical condition where this pathway is turned off or down.

Something like: people getting fever or tissue damage from an immune response without feeling sick, then getting checked in the hospital where they find out that they have a very serious infection and need to rest and get treated. A condition where doctors say: 'weird that this person doesn't feel sick, which such an immune response/virus people normally feel drained and extremely fatigued.' If that exists, it might point to a symptom signalling process that might be relevant to ME/CFS.

 

[StellariaGraminea]

I know it's not quite the same as your question @ME/CFS Science Blog but my (lay) understanding is that it would also depend on the specific virus. There was some discussion earlier in the pandemic about how Covid seemed to turn off the sickness response in a lot of people not long after infection such that they felt "great!" and went out partying and freely spreading the virus around when they were most infectious. I know I had a day of feeling "great/cured!" about 5 days into symptoms before hell descended again and worsened dramatically.

I'm not sure how much science was behind that discussion, but it makes sense to me the body's sickness response would be virus specific and perhaps viruses evolve to inhibit sickness responses which would then facilitate interpersonal spread (& intrapersonal spread also of course).

If there is an ME/CFS deficit in dialling up or down this sickness response, all I can say is for me personally it would have been dialled down previously in my life before covid. I was very rarely sick, even to the point a boss commented at one point I was the only one who hadn't taken sick leave in several years. (And that was because I hadn't been sick, not because I was forcing myself ill into work). So why would the converse be true for me after Covid (i.e. sickness response massively dialled up) if I had a baseline difficulty with this biological system?

Then, perhaps all along I had a weak sickness response that is the culprit behind succumbing to covid/ ME/CFS version in the end? I don't know how to interpret it.

 

[EndME]

So if I'm understanding correctly: If the people that don't feel pain might be taken as a proxy for the opposite thing possibly happening in Fibromyalgia then you're looking for the equivalent of those non-pain feeling people for ME/CFS, i.e. people that could be taken as proxy for the opposite thing that is happening in ME/CFS. Basically a mirror image of people with ME/CFS.

The Fibromyalgia mirror group might be easier to identify because pain can be caused by many things such as blunt trauma. One way of identifying such a ME/CFS mirror group would be by specifically looking things known to cause malaise and fatigue, such as certain infections, certain vaccinations or human challenge studies (exposing people to certain things) or even medication studies (where symptoms were reported). Then one would want to find some signature of such people (immunological, genetic...).

For example something that could be relevant would be a large GWAS on severe acute Covid linked to a list of symptoms the people had so something that allows for a malaise/fatigue subgroup analyis. I only found one very small genetic analysis that did that (https://pmc.ncbi.nlm.nih.gov/articles/PMC10504482/, but it's not quite clear to me to what precision and the sample size is very low). I also found quite a few analysis of people that suffer from something called IRAK4 or MYd88 deficiency and which develop severe infections without clinical symptoms (for example certain inflammatory markers being low or there being no fever) but there the subjective symptoms (malaise/fatigue/headache) tend to not be mentioned. This tends to be the case for most studies, clinicans tend to mention objective clinical symptoms rather than subjective ones. But it does look a bit like people with CIP (genetic conditions that mean you can't feel pain) don't feel malaise and fatigue.

 

[jnmaciuch]

I also found quite a few analysis of people that suffer from something called IRAK4 or MYd88 deficiency and which develop severe infections without clinical symptoms (for example certain inflammatory markers being low or there being no fever) but there the subjective symptoms (malaise/fatigue/headache) tend to not be mentioned.

That's one of the main ones I'm aware of--the trouble with many genetic mutations affecting type I interferon signaling is that prognosis can be pretty poor so you're trying to study a population that is likely to die of opportunistic infection/complications in childhood. MYD88 is involved in interferon signaling downstream of TLRs, especially in pDCs which are the main producers of IFN-I and were found to drive sickness behavior in this mouse study.

GATA2 mutations is the other one I found in my searches that impairs DC maturation but seems to be associated with complications later in adolescence. Similar to the clinical literature on MYD88 mutations, all the documentation focuses on describing opportunistic infections and other medical issues from the mutation. I doubt that any doctor will take the time to ask the right questions and realize that the patient didn't have any initial fatigue or malaise when the main concern is dealing with failing organs or hematological malignancies. Even if they did, it probably isn't deemed important enough to put in the case reports.

I think the only tool we really have to answer @ME/CFS Science Blog 's question is knockout mouse models like in the paper I linked above. In that circumstance, mice without pDCs, the IFN receptor on brain endothelial cells, or the CXCL10 receptor on neurons did not exhibit the same behavioral indications of fatigue/malaise when dosed with LPS. If nothing else, the lack of known cases in humans where someone experiences every sign of infection except fatigue/malaise and isn't also immunodeficient seems to indicate that the culprits for fatigue/malase in infection are probably the very same signaling molecules actively involved in fighting off infection, rather than several steps downstream of them.

 

[ME/CFS Science Blog]

seems to indicate that the culprits for fatigue/malase in infection are probably the very same signaling molecules actively involved in fighting off infection, rather than several steps downstream of them.

Yes, that's also the explanation I was thinking of: that the sickness behavior pathway involves proteins that are too important elsewhere in the body, so that mutations aren't viable.

But that begs the question of why we don't see clear immune dysfunction elsewhere in ME/CFS and why DecodeME didn't signal out one of these cytokines or receptors.

 

[jnmaciuch]

But that begs the question of why we don't see clear immune dysfunction elsewhere in ME/CFS and why DecodeME didn't signal out one of these cytokines or receptors.

I think the answer might just be that if someone has a mutation in a central component of that pathway like an interferon receptor, their main problem tends to be life threatening interferonopathy not ME/CFS (and, consequently, treatment for that serious issue might prevent future ME/CFS).

I suspect it’s the same for MYD88, GATA2, TLR and IRF mutations. Either in the case of loss or gain of function, you probably end up with a much more immediately life threatening problem than ME/CFS.

Even in lupus where the type I interferon response is very important for permitting an aberrant autoantibody problem, the top interferon related hits are generally not the cytokines/receptors themselves (interferon kappa being the exception for cutaneous lupus) and the more secondary players in the pathway (IRFs, other transcription factors, proteins involved in degradation of interferon, etc.) still only show up in a portion of genetic studies. Plus there’s the fact that these important proteins are not going to have a lot of population-wide variance to make it into a GWAS [edit: even in intergenic regulatory regions].

 

[ME/CFS Science Blog]

I suspect it’s the same for MYD88, GATA2, TLR and IRF mutations. Either in the case of loss or gain of function, you probably end up with a much more immediately life threatening problem than ME/CFS.

Yes, so these are probably too important to be defective in ME/CFS; otherwise, we would see other abnormalities in patients.

So it should likely be something more specific to this pathway that is defective in ME/CFS, and if DecodeME results are to be believed, might be more on the brain than the immune side of things.

A quick search suggests not much is known about what happens in the brain after immune signals, such as interferons, are bound. Anyone who knows more?

 

[jnmaciuch]

Yes, so these are probably too important to be defective in ME/CFS; otherwise, we would see other abnormalities in patients.

So it should likely be something more specific to this pathway that is defective in ME/CFS, and if DecodeME results are to be believed, might be more on the brain than the immune side of things.

Yes, there probably isn't a fundamental structural issue that causes interferon signaling to far outpace its normal negative regulatory mechanisms in a way that leads to fatal tissue damage in interferonopathies.

But what we tend to see in chronic diseases is that the symptom-mediating pathways are operating "appropriately," just reacting to an inappropriate self-perpetuating trigger. In which case, what we see from GWAS is not necessarily the genes that are actively involved in mediating the symptoms of the illness itself, but the ones which predispose someone to fall into an unfortunate state to begin with.

Take HLA in MS, for example. There's an extremely strong association, but if HLA signaling were involved in actively maintaining the tissue damage and symptoms of MS, we should see people going into complete remission with T cell depletion therapies. So the much more likely explanation is that a certain HLA haplotype just strongly predisposes someone to fall into the unfortunate series of events that actually maintain the disease. Same with C1q for lupus. There may be some genes that come up in a GWAS that are both predisposing and maintaining, but it's much more likely that GWAS hits are peripheral to the mechanism rather than constituting the mechanism itself.

A quick search suggests not much is known about what happens in the brain after immune signals, such as interferons, are bound. Anyone who knows more?

There have been a couple papers showing that CXCL10 changes neuron excitability in different neuron populations (I discussed one paper here). There have also been other papers that identified specific neuron populations that respond to signals other than interferon (this paper and this paper, for example).

But besides the changes in neuron excitability I don't think much more is known, probably because the tools we have to investigate are quite limited. You can use a mouse model to confirm whether a certain neuron population is required to mediate sickness behavior, or generate a hypothesis about a specific brain region that might be involved and show some (very noisy, usually) differences in brain activity (like in this study of people on interferon therapy). Beyond that there's not really much you can do.

 

[poetinsf]

But that begs the question of why we don't see clear immune dysfunction elsewhere in ME/CFS and why DecodeME didn't signal out one of these cytokines or receptors.

That could be explained by the sensitivity to immune signals rather than immune signals themselves. If your fire alarm is overly sensitive, it would go off by just a hint of smoke molecules in the air rather than an actual fire. My theory is that something, probably in the brain, got hypersensitized to inflammatory signal. And there always will be some inflammatory signal in the body somewhere as long as you are alive. You'd soon die without it.