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Post Exertion Infection

Hip

Senior Member
Messages
17,824
The vagus nerve is not the only route.

Yes, there are four known routes through which inflammatory cytokines deriving from an infection in the body can trigger sickness behavior in the brain. If you wanted to stop all sickness behavior during an infection, I think you would have to block all four pathways.



One thing I can say for sure though is that it is not at all like experiencing PEM.

What would you say were the differences between your PEM symptoms and sickness behavior symptoms, and what if any were the similarities? This question is also for anyone else interested in answering it.

Just to help you, here is a list of symptoms that appear in sickness behavior:

Sickness behavior symptoms:
Fever
Malaise (the feeling you get when you come down with an infection like the flu)
Loss of appetite
Lethargy
Fatigue
Sleepiness
Decreased locomotor activity (general movement from place to place)
Altered sleep-wake patterns (circadian rhythm disruptions)
Cognitive impairment (brain fog)
Impairment of learning and memory
Low mood / depression
Loss of libido
Anhedonia
Anxiety
Irritability
Decreased social interaction
Increased hyperalgesia (more aches and pains)
Reduction in grooming (less keen on performing the normal daily ablutions)

Here is the CCC definition of PEM:
Post-Exertional Malaise and/or Fatigue: There is an inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, post exertional malaise and/or fatigue and/or pain and a tendency for other associated symptoms within the patient’s cluster of symptoms to worsen. There is a pathologically slow recovery period usually 24 hours or longer.



at this point I can say that fatigue and lethargy are a result of poor energy production and a depletion of energy in every major bodily system.

You can of course speculate that poor energy production may be the cause of your fatigue and lethargy, and some researchers have indeed done this, hypothesizing that ME/CFS may be due to mitochondrial problems; but nobody knows for sure what is going on in ME/CFS. There are only theories at this stage.


One thing to be aware of, though, is that even in healthy people, the muscle fatigue they feel in their mind when they have significantly used their muscles is in part a psychological fatigue, and in part a real depletion of energy in the muscles.

I only recently became aware of this, but in there are in fact two mechanisms which lead to fatigue during normal muscle use: central fatigue and peripheral fatigue. I am talking about healthy people here.

Central fatigue is the psychological feeling of fatigue generated in the brain, and contrasts to peripheral fatigue, which is defined as the physical running out of energy in the muscles, or the running out of other factors needed to make the muscles work. For a fuller description of the two types of fatigue, see here: Muscle weakness - Wikipedia

One study I read on this subject discovered that when you use your muscles a lot, you get a serotonin build-up around the motor neurons in your brain (the motor neurons that are activating your muscles). The more you use the muscles, the more this serotonin engulfs your motor neurons. This flood of serotonin then creates a psychological feeling of muscle fatigue. This is central fatigue.

This central fatigue is not a real loss of physical muscle energy, but a feeling created in your brain that the muscles are tired. The idea of deliberately creating this psychological feeling of muscle fatigue is presumably to protect you from overusing your muscles, which could lead to muscle damage.

So you see that even in healthy people, a deliberately created psychological feeling of muscle fatigue is used to make sure you don't overwork yourself. Just as in sickness behavior, a deliberately created feeling of overall fatigue is created so that you conserve energy.

I mention this just to show that it is not so straightforward to work out whether the feeling of fatigue you have comes from a physical depletion of energy, or a feeling of psychological fatigue imposed on you by your own brain.
 
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Hip

Senior Member
Messages
17,824
And this fits with established research showing failed 2-day CPET tests how? The failed 2-day CPET is evidence of clear physiological abnormality, not a sickness behavior-induced psychological state.

I agree that it is clear evidence of a physiological abnormality, and that it cannot be explained by sickness behavior. In fact I mentioned this in a previous discussion: see this post.

I am not proposing that the sickness behavior pathway can explain all aspects of ME/CFS, but it may explain many, and so I think warrants exploration. That's if you are the exploratory type. I like exploring all avenues.



Neither daughter nor I have, or have every had, abnormal IL-6. We are not alone in that. As far as I know, elevated IL-6 is not a universal finding in ME/CFS.

Yes, post-exercise IL-6 levels have been shown to be normal in ME/CFS, and this has lead some researchers to conclude that IL-6 cannot be the cause of PEM. However, I think that view is somewhat shortsighted, especially in the light of the sickness behavior perspective on ME/CFS.

Note that the cytokine IL-6 is released in copious amounts from the muscles during exercise, and remains high in the blood for days after. That's why it looks like a good candidate to explain how exercise might cause PEM.

IL-6 is also a sickness behavior cytokine, which worsens sickness behavior; even when experimentally injected into healthy people, IL-6 causes fatigue and cognitive impairment.

I proposed an increased IL-6 sensitivity theory of PEM (outlined at the bottom of this post), which may explain how IL-6 can cause PEM. I suggest that the brain during sickness behavior may become very sensitive to even the normal post-exercise levels of IL-6, and thereby trigger many aspects of PEM.



Additionally, many of us do not suffer the psychological symptoms of depression, lack of motivation, and so on associated with sickness behavior as part of our ME/CFS or even just during PEM. That throws another wrench in the theory of sickness behavior = ME/CFS or even sickness behavior = PEM.

I don't see how that throws a wrench in the theory of sickness behavior. Rather the opposite, what you say actually supports the sickness behavior theory of ME/CFS.

This is because first of all, I should think that the complete list of sickness behavior symptoms are not all going to be present in every person that gets sickness behavior. There will be individual variations, just like you don't find the complete list of ME/CFS symptoms present in every ME/CFS patient. There are four known metabolic pathways of sickness behavior, and the symptoms evoked by each pathway are slightly different.

Secondly, the fact that a PR poll recently conducted on this forum found that around one-third of ME/CFS patients suffer comorbid depression, and the fact that many ME/CFS patients suffer comorbid anxiety, both of which are sickness behavior symptoms, actually adds weight behind the idea that ME/CFS involves sickness behavior. Psychiatric comorbidities have in some studies been found in two-thirds of patients, if I recall correctly, meaning that psychiatric comorbidities like depression and anxiety are probably the rule, not the exception in ME/CFS.
 
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Mij

Messages
2,353
I went out for walk feeling and thinking I was able to do it, but after 5 minutes my legs started to tremble and I seriously thought they would buckle. I actually had ENERGY but my legs did not have the strength, I couldn't tell whether it was fatigue or weakness. I turned around immediately and came back home. I was fine once I stopped walking.

My symptoms in the last 2 months, swollen glands, very low wbc, vertigo, extreme fatigue at time, SLEEPINESS, just can't break out of it at times, little appetite which is not common for me because I have a healthy appetite, no fever but it's difficult to know because I'm experiencing hot flashes and severe night sweats. I'm a mess but I haven't experienced any PEM for many months. It is a totally different experience.
 

Hip

Senior Member
Messages
17,824
I went out for walk feeling and thinking I was able to do it, but after 5 minutes my legs started to tremble and I seriously thought they would buckle.

Just a thought, Mij, but do you suffer from anxiety symptoms by any chance? One of the things that can happen in anxiety disorder is that your legs seemingly feel like they are going buckle and collapse. See for example: How Anxiety Can Make Your Legs Feel Like Jelly
 
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I mention this just to show that it is not so straightforward to work out whether the feeling of fatigue you have comes from a physical depletion of energy, or a feeling of psychological fatigue imposed on you by your own brain.

Agreed, this is tough to differentiate and there might be different types of fatigue mechanisms underlying the physical and the mental parts of the illness. I also agree that the brain probably contributes to the feeling of fatigue in order to prevent the body from damaging itself. For example, as I mentioned earlier, I know my body is depleted of energy when I feel my heart working harder at rest (I presume because I require more oxygen to do the same amount of work). However, the feeling of a rapid heart rate itself does not stop me from further exerting myself, but rather the feeling of fatigue that accompanies it, thus preventing me from making my heart work beyond its capacity in a self-protective way.
 

Mij

Messages
2,353
Just a thought, Mij, but do you suffer from anxiety symptoms by any chance? One of the things that can happen in anxiety disorder is that your legs seemingly feel like they are going buckle and collapse. See for example: How Anxiety Can Make Your Legs Feel Like Jelly

My legs were not jelly, they were stiff and would not move forward. A virologist told me years ago that stiffness/weakness is consistent with viral infections.
 

Hip

Senior Member
Messages
17,824
My legs were not jelly, they were stiff and would not move forward. A virologist told me years ago that stiffness/weakness is consistent with viral infections.

These symptoms of stiff, buckling legs, and leg weakness, may be from some comorbid condition you have.

I also have leg and pelvis symptoms: my pelvis feels a bit lax, as if my legs are not properly fastened into my hips. This symptom appeared soon after I caught my ME/CFS virus, but I don't think it is part of ME/CFS. It may be very mild polymyositis, but I am not really sure. Could also be some pelvic ligament laxity.
 

cmt12

Senior Member
Messages
166
I've been in a continuous state of muscle contractions from the top of my head to my feet and down both arms for over 6 years now. I can help shed light on this because I'm quite sure I'm the only one here who is fully symptomatic.

If you google around, you'll find there is an association of cfsme with headaches, TMJ (jaw), neck and back pain, tightness in chest (shortness of breath), tight hips, weaknesses in arms and legs, and hand/foot pain.

This is because the mechanism at play here involves not only the immune system, CNS, digestive, and endocrine systems but absolutely the muscular system as well. Imagine tensing your muscles all day and then going to the gym and lifting weights and then it makes sense why we experience PEM.

Hip I do agree with what you're saying about fatigue occurring in more than one way but I'm confident that the crashing, fluctuating fatigue is a direct result of muscular contractions that are occurring likely below the surface of your awareness.
 

Mij

Messages
2,353
I'm going to back to the original post of this thread and whether we have post exertional infection. Well, sometimes I do but it is definitely not PEM. I do not have delayed PEM from infections, the weakness/fatigue presents itself immediately upon exertion when I have a viral infection.
 
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15,786
I have been working on a theory for some while now that the flu-like PEM symptoms which some ME/CFS patients experience after physical exertion are due to an increase in sickness behavior.
Perhaps partially, but certainly not entirely. A typical sickness response doesn't include several of the PEM symptoms, including swollen lymph nodes, which would suggest it's primarily a different immune response. The sickness response could certainly be triggered as part of the immune response (and probably is), but it doesn't account for all PEM symptoms by itself.

And like others have reported, I don't feel depressed or anxious, even during PEM. Mostly I feel like crap, unable to think clearly, and rather annoyed about being unable to sit up long enough to do anything useful or enjoyable. So perhaps that would suggest we are not having a substantial sickness response.

PS - I also dislike the "sickness behavior" terminology, even though I understand it's a 100% biological reaction to illness. The problem is that many people (uncluding psychobabblers) are not capable of understanding that distinction. Hence I opt to use "sickness response", though "sickness reflex" might be even better, come to think of it.
 
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Messages
15,786
Just a thought, Mij, but do you suffer from anxiety symptoms by any chance? One of the things that can happen in anxiety disorder is that your legs seemingly feel like they are going buckle and collapse. See for example: How Anxiety Can Make Your Legs Feel Like Jelly
Ah yes, ye ol' "orthostatic anxiety" :p When someone is not feeling anxious, I think it's safe to assume that the symptoms of OI are in fact OI, especially for a patient with a disease where nearly everyone has OI.
 
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Hip

Senior Member
Messages
17,824
Perhaps partially, but certainly not entirely. A typical sickness response doesn't include several of the PEM symptoms, including swollen lymph nodes, which would suggest it's primarily a different immune response. The sickness response could certainly be triggered as part of the immune response (and probably is), but it doesn't account for all PEM symptoms by itself.

Can you suggest other PEM symptoms that might not be encompassed by sickness behavior? I am trying to work through this theory of IL-6-triggered increases in sickness behavior being responsible for many of the PEM symptoms, so any criticisms or ideas would be welcome.

Swollen lymph nodes probably cannot be explained by the brain's built-in sickness behavior response, but they might perhaps be explained by an increase in pro-inflammatory cytokines levels, such as the increase in IL-6 blood levels that occurs after exercise. A swelling of the lymph nodes is presumably a sign of an increased inflammatory response in these lymph nodes, and pro-inflammatory cytokines are the controllers of inflammatory responses.

Having said that, the increased inflammatory response in the lymph nodes could also involve some type of viral reactivation, which would fuel the inflammation. There does not seem be much in way of studies looking at possible viral reactivation during PEM.



Mostly I feel like crap, unable to think clearly, and rather annoyed about being unable to sit up long enough to do anything useful or enjoyable.

Could you articulate a bit more what this "feeling like crap" state involves. Is that just a general feeling of malaise, like you would feel if you were coming down with a bug? If so, then that is a sickness behavior symptom.

The not being able to think clearly is also a sickness behavior symptom.



I think it's safe to assume that the symptoms of OI are in fact OI,

@Mij's leg symptoms are: stiff legs, buckling legs, and weak legs. What category of OI would you say these symptom come from, since you are saying they are due to OI?
 
Messages
15,786
Can you suggest other PEM symptoms that might not be encompassed by sickness behavior? I am trying to work through this theory of IL-6-triggered increases in sickness behavior being responsible for many of the PEM symptoms, so any criticisms or ideas would be welcome.
Ataxia, aggravated OI, increased heart rate when doing nothing and rising much faster than usual with any activities, twitching of any muscles which were overused in the process of provoking PEM, swollen lymph nodes ... probably others as well.

Whereas I never get anxiety, depression, loss of appetite, sleepiness, fever, or a reduction in grooming with PEM.
Could you articulate a bit more what this "feeling like crap" state involves. Is that just a general feeling of malaise, like you would feel if you were coming down with a bug? If so, then that is a sickness behavior symptom.
It's a combination of the above symptoms, in addition to body-wide pain, cognitive dysfunction, and often a headache as well.
@Mij's leg symptoms are: stiff legs, buckling legs, and weak legs. What category of OI would you say these symptom come from, since you are saying they are due to OI?
Hypotension and/or low pulse pressure are present when I have those symptoms, and it makes sense that difficulties with circulation will cause muscular difficulties. Currently I'm having a flare-up of OI, and one of the problems is that my legs are getting very shaky and on the verge of buckling if I stand for longer than a minute. Whereas when I'm not having a flare, the stiff or heavy legs seem like a more common problem. They sure as hell aren't an anxiety problem :)
 

Mij

Messages
2,353
@Mij's leg symptoms are: stiff legs, buckling legs, and weak legs. What category of OI would you say these symptom come from, since you are saying they are due to OI?

I never said that the symptoms you're describing are from OI, they are from a viral infection.
I have never been properly diagnosed with OI, my symptoms suggest that I may have a form of OI/autonomic disorder. For example, lifting my arms above my head, looking up, down or side to side makes me feel very unwell- I need to lie down to recover. I also experience chest discomfort when I'm upright or if my legs are dangling for too long. I can not tolerate high temperatures.

PEM symptoms affect both mental and physical symptoms with me, it comes on 16-18hrs after going over my energy envelope. I can feel completely fine but when it starts I start to feel shaky, unbalanced, tired legs/ arms, dehydrated, hot and unable to deal with simple tasks. It's a complete body and brain distress that takes at least 24hrs to resolve,
Yeas ago i used to get flu-like symptoms with PEM but no longer.


I don't experience anxiety or depression.
 

Hip

Senior Member
Messages
17,824
Ataxia, aggravated OI, increased heart rate when doing nothing and rising much faster than usual with any activities, twitching of any muscles which were overused in the process of provoking PEM, swollen lymph nodes ... probably others as well.

The ICC definition of ME/CFS talks more about these type of symptoms occurring in PME/PENE. The ICC mentions increased heart rate during PEM, abormalities in walking gait (which can be a sign of ataxia), insufficient blood pressure on exertion, a reduction in VO2 max, which presumably indicates that energy metabolism is under par, and ion transport problems (which if they involves magnesium might explain your muscle twitches, as these can be caused by low magnesium — just a thought).

I'd love to come up with an explanation that could link the appearance / exacerbation of these symptoms with some of the metabolic changes that occur during exercise. There are a number of cytokines and other immune factors released during exercise, which could conceivably be playing a role in these symptoms. In addition, there might be factors in the mitochondrial energy production process that may give rise to these symptoms, such as the reduction in V02 max after exercise.
 

xrunner

Senior Member
Messages
843
Location
Surrey
I can not help but think some of us suffer from post exertion infection.
This which was a major symptom for me. I struggled with it for a long time and never found a convincing explanation for it.

Often times exertion causes flu-like symptoms
The exertion followed by flu-like symptoms went away after treating Lyme.
In the past couple of years I can't recall ever happening again. Now If I overexert I get an excess of lactic acid, muscle soreness, tiredness and, if I really push it, dizziness but no more flu-like symptoms.

If an infection is in progress it usually worsens (especially in the cold season).
Unfortunately this hasn't gone away completely. If I get a cold and rest, it's usually over in three four days.
However if I can't rest, which has been the case in recent times, it either develops into a chest infection requiring abx or in the best of cases it takes at least a week or even two to fully recover.
 

Hip

Senior Member
Messages
17,824
One piece of evidence (which I just remembered now) that does suggest that physical exercise can significantly worsen virus infection, and thereby worsen ME/CFS symptoms, is Dr Chia's study using a course of intravenous interferon to treat his enterovirus-associated ME/CFS patients. Some of these patients achieved full remission from their ME/CFS after this interferon treatment, and this remission lasted as long as 14 months in one case. There is an article about Chia's interferon treatment here.

However, Dr Chia noted that the main factor that caused these patients to relapse back into ME/CFS was significant physical exercise. In the case of Dr Chia's son who had ME/CFS, I believe he was doing fine, and was in full remission after his interferon treatment, until he went on a hiking trip for a week, where the increased level of physical exercise caused a relapse back into ME/CFS. And there was a similar pattern to Dr Chia's other interferon patients: they were in remission, but relapsed as a result of doing exercise.

So this seems to show that in enterovirus infections at least, even if these infections are all but eliminated with interferon, they will come back again if you exercise to any significant degree.
 

Mij

Messages
2,353
So this seems to show that in enterovirus infections at least, even if these infections are all but eliminated with interferon, they will come back again if you exercise to any significant degree.

This I agree with. I had similar experiences many yrs ago with immune modulator.
 

Hip

Senior Member
Messages
17,824
POSSIBLE THEORY ON THE CAUSE OF THE VIRAL SYMPTOMS OF POST-EXERTIONAL MALAISE

An idea just occurred to me about what might be causing the viral reactivation symptoms some ME/CFS patients experience during PEM:

I found a link between the large amounts of IL-6 released during exercise, and a reduction of the intracellular immune response — a reduction which might explain the apparent viral reactivation symptoms that some ME/CFS patients experience during PEM.

It turns out that IL-6 up-regulates the STAT-3 pathway in cells, and STAT-3 inhibits and weakens the intracellular interferon immune response which helps keep intracellular viral infections in check.

Now since IL-6 released during exercise remains significantly elevated in the blood for days or even weeks after the exercise, this IL-6 will be constantly weakening your intracellular immune response by ramping up STAT-3 all during this period, so then under this state of weakened intracellular immunity, latent or non-cytolytic viruses in your cells may slowly start coming back to life and reactivating, creating these viral PEM symptoms.

There is no doubt that STAT-3 is increased through exercise. See these studies:

STAT3 signaling is activated in human skeletal muscle following acute resistance exercise
Exercise-induced activation of STAT3 signaling is increased with age
Impact of resistance exercise training on interleukin-6 and JAK/STAT in young men

So this IL-6 and STAT-3 mechanism may well explain how the flu-like or viral PEM symptoms arise.

This IL-6 and STAT-3 mechanism may also explain why there is often a delay hours, or even several days, before PEM appears after exercise: because once IL-6 and STAT-3 start weakening the intracellular immune response, it will presumably take a while before the reactivated viral infections inside the cells begin to build up steam, so to speak, and ramp up their replication and protein synthesis. So this may be why PEM can be delayed.

This STAT-3 mechanism may not explain all the symptoms of PEM; my guess is that many of the PEM symptoms may be mediated by an IL-6-triggered increase in brain inflammation and sickness behavior; but this IL-6 and STAT-3 pathway may well explain the flu-like viral reactivation symptoms that can appear in PEM.



The possible involvement of STAT-3 and STAT-1 in preventing viral clearance in ME/CFS has recently been discussed in this thread:
Are Infections Just a Trigger of ME/CFS, or an Ongoing Cause of ME/CFS? | Page 19
A brief summary of that discussion: a subset of ME/CFS patients appear to have a deficiency of STAT-1, and STAT-1 mediates the interferon intracellular immune response, so this STAT-1 deficiency may lead to weak intracellular immunity (note that STAT-1 and STAT-3 work in the opposite way: for interferon intracellular immunity, STAT-1 is the gas/accelerator pedal, and STAT-3 is the brake).



Any thoughts on this, @Jonathan Edwards?
 
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