Comparing acute sickness symptoms with ME/CFS

I thought it might be worthwhile to have a discussion comparing and contrasting the symptoms of an acute infection (a week or two of flu, cold, staph, etc.) and ME/CFS. Viral persistence is often mentioned in discussions of mechanism theories. I personally think there's a good chance ME/CFS is literally a "long" infection. Maybe something is wrong with the immune system that allowed it to become "long", but just in terms of symptoms, simple infection might be able to mostly explain those.

This paper did something like this comparing and contrasting:

A narrative review on the similarities and dissimilarities between [ME/CFS] and sickness behavior, 2013, Morris et al

Here's their table comparing the symptoms of each: Link

There are a lot of similarities in symptoms:

I think one of the biggest questions to drill down on is, does PEM occur in acute illness in otherwise healthy people? If it does, I think that'd be strong evidence that the two conditions are related (and evidence of what PEM is). In that case, the difference between the two would be some unknown factor that allowed the pathogen to hide away somewhere.

If acute illness doesn't include PEM, that doesn't necessarily mean ME/CFS is not pathogen persistence. In that case, maybe the reason an infection becomes a "long" infection is precisely because of PEM: someone with ME/CFS's immune system gets all wonky after exertion, which allows the pathogen to spread and take root somewhere, and this doesn't occur in healthy people because exertion doesn't mess with their immune system.

The paper says:

I mean, most everyone has been sick, and we don't really think of PEM as being a part of it. But I think there are potential explanations for that.

First, the short duration of acute infections. It's only a week or two, where someone's energy levels and other symptoms are already rapidly changing over only a few days. If someone went for a run while sick, then got even worse two days later, I can see how they might think their illness just got a bit worse, as illnesses sometimes do, and it had no connection to the running. They don't have the advantage (ha) that people with ME/CFS do, where they experience PEM over and over and over, and can start to detect a pattern of exertion causing it. From what I recall, it took me quite a long time to realize fatigue randomly getting much worse was tied to something like a long walk two days before. Because why would I ever think that when I've been told my whole life that exercise can only be healthy.

Second, maybe they do make the connection that exercise caused them to get worse after a day or two, but they don't think of it as "PEM". Maybe they think of it as "I went for a run, and that weakened my immune system, so the infection got worse." The symptoms might be similar, but doesn't seem obviously to be the same as PEM, because in acute infection the "effect" is "worse infection", with its expected increase in fatigue and other symptoms, while in ME/CFS, the "effect" is "worse fatigue and other symptoms". The lack of infection in ME/CFS to explain things might get in the way of seeing the similarities in symptoms.

 

Data that would be useful for this would be how bed rest affects the duration/severity of a sickness. That's the commonly prescribed advice from our doctors and parents. "Rest so that the body can heal." If this advice is based on a real effect, I think that's basically evidence of PEM: if you get up and exercise, your sickness will get worse.

I found an observational study from 1936 (!) that looked at the effect of delaying bed rest on acute illness: The common cold and the effect of rest in bed on its course, 1936, LeBlanc et al

They compared nurses hospitalized for "common cold" that reported that they started bed rest within 30 hours after the start of their infection symptoms, with those that waited longer.

Being an observational study, there are of course confounders that make it difficult to infer causality, some of which they go into:

I don't see how the limitations they list could explain illness being so much worse in the delayed group. It seems they would explain the opposite. But I'm sure there might be reasons people who waited longer to rest got sicker. One possibility is maybe people who are unhealthy and prone to severe complications are unhealthy because they are worse off socioeconomically, and thus would work longer to not miss out on the money. These are all nurses, so I assume their incomes are similar, but maybe some have wealthier family which allows them better healthcare and diet, and less need to work through a sickness.


Nevertheless, the outcomes at least support the possibility that not resting during a cold leads to worse illness.

Non-delayed group entered the hospital and commenced bed rest an average of 18.8 hours after onset. Delayed group entered hospital 138 hours after onset. They measured days of fever, days in hospital, days off duty, total length of illness, loss of weight, and number of nurses with complications. All were worse in delayed group, although fever and weight loss were not significant. Strikingly, the delayed group had over five times the prevalence of complications.

I'll see if there are any more bed rest studies. I assume an RCT wouldn't be approved as ethical, but who knows.

 

My first PEM episode was hard to distinguish from the initial phase of a mild infection, where the fever hasn't yet started but you can feel that you're sick.

In September I probably had covid and it took a few days to realize it was an infection and not just ME/CFS. when the infection / immune response peaks and fever appears, it's clearly distinguishable from ME/CFS, but before that it can pass for ME/CFS.

 

What exactly makes it distinguishable? Just the fever or something more?

 

Similar for me, I can only be sure PEM isn't a virus when it stops at sore throat, swollen glands, and a slightly runny nose. It never causes sneezing, coughing, sinus pain or earache, and while PEM sore throat's annoying, it isn't as painful as some colds.

But while it seems plausible that some of the 'bleuurgh' in PEM is caused by the same immune factors as the response to a respiratory virus, I'd argue it's important to regard it as different for now. If researchers make assumptions, they could completely miss the most important clue.

 

The fever and the symptom profile and intensity. It just feels different. I wonder if the "feels like the beginning of an infection" is a clue that the innate immune system is a key player in ME/CFS.

 

Surprisingly, I found an RCT of bed rest for tuberculosis. Also an old paper.

Bed rest in the treatment of pulmonary tuberculosis, 1956, Tyrrell et al

They admitted every other patient who presented with TB to a hospital for 3 to 6 months bed rest, and instructed the rest to continue normal exercise.

The conclusion was basically they found no differences in outcomes.

 

I experienced delayed muscle weakness/fatigue in my legs from Covid infection after going out for my regular power walk after I felt recovered. It did not affect my cognitive energy. It was not the same experience as ME/CFS delayed full body toxic PEM.

 

I should also mention that in early 2000 when HHV6 and EBV was reactivated I had to rest for 2.5 months. I went out for a short run after I felt recovered and the next day the delayed PEM completely changed my baseline for good. This was when OI set in and I've had it ever since.

 

Convalescence for TB was the norm back in the day;
see film 'Twice round the daffodils'

 

Another two that found no benefit from bed rest in tuberculosis:

Is cavity closure in pulmonary tuberculosis influenced by bed-rest?, 1960, Wynn-Williams et al

I can't access this one, but the article below it describes the results:

Late Results of Modified Bed Rest in Active Uncomplicated Minimal Pulmonary Tuberculosis, 1953, Mitchell

Bed rest in tuberculosis

An RCT of bed rest in infectious mononucleosis also found no benefit:

INFECTIOUS MONONUCLEOSIS. 2. RELATION OF BED REST AND ACTIVITY TO PROGNOSI, 1964, Dalrymple

No benefit found in a review focused on rheumatic fever:

Role of bed rest in treatment of rheumatic fever; review of literature and survey of current opinions, 1957, Duman et al

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I think there is a possibility that bed rest has no benefit if the patient doesn't desire to rest. Maybe only if someone is very tired from an infection and is forced to exercise/work will they have a worse outcome.

For example, the mono study above said the non-bed rest group did activity "as desired", so maybe their body didn't require rest to heal.

 

Yes, I was wondering why I'm seeing so many papers talking about bed rest in TB, but almost none in other infections.

 

Four references in this study about exercise worsening health during an acute sickness, three of which are in rats.

Acute Infection: Metabolic Responses, Effects on Performance, Interaction with Exercise, and Myocarditis, Friman et Ilbäck, 1998 (thread)

 

There are some researchers, like John Chia and Maureen Hanson, that think chronic enterovirus infection plays a role in ME/CFS, so research on poliovirus, an enterovirus, could be useful.

Looking at the reference from the study above for exercise worsening polio. It's a book available to borrow on Internet Archive:

Exercise Immunology by Bente Klarlund Pedersen, 1997

A lot of this looks like it could be interesting in the table of contents, but I'm just looking at chapter 9, Exercise and Infection.


On strenuous exercise during poliovirus infection leading to increased paralysis:

In regards to hepatitis infections, exercise has not been found to be harmful.

A couple mice studies found exercise caused increased mortality or myocardial damage from Coxsackie B. There was also some discussion about an unexplained cluster of increased deaths in orienteers; a very speculative claim was made about this being due to exercise worsening Chlamydia pneumonia infections.

A few other animal studies looked at different infections, including type I pneumococcus, Toxoplasma gondii, influenza, Salmonella typhimurium, Streptococcus pneumoniae and Francisella tularensis. Of these, exhaustive, but not moderate, exercise in influenza increased lethality, and exercise after infection with Streptococcus pneumoniae or Francisella tularensis increased lethality, but the rest of the infections weren't worsened by exercise.

The book talks about increased rate of upper respiratory tract infections in competitive athletes, but this is still a very contested claim. The following paper is a debate between those who do and don't think exercise increases rate of URTI in athletes:
Can exercise affect immune function to increase susceptibility to infection?, 2020, Simpson et al

This could be interesting:

In the same vein, a much earlier review on exercise and polio talked about the observation that trauma or exercise to a certain body part during infection seemed to make it more likely for that body part to become paralyzed. Intros for those sections:

Paralytic Poliomyelitis, Russell, 1949

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Now I'm wondering if there might be any data on physical activity during acute COVID infections, and whether it is associated with increased incidence or severity of long COVID.

 

There's also the apparent—and curious—link between motor neurone disease and very high levels of activity.

MND may not be infection-associated, but it seems to affect people who're particularly fit and active. Much the same has been said about ME/CFS, though of course it's a totally different beast. But ME/CFS is much more common than MND, so any link ought to be easier to study as part of a prospective project.

 

Thanks, I'd never heard this. Found this BBC article from 2021:

Motor neurone disease: Intense exercise increases risk, say scientists

Here's the study, which appears to be specifically about ALS, a type of motor neuron disease:
Physical exercise is a risk factor for amyotrophic lateral sclerosis: Convergent evidence from Mendelian randomisation, transcriptomics and risk genotypes, 2021, Julian et al

 

You can put a flu/cold patients on 2-day CPET test and see if the performance decreases on the second day. No reason why you can't. It may need to be controlled for the worsening of infection on the second day though. Perhaps you can do that by comparing the viral load, etc. People who are sick with typical flu/cold should do fine with 10-100W in 10 minutes, I'd think.

Or, you can ask Michael Jordan. He once played full 60 minutes during a championship game with flu.
In my personal experience, moderate exercise during flu/cold, when I can muster, does not make the symptoms worse the next day.

I don't know what you are trying to get to. We are talking whether acute infection in healthy people includes PEM, right? It's a separate topic whether ME/CFS PEM is caused by viral persistence. It isn't, if you ask me. Viral load change is organic and has very wide variance. PEM, on the other hand, is often extremely precise in moderate/severe ME/CFS cases. It's very unlikely higher viral loads caused by exercise is the cause of PEM.

In any event, you should be able to test that hypothesis by checking the viral load before/after exercise. But then, the test is unlikely turn up anything if the patient was negative for virus to begin with.

[edit: added the last paragraph]

 

I think researchers may consider this kind of testing to be unethical. I'm guessing because the tested hypothesis would include increased risk of death from infection, among other things. From the Friman study a few posts up:

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Basically, it seems like the most obvious hypothesis is ME/CFS is long infection, and that PEM is viral load increasing due to exertion, and I'm astounded that I haven't seen this PEM idea mentioned even a single time in research. (Edit: Not that I've searched that deeply. If anyone has seen something like this, I'd love to know.)

The three main reasons I think so, which I wrote in another thread:

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The connection is that if exercise causes increased viral load during acute infection, and if it is found that ME/CFS is at least partly a "long" infection, the obvious question is if exercise also causes increased viral load during ME/CFS, which could explain PEM.

Yes, there are differences. I know they very well could be totally unrelated, and viruses be totally uninvolved. But I'm sure there could be ways of explaining the differences as well under this hypothesis. For example, maybe it's because during acute infection, everything is very uncontrolled. The virus enters through some random route with a variable initial viral load, and the body has very little "memory" of this pathogen. In contrast, in ME/CFS, maybe the virus is kept in a little highly controlled zone in a tissue, and the method and degree of "escape" or proliferation of the virus is very consistent after exercise. The adaptive immune system is constantly seeing it, so it can respond very predictably every time.

(Edit: I think I misunderstood what you were saying here and answered about the delay always taking the same amount of time in ME/CFS and not in acute infection. But in terms of symptoms flipping on like a light switch after a delay, see the next text and the edit added at the end.)

You already saw me say this, but for anyone else, I previously found two anecdotes of a symptoms "flipping on" like a light switch some time after a COVID infection, kind of like how some describe PEM. Yes, it's only two people, but still may point to more of a connection between the conditions.

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Yeah, that's one thing I'm hoping for, but if viruses are involved, it will require technology to detect them in the first place. It seems like they're gradually getting better at detecting the COVID virus persisting, so maybe eventually they'll test viral levels before and after exercise in long COVID ME/CFS, probably long before something similar is done in pre-COVID ME/CFS.

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Edit: I will say, for those whose symptoms just "switch on" after some time, it is harder to compare that to the gradual increase of viral load. I may be biased by my own symptoms, where it feels like a very gradual increase in symptoms over a couple days. I don't know exactly how or if a sudden symptom increase could be explained by viruses.

Maybe something like at first after exercise the virus increases in a "safe zone" of a tissue where it doesn't cause symptoms. But the moment it reaches levels where it escapes, one or two days later, maybe into the blood stream, the symptoms start.

But I agree it makes the hypothesis harder.

 

I looked at the study to see what it says about this "mental stress" and it's just two people (participants 34 and 38) that took >250 mile drives during the preparalytic stage of polio. It's not totally clear, but it looks like one died, and it doesn't give details about the other. I think maybe he wrote the wrong participant number, because there is no data for No. 34 in the table. I don't think much can be concluded from this about mental stress.

But here's the main data for the physical activity causing worse outcomes:


Here are the degrees of physical activity:

All 5 that had a day during the preparalytic stage doing level 3 activity died. Out of the 10 that did bed rest every day, 6 had no paralysis, and all 10 survived.

 

I was very athletic before my ME/CFS onset. I did strenuous workouts regularly, HIIT and strength training mostly. These were really hard workouts, not for untrained or moderately trained people. Since this was a lifestyle for me, whenever I caught a cold, I kept doing my workouts like nothing happened. Colds are not so bad (not bad enough to stop you from working out) and I never noticed any PEM-like experience after my workouts. Maybe some mild discomfort during the workout due to the cold symptoms but not afterwards.

I never tried to do a workout with influenza, influenza is just too horrible with the very high fever. Even purely existing feels terrible. Getting off the couch is a challenge.

I tried to work out with mono/glandular fever, which triggered my ME/CFS, but gave up quickly as I felt way too ill to begin with. I don't remember any PEM-like experience during the infection but again, I felt really ill to begin with.