Do the findings in LC suggest two distinct phases for ME/CFS onset?

A bit of speculation for discussion. I'm not sure if the broad concepts here are all old news and previously hashed out, but recent publications had me wondering.

Assuming for the moment both the following papers turn out to be validated findings: I wondered how the results presented for the ME cohort (WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in ME/CFS) might relate to the recent findings in Covid and potentially LC (Core mitochondrial genes are down-regulated during SARS-CoV-2).

ME Findings
In the ME cohort, the findings suggest there is an ER stress response failure in muscle cells, that leads to upregulation of WASF3, which impairs the ETC's CIII(2)-CIV supercomplex formation, resulting in downregulation of respiration, with various metabolic compensatory mechanisms. In particular OXPHOS was downregulated and glycolysis upregulated.

Covid Findings
In a Covid cohort, they found that SARS-CoV-2 specifically inhibited mitochondrial ETC-related proteins and mRNAs associated with related mitochondrial protein importing. In particular this seemed to involve the microRNA miR-2392.

LC = ME or predisposes to developing ME?
Perhaps these two findings just represent completely different viral mechanisms, that can lead to a similar spectrum of exertional intolerance/PEM. Maybe there are many different forms of viral-induced OXPHOS suppression that are virus-specific, leading to heterogeneity and confusion when we try and evaluate them.

Some people get a short-run fatiguing illness for some months, often termed postviral fatigue syndrome, which may have symptoms of ME/CFS. Others develop ME/CFS (proper) that continues or worsens for a few years before recovery, while others go on to have years/decades of ME/CFS of varying severity. Sometimes multiple family members are affected, including over generations.

In Covid there is some evidence for persistent SARS-CoV-2 proteins in only some patients.

So perhaps a 2-stage process?

Stage 1
1. An acute viral infection (eg SARS-CoV-2) is associated with down-regulation of mitochondrial function as part of host response to deny resources to the virus [1] +/- viral immune evasion strategy [2].
2. This can lead to a short term illness with ME/CFS-like features such as exertion intolerance and PEM (characterised as a "post-viral fatigue syndrome").
3. Some/many/most people recover over months (eg here) after the virus has been controlled and the mitochondria are repaired or replaced (possibly mis-attributing various factors such as supplements, "brain rewiring" or manly thoughts)

Stage 2
4. However in some (possibly with a genetic component), this downregulated mitochondrial and innate immune (metabolically re-wired) dysfunction favours loss of immune control and consequently partial/early reactivation of latent herpesviruses
5. This secondary early-type reactivation adds further immune-evasion pathways (eg via different microRNAs [3], and perhaps causing the ER stress response failure [4]) which adds even more mitochondrial impairments, potentially across more cell types (esp immune cells, eg NKs [5])
6. Mitophagy may be specifically subverted as part of the immune evasion, preventing mitochondrial replacement and keeping the mitochondria energetically impaired and favouring ongoing "active" viral latency.
7. The sum of these mitochondrial impairments might now be too much for the natural recovery seen in #2, with continued immune evasion allowing ongoing latent herpesvirus activity, feeding back.
8. Because the latent herpesvirus reactivation is merely early (non-replicating), antiviral agents that target viral replication are likely ineffective [6]

---
[1] Innate metabolic responses against viral infections (2022, Nature Metabolism)
[2] Cellular metabolism hijacked by viruses for immunoevasion: potential antiviral targets (2023, Frontiers in Immunology)
[3] Selective inhibition of miRNA processing by a herpesvirus-encoded miRNA (Nature, 2022)
[4] Endoplasmic reticulum stress signaling: the microRNA connection (2013, American Journal of Physiology-Cell Physiology)
[5] Human NK Cells and Herpesviruses: Mechanisms of Recognition, Response and Adaptation (2019, Frontiers in Microbiology)
[6] Antiviral agents for infectious mononucleosis (glandular fever) (2016, Cochrane)

 

Personally, just talking about my experience, I do feel like there are different stages, 2 more or. The acute or post-acute illness phase, followed by the chronification of this post-acute phase.

I've seen researchers express the same beliefs, in particular Carmen Scheibenbogen.

This makes Long-Covid research even more crucial since it might be essential to look at groups of the same illnesses durations, especially if there are more than 2 stages which, isn't widely possible in ME/CFS research, but with Long-Covid it's even possible to track people prior to illness onset to the exact day of their illness onset and further whilst having a lot of data for the same time frame, both in other patients as well as controls.

 

My experience is slightly different but shares some similarities to what @Trish states here. Two months after my first Covid infection I has a severe mononucleosis infection. After that I experienced months of post-viral illness, however I wasn't radicially resting and instead doing a very slow build up, something akin to GET, one could even say. I did experience things that can be considered akin to PEM, perhaps a form of extreme whole body deconditioning, but my baseline was improving throughout the whole time until I made a full recovery.

After my second Covid infection, it again took exactly 2 months for Long-Covid to begin from one day to the next. My GET approach didn't work this time, perhaps also because after my third Covid infection followied shortly after and it took two months until I had an onset of very severe ME/CFS from one day to the next (which can only be said retrospectively as I of course didn't meet the 6 month mark yet on day 1).

Perhaps I could have rested more, but the continuous viral onslaught and my body's reaction to it seems the main problem. Millions of other people didn't have this experience whilst still being active, tons of professional athletes do not develop ME/CFS after their Covid infection even though they continue to be extremely active. My activity wasn't different during the time where I fully recovered and where I developed ME/CFS.

In Long-Covid I've very commonly seen patients describe that they fully recovered from the acute infection only then a couple of weeks later to have an onset of Long-Covid from one day to the next. I would even say it applies to the majority of long-term Long-Covid patients. This refractory period is certainly very interesting. Unfortunately, this hasn't translated into research yet. Since the researchers have been very slow to pick these type of things up, I hope that in a few years we'll at least see some studies looking at Long-Covid where continuos onset during infection or sudden onset after recovery within weeks of infection is part of the study data. I certainly see the one group leans more towards the acute damage type of thing, i.e. cough or heart problems, whilst the other group seems to be closer to the ME/CFS and neurocognitive Long-Covid cluster.

For now it seems like we'll have to see more studies of the kind "this persons cough/shortness of breath hasn't resolved 4 weeks after the acute infection".

 

Yes, I think true convalescence may make a huge difference. I often wonder where we would be if we hadn't followed the " Bath activity sheets" in early illness with a very competitive child.

We need info on other factors too
Genetics / epigenetics
Existing viral / bacterial status

Given what we know about EBV ' s contributing factor to developing a wide variety of conditions , it may be interplay with viral infections / bacterial infections which contribute to the eventual development or recurrence

We lack basic epidemiology and studies over time which explore relapse . This lack of basics is truly staggering after decades .

Long COVID could be very useful if study design and ME comparison arms are well considered .

 

In my n=1 experience, I can date both my infections to the day

25 June 2001:

Unknown virus caused a severe reaction whilst on my lunch break at work. Had to be collected to be driven home. Eventually diagnosed PVFS (November 2001)

Extremely debilitated, unable to drive, enforced rest, even folding tumble dried laundry caused air hunger and I experienced what I recognise now as PEM. I had no choice other than to rest as I was so restricted.

7 months off work. Graduated return plus use of saved leave got me back to work but forced to reduce from 37 hours full time to 22 hours (5.5 hours x 4 days) a week.

Slow pacing and I returned to about 95% good health by 2005-6.

30 August 2013:

Blue lighted to hospital with sepsis, after UTI infection (E-coli) was resistant to the antibiotic given. Eventually diagnosed “cfs” by NHS
U.K. ME/CFS Biobank accepted me as an ME patient for studies.

Despite my prior PVFS experience I kept pushing, attended a CFS clinic, was trying to keep my job and it all fell apart. Occupational Health/ Employer interviews. Eventual dismissal from work. Followed by ESA application which ended up going to Tribunal. It was 2 years after the sepsis that it all the paperwork was done and I could actually rest properly.

I am now moderate at about 45-50% level of function.

ETA 2001 date of infection.

 

I'm in the relapsing remitting subgroup. I felt recovered after resting for 9 months during PVFS, but after less than a month of returning to work, I could no longer stand upright (not OI) or walk a straight line. Rested for the following 5.5 years and started feeling 90% improvement again only to start destroying my health by exercising and experiencing severe PEM.

 

Yes, my onset was gradual over months, and I don't know the trigger.

There was no illness, just able to do less and less over many months. Odd as it might sound now, it never occurred to me that I was ill. I didn't even feel unwell, I just had weakness, low energy, and slow recovery that were increasing at a barely perceptible rate.

No-one would have had reason to suggest convalescence. I probably wouldn't have been able to do it anyway, unless I'd had someone to diagnose ME and explain it to me. But I didn't, and it was years before I'd even heard of it.

 

I agree that there seem to be two stages. Many people report often fairly mild post-viral illness lasting on the order of six months. We don't have good data on this, but LC and mono, for example, suggest that recovering after months is more common than developing years-long ME. At this point, I don't think we have any strong evidence either way that PVFS and ME are two different stages with different pathologies or just different manifestations of the same core problem.

My own experience was a full year of mild impairment of energy output (especially on the second day) before I became properly ill after a particularly physically strenuous effort. And then after recovering by 98%, my second round started with what I'm certain was an infectious event, followed by a few months of worsening physical capacity.

 

Taking Immunovir for 3 weeks reactivated both HHV6 and EBV that caused a terrible relapse when I was feeling 90% after 10 yrs of M.E. I developed OI and lowered my baseline permanently.

 

i appreciate this is your, an quite a few good peoples onset experience. i have to say mine is totally different, one day fine after about a week post acute covid recovery, the next day completey bedridden with severe ME/CFS long covid