Hypothesis: inflammatory acid-base disruption underpins Long Covid 2023, van der Togt & Rossman

Sly Saint

Sly Saint

Senior Member (Voting Rights)
The mechanism of Long Covid (Post-Acute Sequelae of COVID-19; PASC) is currently unknown, with no validated diagnostics or therapeutics. SARS-CoV-2 can cause disseminated infections that result in multi-system tissue damage, dysregulated inflammation, and cellular metabolic disruptions.

The tissue damage and inflammation has been shown to impair microvascular circulation, resulting in hypoxia, which coupled with virally-induced metabolic reprogramming, increases cellular anaerobic respiration. Both acute and PASC patients show systemic dysregulation of multiple markers of the acid-base balance.

Based on these data, we hypothesize that the shift to anaerobic respiration causes an acid-base disruption that can affect every organ system and underpins the symptoms of PASC. This hypothesis can be tested by longitudinally evaluating acid-base markers in PASC patients and controls over the course of a month. If our hypothesis is correct, this could have significant implications for our understanding of PASC and our ability to develop effective diagnostic and therapeutic approaches.

https://www.frontiersin.org/articles/10.3389/fimmu.2023.1150105/full
 
Good on them for proposing ways of testing their hypothesis. There is some reporting of preliminary and sometimes questionable research findings in support of their hypothesis, but I can't recall the last paper I saw that didn't do that.

For what it is worth, I bought a home lactate meter and tested myself at different times of day and before and after brief exercise. I've written about it somewhere, here or on PR. I didn't find anything unusual.
 
Hutan said:
Good on them for proposing ways of testing their hypothesis. There is some reporting of preliminary and sometimes questionable research findings in support of their hypothesis, but I can't recall the last paper I saw that didn't do that.

For what it is worth, I bought a home lactate meter and tested myself at different times of day and before and after brief exercise. I've written about it somewhere, here or on PR. I didn't find anything unusual.
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What were your findings? Could you find any connection to how you felt and your levels?

I know most times when I have to go to the ER, my lactic acid is elevated on their panel. 2L of iv saline will usually bring it down to the high side of normal.
 
belbyr said:
What were your findings? Could you find any connection to how you felt and your levels?
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My lactate levels were normal, and the response to exercise in terms of lactate was normal. I didn't find anything unusual at all.

I have had an anion gap test twice. Both times it was highish. It's one of the issues with my lab testing that I have marked as being odd. It was a reason why I bought the lactate meter. Doctors have never commented, I think I raised it with my GP once and was told things just jump around a bit.

It was only just above range or high normal (18 and 15 with normal range 8-16), but with my albumin levels typically lowish both times it's perhaps a bit more unusual.

I see a symptom associated with a high anion gap is fatigue. Perhaps I should have followed up more.

I'd be interested to know if anyone else has done an anion gap test.
 
Sly Saint said:
The tissue damage and inflammation has been shown to impair microvascular circulation, resulting in hypoxia, which coupled with virally-induced metabolic reprogramming, increases cellular anaerobic respiration. Both acute and PASC patients show systemic dysregulation of multiple markers of the acid-base balance.

Based on these data, we hypothesize that the shift to anaerobic respiration causes an acid-base disruption that can affect every organ system and underpins the symptoms of PASC.
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This is the central claim in the abstract. But it doesn't add up.
If it was right
1. LongCovid patients would be frankly acidotic
2. to a degree that could cause symptoms.

Symptomatic acidosis isn't that easy to miss in hundreds of thousands of people, some at least of whom will have been investigated for whatever reason.
 
Jonathan Edwards said:
to a degree that could cause symptoms.
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Symptoms like this? Symptoms that sound a lot like a lot of Long Covid?

Common signs and symptoms of metabolic acidosis include:
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I agree that you'd think it would have been noticed and raised questions. But...
I haven't read this paper, or looked at the references that the authors cite to support their claim of
Abstract said:
PASC patients show systemic dysregulation of multiple markers of the acid-base balance.
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I'm going to up the water intake and add in some acidic fruits, can't hurt I figure. My second worse symptom is muscle pain that is worsened by weight lifting. Which also worsens my other symptoms (gastro, fatigue, tension headache, etc)
 
Maybe I am missing something, but why is this an hypothesis?
We've been taking ICPETs for a while know, both in research and clinical practice. There you get a great profile, not only of lactate byproduct, but the respiration levels itself.

But this is all a downstream effect anyway. Question is what is impairing cellular respiration in the first place.
 
In PASC patients, abnormally high blood lactate has been found after even mild exertion, suggesting metabolic dysfunction and muscle acidosis (7)
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Forum thread here for this Ref #7:
Decreased Fatty Acid Oxidation and Altered Lactate Production during Exercise in Patients with Post-acute COVID-19 Syndrome, 2022, de Boer et al

It found higher lactate in people with post-acute COVID-19, even with no co-morbidities, using catheters during CPET, including compared to people with metabolic syndrome.
 
Abstract said:
Both acute and PASC patients show systemic dysregulation of multiple markers of the acid-base balance.
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MY point is that this is flanneling. 'Systemic dysregulation' can mean anything and one finding might be the opposite of another. What they need for their idea to work is for patients to be measurably acidotic - if they are attributing symptoms to acidosis as they seem to imply.

Lactic acidaemia after exercise could explain why people with PASC find exercising hard but it isn't the same thing as feeling rubbish all the time because you are acidotic.

What bothers me is that this doesn't work as a thought-through physiological mechanism. When I see 'dysregulation' I usually find that things have not been thought through. It nearly always means 'oh, well there's evidence that things are all muddled up so that would fit'.

During my post Covid phases I have had repeated nausea but no way did I feel I had a metabolic acidosis. Lots of these symptoms occur in lots of situations but a clinical pathophysiological diagnosis is made on the way they all fit together and, when available, the right test result, not just a vaguely similar test result.

And as marcjr says, this would all be downstream of something and very likely something that produces the symptoms in its own right. The stuff about inflammation reducing microvascular circulation is basically wrong. The first thing you learn about inflammation is that the bit goes red and hot because there is an increase in microcirculation.
 
Completely agree with the above.

Coincidentally, I have bought a lactate meter too, as I wanted to see how much it increased with daily exertion as a possible signal for impending PEM, and also if it was up at unusual times. In particular if it might be up on waking. Similar to the authors who were talking about gentle stretching and motion to dissipate, I was curious about the "unrefreshing sleep" aspect. I would wake up with the feeling that lactate is up in my muscles, but that can clear after walking down the hallway to the bathroom and returning to bed for a bit. When I was much sicker, the feeling never left. Between then and now there has been a (highly variable) improvement where this feeling would take many hours to clear, through to 1-2 hours depending on how overall symptomatic I was.

As Jo says, I think this is all a downstream effect but not the explanation, or the target for curative treatment. Reading Hutan's comments, I'm not sure I will do many fingerpick stabs with this.

Anecdote: in second year biochem the class all went on a static bike and recorded our lactates before and after. I clustered with the elite athletes with a stonkingly high lactate level. We were mostly fit and sporting 20 year olds and I played team sports and rode my bike, but I was in no way an elite athlete. As I recall it was said that the trained athletes could tolerate the high levels and clear it efficiently after cessation, and that I was probably more fit than I realised or perhaps had some favourable genetics that were flattering.

Looking back now, and with the background that I had been spanked by EBV as an 11yo, I wonder whether this indicated I was less biochemically fit/trained or at least that my metabolism was impaired. Ie I shifted to anaerobic metabolism sooner, and so produced lactate to higher levels. Would have been interesting to have earlier time-point recordings. Perhaps my lactate clearance pathways were indeed more efficient, as if they had been trained, in order for me to adequately keep up with my peers at basic weekend sports level, with the metabolic handbrake on.
 
One thing I'm not sure about is the difference between lactate in peripheral blood from fingerpricks and lactate as measured by a catheter as per that study I linked to above. Is there any reason that the different sources/methods might tell a different story?

There is that one 2022 study which seemed to suggest higher lactate during exercise. I'm sure that there have been more studies on this, but I can't recall them, and haven't checked them out. Is there a body of evidence suggesting people with ME/CFS have higher lactate levels with exercise than matched healthy controls?

That's an interesting thought about levels possibly being different upon waking - I don't think I did tests upon waking. I assume that you haven't found anything unusual there with your lactate meter @SNT Gatchaman?
 
(Yes, arterial measurements would be best, but this might be a reasonable proxy. I wonder if this might have been something they did in the intramural study, although sleeping with an arterial catheter in would be hard and probably affect the 'normal' quality and phases of sleep.)

Yet to try. I'm just trying to get used to making measurements routinely, as it needs a decent drop of blood from your fingertip. Noting the apparent strange accelerations in respiration and heart rate with overnight pulse-ox recordings, I wondered if this might relate to the waking up at 3am with a bang (not the good sort:whistle:). In order to check this I need to be able to reliably do a finger-prick jab as close to waking as possible, while no doubt blurry-eyed etc. This would be a lot simpler to check with a continuous capillary lactate monitoring device, but they aren't available yet as far as I can tell.
 
Is measuring levels with the meter in any way different from doing a routine lab draw for lactic acid?

Wouldn't we see more ME/CFS patients having high lactic acid on labs over the years?
 
belbyr said:
Is measuring levels with the meter in any way different from doing a routine lab draw for lactic acid?
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I don't think lactate would be particularly routine in the general practice sense. I think typically it's part of an arterial or venous blood gas, where it's analysed promptly (ie ICU/ED resus bay type scenarios). If it were done as a community lab test, then another difference would be the timing of the observation. Generally if you go to a lab you drive/are driven there, sit in a waiting room for 10-15 minutes, by which time the lactate might be normal range or only slightly up. Nobody would be doing community lab tests in the middle of the night either. So being able to measure it on-demand could more easily show an abnormal response to exertion or diurnal fluctuations.
 
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