Thread Summarizing "Pathophysiological Mechanisms in Long COVID: A Mixed Method Systematic Review"

Oh, cool, a new systematic review on the pathophysiological mechanisms of Long COVID was published today. Here's a summary (well, more like a play-by-play) of the paper.

I gotta say, I love when thorough papers exactly match my mental model of LC! This paper covers it all!

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For this review, they were intending to do a meta-review, but they found that the existing systematic reviews were lacking, so they just had to do their own. Overall, I think their methodology was pretty thorough.

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Note that this isn't even the most cutting-edge research! The inclusion cutoff for studies in the systematic review was October 2022. The study took about a year to conduct, and another few months to publish, and we've gotten more clarity on these topics since then.

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Overall, their method is robust, and their conclusions are carefully balanced against the strength of the literature!

This image shows the systematic review process they followed for the pair of reviews in this paper.

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One disappointing conclusion was the relatively poor quality of the research. For ex, if a study isn't reporting a sample size justification, we can assume they're pulling it out of their ass. Doesn't mean the results are bad, just that they may be statistically underpowered.

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Diving in to the symptoms most strongly linked to an identifiable pathophysiological pathway... 🥁🧻🙏

The Immune System!

"Symptoms of fatigue, postural orthostatic tachycardia syndrome (POTS), and neurocognitive dysfunction have all been linked to immune dysregulation."

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Latent Virus Reactivation

The major symptoms of fatigue, brain fog, memory difficulty, confusion, and POTS were also associated with latent herpesviruses, such as the Epstein-Barr Virus (EBV; "Mono"), among others.

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Viral Persistence

And, of course, virus persistence is potentially implicated in the persistent immune dysregulation that follows infection with SARS-CoV-2. I say "potentially implicated," because it may be that, plus more complex systemic interactions.

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Other Complex Pathways

Finally, for the last of the symptoms *strongly-linked* to pathophysiological mechanisms of the immune system, there are other more complex pathways, such as interferon-related autoimmunity, vascular inflammation, and endothelial dysfunction.

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CNS Dysfunction

I'm kind of glossing over this section, because it's actually fairly outdated. I've summarized other relevant studies elsewhere (e.g., pandemicpatients.org/home/covid-19-...).

In general, inflammation and metabolic issues dominate.

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They note a smattering of other neurophysiological abnormalities have been associated with LC symptoms, including changes in cerebral blood flow related to endothelial dysfunction, white matter lesions, cortical thinning, and direct damage of brain cells.

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Of course, bringing it back around, they did find a case-control study that associated neural dysfunction with the immune dysregulation that has also been documented.

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Poor lung function is associated with lung damage. Surprise...?

NB: "Although lung damage... has been demonstrated... as a pathophysiology underpinning symptoms of dyspnoea, cough, or fatigue, there is still little evidence describing the causality of this lung damage..."

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The other major issues found are myocarditis and peri-myocarditis (which show up on cardiac MRI, but not other measures), but the observed cardiac issues may overall be related to inflammation and immune system dysfunction.

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Now for the symptoms with a reasonable link to an identifiable pathophysiological pathway. First up, we have endothelial and blood clotting disturbances.

Remember that in this case, "reasonably linked" is related to statistical power, not quantity of raw data.

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This detail is absolutely fascinating: "High-intensity exercise and LC have similar effects on blood vessel function, except that the effect of high-intensity exercise resolved after several hours."

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There do seem to be issues with endothelial damage and oxidative stress, but the studies are too statistically underpowered to draw any significant conclusions. More research is needed!

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Likewise, there is some evidence of mast cell activation, particularly as a side effect of immune system dysfunction, has been associated with LC. Unfortunately, this is an area where there's just not a ton of *good* research that can provide definitive answers.

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Rounding out this Kafkaesque collection of shit are studies that are mostly speculative, that relate gene expression to anti-viral responses to the immune system to the microbiome to autoimmunity, etc.

Lots more research is needed.

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So, let's wrap this up! What can we conclude?

Long Covid is COMPLEX, and can have diverse clinical presentations related to multiple underlying pathophysiological mechanisms. However, there are clear directions to take in the research.

More research is needed NOW.

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Out of the "treatable traits," dysautonomia is one that is potentially the most treatable. Of course, that's not *yet* the case if viral persistence (or latent virus reactivation) is one of the main drivers of symptoms in LC.

And some symptoms may have many pathways.

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Here's their diagram of how all the processes fit together. I love this, because it's basically my current mental model of how things work. They were missing the direct association of neuroinflammation with anxiety and depressive symptoms, so I added that to the chart:

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In conclusion, there's clear evidence of "persisting inflammation, depletion of CD4 and NK cells, and persisting populations of SARS-CoV-2 specific CD8, leading to immune dysregulation with raised IL6 and TNF Alpha. This may be triggered by viral persistence..."

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And, of course, remitting/relapsing LC is likely associated with post-exertional symptom exacerbation.

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More research is needed IMMEDIATELY, on clinical trials, on drug repurposing, on ANY therapeutic interventions. The research needs to be done carefully, but urgently!

Source: doi.org/10.3390/ijerph... (Annotated: dropbox.com/t/cDxjXjadJgXK...)

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