The Causes of Long Covid
science.org156 points by maxall4 a day ago
156 points by maxall4 a day ago
I had a long process with this that mostly manifested as exercise intolerance and general inflammation/discomfort, and sleep struggles. I made no progress for 2 years, lost most of my muscle (I had been very active before) and started thinking "is this how it's going to be forever?". After not finding anything promising from traditional medicine or supplements, I finally made some dramatic life changes. I'm fully past it now (with persistent lifestyle changes), but I really had to rethink my relationship with food.
Ended up doing a paleo diet, avoiding stressors (some of which are not obvious like just being on your phone scrolling, bad posture/circulation/sitting for too long), improving sleep hygiene, and ramping up consistent cardio exercise, with an emphasis on getting up to 4x/week zone 5 cardio without triggering intolerance.
Since then I've discovered a lot of other things that are great for overall health, like HRV-reset breathing and long-duration water fasts (around 3 days is optimal for me). I imagine those would have been very helpful if I had tried them earlier. A water fast is a complete metabolic and inflammatory reset of the body, and it's not as hard as you might think.
Hopefully most affected folks have recovered and are living normal lives by now, but if not, there are things you can do! It seems like the more challenging those things are, the more efficacious.
Having gone through this too, I also had to accept that a lot (not all!) of it was in my head and made worse by it. When I convinced myself that “this will pass” and “this slow steady plan will get me out of this eventually” was when I finally saw regular progress (progress, not immediate relief).
It's amazing how powerful the mind is and it's also sad that the default setting is to use that power against oneself
How do you prepare/deal through a water fast? What kind of supplemens would be needed for the water?
Can I read up on this anywhere? I'd welcome a suggestion over surfing the many many pages I found through a simple search. A book or paper reccomendation to read up on would be nice as well
Honestly AI overviews are a pretty good guide, ask about a 3-5 day water fast. I was nervous going into my first one, but now I don't worry about it. The main thing is to drink a lot of water and have 1-3 LMNT electrolyte packs (unflavored, no sugar) per day, depending on how much you're sweating/exercising (which you absolutely can do, especially the first 2 days).
You can expect to feel colder as your body doesn't conserve as much heat, and after ~2 days more lethargic physically, but your mental energy may actually be higher. I don't sleep as well when fasting, so 3 nights is about my limit. That being said, you feel rested on less sleep, because your body is probably producing a lot less waste.
How do you manage zone 5 cardio 4x a week without PEM?
I thought up to 3x a week and never consecutive days is the maximum.
Zone 5 is usually 1-2 minutes out of a longer 30 minute cardio session for me, I do it as a final sprint. I am not talking about repeated hill sprints where you would get 10+ minutes of zone 5 cardio in a session, which I agree would not be something a normal person should do 4x/week.
From my own experience, it seems like hitting that Zone 5 briefly is a good nervous system reset (overrides any dysfunctional breathing and heart rate effects from long covid); it's less about training the heart, although that's an excellent side effect.
I'm happy you got better - but isn't healthy diet, moderate regular exercise and good sleep hygiene staples of traditional medicine?
Thanks. Unfortunately, not really, especially where diet is concerned. For example, I saw significant improvement after removing wheat, white rice, red meat, and dairy entirely, which is not something your typical US doctor would suggest. The first doctor I saw wanted to put me on antidepressants.
I also think exercise recommendations are generally too low, especially with respect to high intensity cardio.
What do you mean by water fasting? Do you avoid drinking water directly, or do you avoid all food? For example salads are basically sacks of water.
Water fast is when the only intake is water (plus electrolites and vitamines). Basically "eat nothing".
> Basically "eat nothing".
Thanks for this, reading "water fast" and "3 days" gave me a shot of adrenaline. The "water" prefix is just confusing, the word for abstaining from food is just "fast" for those interested.
If this is engagement bait, then well played..
It is a specific type of fasting. Saying only "fasting" can mean a lot of things, saying "water fast" means you only drink water.
Water fasting is used to differentiate from dry fasting, where you don't even drink water.
Is this even a thing? Never assumed you'd ever want to dehydrate like this on purpose. Just why?
dry fasts aren't always what they appear. if you have significant glycogen stores in your body as you begin your fast you wont be dehydrated for the first day or two as water is freed. what usually happens is someone who starts glycogen endowed discovers that they aren't thirsty when they start fasting and tout it as dry fasting.
What you thought of (not even drinking water) is called a dry fast. It is a thing, but for obvious reasons is much more intense and shorter in duration.
A non-inflammatory rocket shock diet can certainly aid in symptoms of long covid in many users, often people megadose on antioxidants to dilate their recovery window and not regress. Glad to hear you are feeling better and I totally agree that movement and diet are key in recovering from inflammatory disease.
Before you can investigate the causes of an illness, you have to define it. Otherwise, you’re chasing an ever-shifting cloud of ambiguous symptoms, any of which could have different causes. The article opens with this admission, so I’m not stating anything new here.
The problem with “Long Covid” as it exists today is that there’s no such definition. Literally anyone who had Covid once and feels bad today (and quite a few people who never had a confirmed case at all) includes their set of symptoms in the communal diagnosis. Thus, if you dig into these studies, you always find that the syndrome is a wide-ranging and variable constellation of symptoms, making it impossible for a study to have any systematic legitimacy. Moreover, the results of any particular study are more strongly influenced by the inclusion criterion (if there even is one) than by any other factor.
It’s perfectly possible to evaluate treatments in this situation, and would be a better use of resources - pick symptoms, make an inclusion criteria, and run a randomized trial of existing drugs or therapies. But this is likely to fail, and it’s much, much easier to write papers with unprovable theories and retrospective analysis.
Interesting. Someone should (or maybe have?) run a cluster analysis on the symptoms to define more specific subgroups. But I suppose getting access to the required health data at that scale is nontrivial?
It’s not that hard to get a long list of symptoms for long covid. Just watch this thread as it grows, and you’ll easily find dozens. Things like this end up being a lint trap for people who just feel bad for whatever reason (which is all of us, at various points in our lives!) Nobody likes to be told that their symptoms are idiopathic.
Massaging this kind of data (clustering, etc.) is much lower value than finding fixed criteria that define a consistent group of patients who have objectively defined symptoms that cannot be more readily explained by another diagnosis. This is a pre-requisite for any further study. It can be done, but it’s hard, and it tends to lead to criticisms because you end up excluding a large number of people who fervently believe they have the illness, but don’t fit the objective standards.
Just for example: it’s not enough to claim that you have “brain fog”. A more valid endpoint might instead attempt to classify people based on standardized tests of thinking. Even that has problems, of course, but if you can just claim that you are fatigued and unable to think clearly, there’s a huge problem of confounding (i.e. maybe your symptoms are caused by something else), let alone the unverified nature of the original claim.
Leading research into Long Covid is already doing this. You’re seeing neural and auto immune clusters gathering around certain immune dysfunction and previously rare diagnosis like Small Fiber Neuropathy. Autonomic dysfunction is being measured in young and healthy people also, and that has its own set of objective testing.
Everything you are saying is happening. But because the suspicion seems more and more that it’s an auto immune condition of some sort, and that we are only catching the downstream effects as some of the immune dysfunction isn’t mapped yet, we are seeing the clusters that you say emerge - overwhelming numbers of symptoms, relatively incoherent connection.
But autonomic dysfunction, small fiber neuropathic and detectable auto immune dysfunction are all known and increasingly mapped positive markers for the condition. Have you read the latest studies ?
> You’re seeing neural and auto immune clusters gathering around certain immune dysfunction and previously rare diagnosis like Small Fiber Neuropathy.
Everything I've personally seen in this space is exactly what I described: they start with a set of people who claim to have the illness, then go on a statistical fishing expedition to look for "signs of immune disfunction" (or whatever, but you're right that these researchers tend to focus on immune-related metrics), then use whatever signals they happen to find to create a class. This is not the same thing as what I'm talking about, and it isn't valid.
I'm not going to claim comprehensive knowledge of the space, but the papers I've read that make it into the high-profile journals are of this sort.
The papers cited by this Lowe article are better than most at least in the sense that they have control groups and are doing experiments. But let's be clear -- the first one is claiming to see "long covid" pain symptoms in mice who are injected with whole human IgG (a notoriously messy and subjective approach) [1], and the other is exactly the kind of fishing expedition I'm describing, where they indiscriminately look for "targets" of said antibodies [2]. The former is at least doing an experiment that I suppose could lead to some kind of claim of cause, but the latter (despite the exaggerated title) provides no evidence that the correlations they're seeing are meaningful in any disease process.
I guarantee that using the high-dimensional screening that the latter paper in particular is doing, I can take 1000 random people, split them into two arbitrary classes ("fooists" and "non-fooists"), and find some "statistically significant" difference in immune marker profile between them. That is the fundamental problem with the approach.
When I say that you have to start from an objective measurement of symptoms, it means literally that -- not starting from an assay result that is unlinked to any symptom.
[1] https://www.sciencedirect.com/science/article/pii/S266637912...
[2] https://www.sciencedirect.com/science/article/abs/pii/S00928...
Aside: this lab is becoming infamous for this kind of statistical fishing expedition. It makes me cry for the state of science.
Then you should fund it. The entire field is to my understanding absolutely starved of science funding.
There are two fairly strong clusters of findings that are objective, repeatable, and consistent. And that is the autonomic testing in long COVID patients is coherent in its dysfunction, and so is the Small Fiber Neuropathy testing that is now consistently showing abnormalities.
Lets go step by step.
Small Fiber Neuropathy. Nerve fiber density is a count with age/sex-normed reference ranges. In previously healthy post-COVID patients with no diabetes and no risk factor, then the test shows whether the nerves are there or they aren't.
https://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1284&c...
https://www.medrxiv.org/content/10.1101/2025.03.04.25323101v...
https://www.neurology.org/doi/pdf/10.1212/NXI.00000000002002...
https://pmc.ncbi.nlm.nih.gov/articles/PMC12847426/pdf/fnhum-...
We have brain structure changes showing in the UK Biobank studies https://pmc.ncbi.nlm.nih.gov/articles/PMC9046077/
Associations with complement dysregulation https://www.cell.com/med/fulltext/S2666-6340(24)00041-2
Muscular abnormalities in long COVID patients reporting reduced exercise function https://www.sciencedirect.com/science/article/pii/S104327602...
Potential that persistent infection shows up in Long Covid patients in abnormal rates https://www.massgeneralbrigham.org/en/about/newsroom/press-r...
If your argument is that people are showing up with abnormalities, then diagnosed with Long Covid, then spurious biomarkers are associated to it - you are just wrong. Wrong multiple times. Demonstrably so.
What we are seeing is more likely to be exactly what it looks like - an novel condition being captured by downstream effects of previously unknown or understudied mechanisms.
All of those are examples of exactly what I told you about: they take a group of people claiming to be sick, and go hunting for signals to claim as “significant”.
The MRI studies are particularly egregious examples of this. Just because you see a difference on an MRI does not mean that the difference is due to the thing you’re blaming. In fact, it almost never is.
> If your argument is that people are showing up with abnormalities, then diagnosed with Long Covid, then spurious biomarkers are associated to it - you are just wrong. Wrong multiple times. Demonstrably so.
I am? I have now followed every link. Literally every paper you posted is following this exact pattern. I don't know how you could possibly conclude otherwise, unless you just didn't read past the titles.
They each take a (typically small) cohort of people who self-identify as "long covid sufferers", they subject them to random combinations of tests, and report only what they find to be significant. It's literally the XKCD comic about jelly beans.
You are just ignoring the evidence, being unscientific, and unless you work for a top medical lab somewhere, plain arrogant.
The UK Biobank study scanned participants before and after infection with matched controls. The difference is measured against their own pre-infection brain. That is the opposite of what you're describing.
> You are just ignoring the evidence, being unscientific, and unless you work for a top medical lab somewhere, plain arrogant.
If you don't know how to interpret evidence, then I suppose it would sound like I am being overly critical. I didn't bother to pick on just one, but since you chose it [1]...
> The UK Biobank study scanned participants before and after infection with matched controls. The difference is measured against their own pre-infection brain. That is the opposite of what you're describing.
It is not. The longitudinal nature of the study is a distraction from the fundamental issues with the approach.
They did a longitudinal case-control study, one group of which had positive covid tests in the past, and the other one did not at the time of the second scan (2021). That's the entire evidence base that this study is built upon -- it has nothing to do with "long Covid", and it's only barely plausible that the control group is actually a control for the factors of interest.
Next, they took two scans for all participants - one from before the pandemic, and one made after (again, in 2021). They made over 6000 different images, and then cherry-picked the ones with differences for further analysis (~70). Ultimately only 6 of these fishing expeditions survived family-wise error correction:
> The main case-versus-control analysis between the 401 SARS-CoV-2 cases and 384 controls (Model 1) on 297 olfactory-related cerebral IDPs yielded 68 significant results after FDR correction for multiple comparisons, including 6 that survived FWE correction
So first off, no statistical correction can compensate for this fundamental bias. You cannot start with thousands of different samples - even if they're taken from the same people at different time points - and winnow that down to a handful by filtering on the outcome of interest, Applying a multiple-sample correction will not fix it. It's not even clear that there is such a correction that is valid for the underlying distribution of the data involved.
But setting that aside, the differences observed, even between longitudinal samples, do not have to be due to Covid! Even if they're not random (which we cannot grant; see previous paragraph) they could be due to everyone being locked inside during 2020. They could be due to factors completely unexamined by the study, like, say, increases in drinking or drug use, or lack of exercise. Or any of a million other things. We don't know. The authors don't know. They're just not intellectually honest enough to admit that they don't know.
I could go on, and point out more flaws (e.g. the "significant" results mostly disappear when you exclude hospitalized patients, yet oddly, the difference between "hostipitalized" and "control" cohorts is not itself significant, indicating inadequate statistics), but this post is already too long.
I'm sorry that you think this is arrogant, but this is how we actually read papers.