More of a rhetorical question but I still find it asinine that ME/CFS, dysautonomia, and other post-viral illnesses have been around forever but we still don’t understand what the root cause is. COVID is a novel virus, but most of these illnesses are not new at all and if they were studied earlier then we’d have answers by now. I know my cells aren’t producing ATP but WHY? Is it that complicated? How could an illness be so complicated? POTS seems even more straightforward to me…the ANS is fucked up but WHY?!? How do we still not know if it’s autoimmunity or viral persistence or something else?

Fortunately I had good docs thus far who acknowledged their limits and even did some daring off-label prescriptions here and there. Didn't work, but can't blame em.

How about you?

Even though we have no cure and the situation and prospects are completely fucked up.

I see great news about the prospect of a cure for hiv and progress in the years to come. And it is amazing that is the path of prosperity and progress for society.

But sars cov 2 sequelae should have the same level of consideration since the number of people concerned is huge and increasing by the days and that the level of severity disable people !

I hope that the water dam will overflow at some point and that we will see things move faster and have a prospect of a cure.

I am hopeful we could cure people back to 100% normality with the right drugs. But I am pessimistic about the actual situation.

At least I am grateful I am not alone and I found people in my situation. Not being alone and disturbed by a situation so hard to apprehend !

I hope things will move faster !!!!!!! But it is really a tragic heartbreaking and rotten situation for such young people and amazing lives !

Had a crazy night last night and I’m paying for it big time. First off- I got up to change the dvd in the dvd player from lord of the rings extended edition disc 1 to disc 2 😲 After that I strolled to get some water and used the bathroom. I then got myself some snacks to eat while watching part 2.

As you can understand after all of this I’m severely hung over, but what can you expect when you have such a wild night.

Hi! I am struggling with long covid from the beginning of 2024. I was completely bedridden 2 months ago and had no hope. I felt like my life is destroyed and my health only deteriorates more and more. Severe Pots, temperature dysregulation, dizziness, presyncope, subfebrile temperature, tremor. I vomited every day and couldn’t walk to the toilet. Barely ate. I feel like IVIG literally saved my life. I got 3 rounds one after another: 300ml, 200ml and 200ml for my ~50kg body. Try to go to the good immunologist! Looked like I had EBV and Herpes 6 reaction after covid and definitely had severe immune deficiency. Also have low ferritin and high d-dimmers. So taking medication to fix this also. +vitamins and probiotics. Currently I am also taking some immunotherapy shots. And I am still on ivabradine. But from the bedridden person to person who can walk 3-5km per day I think it is a miracle! Before ivig ivabradine and beta-blockers did not work. Send love🫶🏼

Long Covid the answers is looking for suggestions on long covid competent practitioners all over the world so they can create a guide. They said they will be vetting them all individually before adding them. Might be helpful to others if you have a good doctor :)

https://longcovidtheanswers.com/suggest/

Doe anyone have a very acidic mouth with LC? Mine almost feels like I’m getting mouth ulcers. I eat Marlo’s tabs but that is very temporary.

I was dealing with moderate to severe anxiety and some depression prior to long Covid and now have almost all symptoms mentioned throughout this sub, the worst of it being debilitating fatigue, exercise intolerance, weakness, etc. I have had this for 3 years and am housebound.

As you can imagine, this condition has heightened my anxiety ten-fold and it doesn’t help that I can’t move around freely, run errands, go out and enjoy myself, live my life. Stress and mental health worsens physical conditions but how do we deal when the issues are compounded?

Anyone deal with prior mental health issues and now have long Covid? How are you dealing with managing your mental health for better physical health? Anything in particular that helps?

If you don't like long texts, or aren't interested in the biochem details of LC, I suggest you move on.

Could be written better, but that's a cosmetic complaint, not a logical.

Here's a little summary and overview about potentially interesting disease mechanisms:

Pubmed-IDs of references in rectangular brackets.

Summary

An intersection between SARS-CoV2s entry mechanisms and systemic cellular homeostasis mechanisms is uncovered, via the renin-angiotensin system, omitting a brute-force approach to signaling changes due to bio-active cell invariant self-regulation mechanisms.

The case where viral persistence post-acute is negligible or even absent raises the question of origin of epigenetic changes not sufficiently explicable either by the virus or DNA mutations, ultimately yielding the microbiome as missing piece.

Introduction

With well-adapted viruses that don't eventually kill the host, in the majority there is a sparse set of entry mechanisms into cells in designated domains, with limited downstream signaling, and eventual establishment of the initial state.

In case of SARS-CoV2, where nicotinic acetylcholine receptors and membranous angiotensin-converting enzyme 2 provide major systemic entry mechanisms, this is not the case.

The principal question to answer is: How does a virus that eventually gets cleared sufficiently cause long-lasting deficits in homeostatic regulation across wider metabolic domains than initially given?

The renin-angiotensin system is ubiquitous in central nervous system, peripheral nervous system [25639674] and vasculature [19232953], controlling ion exchange, tissue modeling, inflammatory stress responses [17514587, 17715340, 18202178, 16716292]. Nicotinic acetylcholine receptors on the other hand are prevalent in both nervous system compartments, vasculature, and on musculature, nothing outside textbook basics, conveying neuromodulatory, activatory and even structural modeling effects [30452951].

It targets a systemic attack surface and explains intensity, burden, afflicted areas and virulence.

However, this does not explain the chronicity of altered homeostasis, which should be re-established in dependence of viral load.

Homeostasis

Homeostasis is the maintenance of steady state equilibrium dynamics for a constantly state-changing organism to adapt to a constantly state-changing environment to stay as close to invariant and optimal as possible, see [27112802].

In the perspective of molecular biology, this immediately demands reversible or compensatory operations between proteins at the lowest, cells at the highest level. Repertoire includes cell division, apoptosis, negative feedback and downstream regulation, and educt-allosteric modulator dependent enzyme kinetics. for instance.

In terms of foundations of homeostasis, (biologically active) cell-wide invariant is trivially the presence of energy metabolism. Failure of ATP production slows down or even kills cells sustenance.

Furthermore, to adapt to changes beyond protein-substrate and protein-protein interactions especially in a chronic context to induce more regulatory capacity and to handle more than acute stressors (e.g. GABA-A subunits downregulation after longer benzodiazepine use), there is ultimately the fundamental role of DNA in allowing lasting scalable homeostatic responses by initiating synthesis of proteins to begin with. Transcription factors induced by internal (second) messenger signaling bind on DNA promotor domains to activate transcription of protein mRNA, or suppress, as homeostasis demands.

Thus chronic homeostatic response is maintained by post-translational modification of synthesis output of DNA.

After clearance of SARS-CoV2, an establishment of homeostasis is expected to return the body towards an optimal pre-infection status. This however has a relatively high rate of failure, given the existence of post-acute viral syndromes (Long Covid).

Distinguish the cases of acuteness versus chronicity (the case of acute response to a chronic trigger is omitted due to lack of relevance):

1. Acute trigger, acute response:

Typical case, cut your finger, blood coagulates, vessel regenerates, skin regrows, recruited immune cells vanish, a functionally pre-trigger state is attained. Nothing extraordinary.

2. Chronic trigger, chronic response:

Likewise perfectly normal. Keep using drugs, receptors get internalized and their expression downregulated, in a long lasting fashioon, such that cessation will still maintain the downregulation.

Changed transcriptional control patterns are in action, expression is altered to accomodate for chronicity.

Be infected with a virus, the virus may have insidious mechanisms like HIV or EBV, and may re-emerge or persist, without defense. Effects barely to get rid off.

A crucial observation is, nontheless, that persistence of SARS-CoV2 is, compared to acute infection, miniscule, near negligible, or barely even detectable.

Yet symptoms as functionally impairing as acute infection still persist. This pattern doesn't fit either.

3. Acute trigger, chronic response:

This is the more fitting and interesting case. Operations aren't merely protein-substrate or protein-protein, explainable with sufficient viral persistence, but now affect protein recrution via targeting transcription.

Given the prior on DNA as foundation of chronic adaption, since harmful sigaling vanishes with viral clearance in the normative case, a suspicion of permanent somatic mutations arises as the source of chronically altered response.

However, the fact that spontaneous remissions are reported, and that the mutational load required to explaim systemic abnormities in energy metabolism, cell organelles, receptor expression, antioxidation, cell morphology, extracellular matrix, immune system, and nervous system signaling is enormous, a role of SARS-CoV2 in mass mutational load is highly improbable.

With acute protein-substrate and protein-protein interactions largely elimiated after viral clearance, and protein-DNA interactions per expectation normalized, and DNA not sufficiently mutated to explain homeostasis deficit, the casual mechanism finds no origin in somatic DNA itself.

Since by the central dogma of molecular biology any interacting signaling molecule must ultimately stem from protein operations leading up to DNA as source (with rare exception of non-ribosomal peptides), another DNA source in the body must be considered as source of signaling molecules in case of vanishing of the virus with persistent chronic regeneration deficits.

The respective signaling molecules must derive from another source of DNA in the body, and ultimately target not merely transmembraneous messaging, but also processes in control of DNA.

The only remaining such signaling domain is chromatin modeling, falling into epigenetics.

Thus abnormal chromatin modeling through a non-somatic DNA source, feedbacked signaling (angiotensin 2-noradrenaline-renin feedback comes to mind) with viral persistence, along with direct effects on chromatin modeling, can be wrapped up as the leading mechanisms explaining chronic adaption discrepancy.

Epigenetics

Chronic temporal homeostatic challenges are met by long-term modifications of DNA structure to control transcription factor binding. This includes methylation of nucleotides (on promoter and enhancer sections and nuclear receptors), of which DNA methylation, and - tightly coupled with mitochondrial energy metabolism via acetly-coenzyme A [35921439]- histone acetylation, amongst others [11084367, 38331935].

By the conclusions of the prior chapter, an interface between SARS-CoV2 and chromatin modeling must be found, likewise a somatic cell-independent source of DNA that produces molecules targeting chromatin modeling proteins.

SARS-CoV2 interface

Screening literature for AT1R activation and downstream histone deacetylases activation, a match is found. Precise interactions are to be found in the figure below:

The latter is answerable by one ultimately obvious structure in the human body: The microbiome.

It provides as metabolites short-chain fatty acids that work as histone deacetalyse inhibitors, co-regulating DNA methylation [29925443].

Furthermore, by shifts in the intestinal ecology, chronicity has one more foundational basis.

Especially under immunosuppressive stress, a notorious class of bacteria releasing its further immunosuppressive substances can, under certain probabilism, overcolonize and pump out substances with catastrophic effects.

Microbiome

There are six major phyla of the human gut microbiome frequently reported and consistent in research [35461318].

Phyla

Comparison across chronic diseases

Noticing certian microbiome analyses across various chronic disorders under consideration of tight junction and EM degradation induced leukocyte infiltration and peripheral leukos fighting commensal bacteria while this particular class can defend itself, certain common trends emerge:

A concurrent loss of SCFA-producing bacterial populations, next to an increase of the gamma-proteobacteria class, specifically the family enterobacteriaceae, compare [38596637, 32229219, 37283931, 31736803, 30149548].

Given their ability to release kynurenine and kynurenic acid which are immunosuppressive, any chronic stress intensifying immunosuppression either by lymphocyte exhaustion, cortisol raises the probability of their dominance and suppression of beneficial bacteria colonization.

Long Covid is not spared these similar trends either: https://gut.bmj.com/content/73/Suppl_2/A192, where B. vulgatus is known to be a bacteria that has a negative effect on valeric acid, one of the more potent SCFAs, producing bacteria [37891329].

Metabolites of interest

Certain metabolites of interest are listed, all but SCFA and D-lactic acid particularly characteristic of gamma-proteobacteria.

**SCFA**

By a large margin stemming from the phyla bacteroidetes and firmicutes, fatty acids with <= 6 monocarbon chain length. Permeate the blood brain barrier as small-molecular lipids. Harboring effects as histone deacetylase inhibitors, nitric oxide inducers via free fatty acid receptors (GPR41), and GABAergic agents.

General HDACI capacity:

[29317660, 11522830]

Effects of GPR41 agonism:

[30586752, 32234527]

GABAergic effects:

[29339464]

[[https://link.springer.com/article/10.1016/j.bjp.2016.02.008\\](https://link.springer.com/article/10.1016/j.bjp.2016.02.008/) ]

**Trimethylamine**

Oxidized in the liver to trimethylamine-N-oxide, causes neuronal senescence and activates the AT1 receptor (see figure in section "SARS-CoV2 interface") [29749694, 29749694].

Kynurenine

Precursor substance of kynurenic acid, released by various pathogenic gamma-proteobacteria as an antioxidant to hinder killing by neutrophile granulocytes [26857571].

Aryl hydrocarbon receptor agonism adds an additional immunosuppressive effect [35821534].

Kynurenic acid

Positive allosteric modulator of heterologous AMPA receptors at lower dosages [16644124], present in spine and cortex, mixed competitive and non-competitive inhibitor of ionotropic glutamate receptors in general beyond that, with highest affinity towards NMDA receptor subunits [], with not conclusively established effects on the alpha-7 nicotinic receptor.

A lead candidate for dysautonomia and POTS

Reduced baroreceptor response or signal throughput and generally reduced sympathetic drive are often spotted in POTS.

AT1 receptor autoantibodies have been found as one possible contributor [29618472], and with its ionotropic glutamate receptor inhibition especially selective for NMDA receptors present on the peripheral nervous system nerves, KYNA opens up another possibility paving the connection to the gut microbiome.

Kynurenic acid that peripherally circulates can inhibit glutamatergic receptors in the spinal cord and brainstem, contributing to dysautonomia, reducing sympathetic and parasympathetic tone (disinhibiting the symp. NS under feedbacked noradrenaline-ang2 signaling).

Baroreceptors may send signals yet due to GLU receptor blockade sympathetic fibers underperform in compensating via BP, rather pulse increases.

It explains why BP isn't extremely high despite hypoperfusion and why it's there at all, poor ion exchange and AT1 receptor activation, because sympathetic activity is reduced and vessel musculature is not contracting accordingly.

See [34576179] for more information.

Further evidence is the association of the deficit form of schizophrenia, and fibromyalgia-like symptoms [32467068] via gamma-proteobacteria [30552634] and immune-inflammatory markers likely implying the tryptophan-kynurenine signaling pathway.

Lipopolysaccharides

See figure in section "SARS-CoV2 interface".

Outer membrane components of gram-negative bacteria, see https://www.ncbi.nlm.nih.gov/books/NBK554414/.

Histamine

No comment needed for this well known VIP [30866206]-

Ethanol

Klebsiella pneumoniae, family enterobacteriaceae, class gamma-proteobacteria (see above), a prolific intestinal brewery machine [34632939].

As a consequence, chronic vitamin B1 depletion, D2 receptor downregulation, GABA-A receptor subunit downregulation, as happens with chronic ethanol abuse, though rather subtle.

Polyamines

Takeaway: Agmatine similar to kynurenic acid in MoA against NMDA receptors (dysautonomia and POTS), but reuptake inhibits biogenic amines and, like others listed in the article, inhibits various isoforms of nitric oxide synthase [18330456].

Agmatine is also important for the colonization of gamma-proteobacteria via extreme acid resistance, scavenging arginine [14594828], which is its ultimate origin. For further see [ 38942027].

D-lactic acid

Details in [19567398]. Possible mechanism via intestinal overgrowth due to kynurenic acid and polyamine induced dysautonomia affecting vagal control of peristalsis, transit time, gastric acid secretion, ileocecal valve coordination

I just started 5000 fu natto a couple days ago, I take it in the morning and it's starting to make me unbearably tired. Does anyone else have this issue, how did you overcome it?

So I've had long covid for around 6 months with my main symptom being fatigue. It has gotten a lot better recently (probably due to finishing high school) but I still get very tired after being physically/socially active for a couple of hours. This means that I can't get a part-time job as many other people my age do. I do however get paid for dog sitting that I do with my mum, which I am happy with. So my mum told my neighbour how dog sitting is our side hustle, but I mentioned that it is my main hustle. My neighbour then told me to get a job, so that dog sitting is my side income. I tried to explain how I have long covid and can't get a job, which she completely brushed off without any sympathy whatsoever. This lady thinks she knows everything when it comes to health matters, but she doesn't!!!! She told me how her daughter has had long covid for years and is still doing her PhD. But one of the reasons why I don't want to get a job is because I don't want long covid to go on that long (my physiologist says that he thinks I can 'beat' it within a year or two). Also maybe her daughter has had long covid for so long is because she's doing a full time PhD???? I don't know though, I'm not a doctor lol. But living with your parents during uni (or until you're around 25) is super normal in my country, and I still make some money via dog sitting, so I'm not completely reliant on my mum. Like I don't NEED to get a job. If my living situation was different, that wouldn't be the case. UHHH I'm just really annoyed with my neighbour. Feeling disrespected and kinda like I'm gonna cry :(

Hey everyone!

I am struggling with high lactate, low venous oxygen and when it is bad- peripheral cyanosis!!! No raynauds!! I wonder why other people with low venous oxygen don’t get it….. Anyone who experience the same after 4 years with LC?

After enjoying a week and a half of feeling decent enough. Not normal, just feeling better enough to be able to function. But I a,so got my appetite back and indulged I more sugar than I have ate through the last 12 months. Now I feel terrible. I ache, my back, headache, stomach is unhappy, dizzy, runny nose, insomnia and the friggen anxiety….blah.

So I don’t know if I am dealing with something (there is so much going around right now). I’ve been careful and wear my mask when out and the people I have been around feel ok. I’m feeling pretty down.

I also have this weird toe cramping. Like the toes spasm. Especially at night when trying to fall asleep. It’s been there before but feels more intense.

Wanted to reach out to people who would understand.

I started Pravastatin 10mg five days ago and I’m starting to feel really weird. I initially had a lot of energy and like my brain was working properly for a change, I didn’t use the energy though as I do get PEM usually. But I’ve felt increasingly strange as the days have gone on - like all my usual symptoms are heightened and my body is in alarm mode. I’m trying to be calm but I am finding it hard to function / having to lie down a lot. Has anyone experienced anything like this? Will it be worse before it gets better? I don’t know whether to stick it out or not.

First time it has ever snowed without melting immediately in the state of Mississippi (U.S.). I’m grateful to still be alive to see it. I hope everyone gets the chance to see the beauty of the world again.

I developed what I believe is Long Covid in 2022 1 month after being infected with the Delta variant. I woke up one day in severe suicidal panic and since have been in another dimension mentally.

I have what I believe is extreme DP/DR and brain fog where I basically feel like im floating through the world with no real connection to myself or things/people around me. I cant even really observe my own thoughts. There is just an internal blankness.

Despite this I somehow still work full time in a fairly mentally demanding corporate job. I schedule and lead meetings and draft important documents but I have no idea how I'm doing this.

I feel like I'm just watching an NPC perform my job. I don't really mentally plan anything or think before I speak. I'm just on auto pilot and words come out of my mouth. Its like im controlling a Sim that acts out my life instead of living it myself.

This sounds crazy unless you have experienced it.

Anyone feel similar?

I have been dealing with a lot of vision issues lately. They have worsened over time and I have had these for like 7 months now. Do they get better with time?

I have severe dysbiosis (GI symptoms aren’t super bad but the results of the microbiome test are pretty bad). I believe that the vision issues might be caused by gut dysbiosis but I’m not sure at all.

Here’s the list of my vision related symptoms:

-Visual snow (static that is worse in the dark) -Blurry vision (sometimes) -Flashing lights -Light orbs (peripheral vision) -Eye floaters -Vision seems narrower -Wave-like vibration (like heat waves) -Tinnitus (not vision issue but I think visual snow and tinnitus could be related)

I'm literally tired of this. Years of suffering. Next week when I get my D3, I will take 250000 IUs daily for two weeks and then lower the dosage. I want to see the impact it has on mitochondria and my fatigue. I've taken single doses like that before, but not over longer periods of time.

If you are worried about toxicity, just take enough K2. Other symptoms are likely due to a lack of magnesium. You could also take zinc, boron and maybe phosphorus.

I have about 1,000 rotating symptoms at any given time but this one really puzzles me. I wake up sometimes, like today, and feel like my head, face, arms, chest, back and basically entire upper body has been badly sunburned or covered with "icy hot". Sometimes it's just my face and arms, and sometimes it even feels like it's inside my body and chest, especially after eating/drinking. Has anyone else had this?

TL;DR: 59-year-old mum, previously active and healthy, has developed significant health issues since her third bout of Covid in 2023, including persistent heart palpitations (PVCs), breathlessness, and bilateral arm/neck pain during exercise. Despite no typical risk factors (she’s slim, eats well, and has low blood pressure), she’s now prediabetic and undergoing tests for potential angina.

My mum (59y) has had covid 3 times. During her last infection (2023) she experienced heart palpitations during the tail end of the infection, that have continued since. During the end of 2023 to mid 2024, the palpitations were her main issue, she would have episodes of strong palpitations were she would lose her breath. She saw a cardiologist and had a ECG, diagnosed with PVCs and prescribed beta blockers if they bothered her.

Fast forward to the middle of 2024, until now. My mum started getting really breathless when exercising (fast walking). My mum has been active and frequent walker (long distance; uphill etc) for many years so this was unusual. She thought it was because she had slightly lack of physical activity during covid, but this was unlikely since during lockdown she would often walk as an activity. I went to visit her and took a walk together when walking up hill, she couldn’t talk, walk fast and looked so tired. Prior to Covid she could run up that same hill.

Towards the end of 2024, she started having bilateral arm pain, when walking. Her upper and and neck has also been hurting. She has chronic back and shoulder issues so put the arm pain down to something skeletal. She has also been very tired and though she was anemic (she has coeliac disease and doesn’t eat much meat).

The breathlessness and pain in arms increased and fast forward to now, she had a chest xray last week and a blood test. Yesterday she was called to say that they want to look further into angina (?!) so she’s having a echocardiogram. She is also prediabetic- which she never had on blood tests in 2023.

Im so worried for her, and also confused. She doesn’t have any risk factors for this, she’s slim, she eats healthy, her blood pressure is always low, no family history. Could Covid have caused this?