Editing Etiology

There are many different theories regarding post vaccination syndrome (the most debilitating and common form of COVID vaccine injury) and long COVID.  While most theories could explain both conditions, some theories only apply to long COVID.

It is entirely possible that none of the current theories are correct.  So, we should keep an open mind and be willing to change our mindset when the facts change.

=Post vaccination syndrome (vaccine injury)=

==S1 spike protein==

[[File:Patterson_long_COVID_spike_in_monocytes.png|thumb|S1 spike found 15 months post COVID infection]]
[[File:Patterson post vax spike in monocytes.png|thumb|S1 spike found post vaccination]]

Both long COVID and vaccine injury seem to be very similar conditions due to similarities in symptoms and how patients respond to the same treatments.  There are various theories as to why ‘long haul’ occurs in both groups.  One theory is that the S1 subunit of the spike protein is the root cause.  Bruce Patterson, a former Stanford researcher, led a team that found persistent S1 spike protein in non-classical monocyte (CD14+ CD16+) cells up to 15 months after initial infection.

There are two possibilities as to why spike proteins persist in non-classical monocytes.
* The monocytes are immortal or near-immortal.  They do not die in [https://doi.org/10.1016/j.immuni.2018.10.005 7 days] like typical non-classical monocytes.
* The S1 spike protein is like a ‘bone’ that the body cannot break down.  It is passed on from monocyte to monocyte.

'''References''':
* ''Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) Up to 15 Months Post-Infection'' https://doi.org/10.1101/2021.06.25.449905 
* (Youtube presentation) ''Immune-Based Prediction of Long Covid and Implications for ME/CFS'' https://youtu.be/O_XX9_IujeY

==S1 spike protein causing vascular inflammation==

According to this theory, persistent S1 spike protein leads to non-classical monocytes provoking vascular inflammation.  That vascular inflammation is somehow able to drive the diverse range of symptoms that long haulers experience.
*Drugs like '''statins''' interrupt the fractalkine/CX3CR1 pathway, disrupting nonclassical monocytes from sticking to the walls of blood vessels and engaging in pro-inflammatory behavior.
*Various drugs may affect the survival of non-classical monocytes or have been shown to affect monocyte repolarization in vitro: '''statins''', '''melatonin''', '''omega-3 fatty acids''', '''vitamin C''', '''vitamin D'''.

Bruce Patterson’s company, IncellDX, produces a test kit that measures various inflammatory markers.  Various cytokine levels are elevated in long haul patients.
* CCR5 antagonists like '''maraviroc''' and the experimental drug '''leronlimab''' may counteract the elevated levels of CCL4/RANTES found in many (but not all) long haulers.  Cytodyn’s study of leronlimab on long haul did not reach statistical significance.  Nonetheless, the company states that the trial was not designed to reach statistical significance (the sample size was 56 patients) and that the early-stage trial delivered “positive preliminary results”.

'''References''':
* ''Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning'' https://doi.org/10.3389/fimmu.2021.700782 
* (Youtube discussion) ''Spike Proteins In Immune Cells - Dr. Bruce Patterson Discusses COVID Long Haul'' https://youtu.be/JwjJs5ZHKJI 
* FLCCC I-RECOVER Protocol - https://covid19criticalcare.com/covid-19-protocols/i-recover-protocol/
* Cytodyn press release dated June 21, 2021 - https://www.globenewswire.com/news-release/2021/06/21/2250254/19782/en/CytoDyn-Inc-Announces-Positive-Preliminary-Results-of-Unblinded-Data-from-Long-Haulers-Trial-Showing-Greater-Improvement-in-Leronlimab-Group-over-Placebo-in-18-of-24-Symptoms.html

==S1 spike protein persistence in exosomes==

Whereas Bruce Patterson found evidence of persistence in non-classical monocytes, Bansal et al believe that spike protein is persistent in exosomes at 4 months after the second round of vaccination.  An analysis of the study by Michael Palmer and Sucharit Bhakdi argues that the surprisingly long persistence " raises the prospect of sustained inflammation within and damage to organs which express the spike protein".

'''References''':
* ''Long-term persistence of the SARS-CoV-2 spike protein: evidence and implications'' https://doctors4covidethics.org/wp-content/uploads/2021/11/bansal-notes.pdf
* ''Cutting Edge: Circulating Exosomes with COVID Spike Protein Are Induced by BNT162b2 (Pfizer-BioNTech) Vaccination prior to Development of Antibodies: A Novel Mechanism for Immune Activation by mRNA Vaccines'' https://doi.org/10.4049/jimmunol.2100637

==S1 spike protein toxicity==

An experiment on a mouse model (K18-hACE2 transgenic mice) demonstrated that an injection of spike protein leads to acute lung injury.  

The researchers in the study also examined whether the splitting of the spike protein is relevant.  The spike protein consists of S1 and S2 subunits joined at the furin cleavage site.  The researchers used a protease inhibitor cocktail to prevent the splitting of the spike protein (into S1 and S2) at the furin cleavage site.  Unsplit spike protein did not lead to damage while split spike protein led to damage, presumably due to how S1 spike protein affects the ACE2 pathway.

This study may not necessarily generalize to vaccine injury because it was focused on an acute COVID context.  Because there are differences between acute COVID and vaccine injury, the mechanisms for each may be different.  Whereas acute COVID patients generally have low oxygen levels in their blood (presumably due to lung damage), vaccine injured patients generally have normal oxygen levels.

'''References''':
* ''The SARS-CoV-2 spike protein subunit S1 induces COVID-19-like acute lung injury in Κ18-hACE2 transgenic mice and barrier dysfunction in human endothelial cells'' https://doi.org/10.1152/ajplung.00223.2021

==Full length spike protein toxicity==

Some believe that full-length spike protein may be the cause of vaccine injury, as full-length spike protein has been shown to impair DNA repair in a laboratory setting.  One of the problems with this theory is that it predicts that partial-length spike vaccines like Pfizer would have far fewer side effects than full-length spike vaccines.  In practice, both types of vaccines lead to vaccine injury.  The [[Vaccine_differences|vaccine differenes]] page contains some additional information on spike protein differences between COVID vaccines.

'''References''':
* ''SARS–CoV–2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination In Vitro'' https://doi.org/10.3390/v13102056

==Exosomes containing microRNAs==

Mishra and Banerjea performed in vitro experiments which suggest that mRNA vaccines lead to the creation of exosomes containing microRNAs such as miR-148a and miR-590.  These microRNAs are internalized by human microglia (immune cells in the central nervous system) and suppress target gene expression of USP33 (Ubiquitin Specific peptidase 33) and downstream IRF9 levels", ultimately resulting in "CNS damage through hyperactivation of human microglia".

'''References''':
* ''SARS-CoV-2 Spike Targets USP33-IRF9 Axis via Exosomal miR-148a to Activate Human Microglia'' https://dx.doi.org/10.3389%2Ffimmu.2021.656700

==Auto-immunity==

''(Auto-immunity is when the immune system engages in ‘friendly fire’ and attacks host tissues instead of foreign invaders.)''

Long haulers tend to have elevated auto-antibody levels when their blood is tested by Cell-Trend, a German lab.  This has some similarity to auto-antibodies found in the blood of acute COVID and long COVID patients:
* A study by Gerd Wallukat and his team examined the antibodies of 31 recovered COVID-19 patients.  All had between 2 and 7 different auto-antibodies of the GPCR-fAAB type (g-protein coupled receptor functionally active auto-antibodies).  In healthy controls, such auto-antibodies are only found in a small percentage of people.
* Yale researchers looked for auto-antibodies against a library of 2,770 human extracellular proteins.  They found correlations between the progression of disease and auto-antibody levels, suggesting that a COVID-19 infection causes auto-antibody production.  They also found that “mouse surrogates of these autoantibodies increase disease severity in a mouse model of SARS-CoV-2 infection”.

To treat long haulers, many doctors are repurposing treatments normally used for auto-immune conditions: '''corticosteroids''', '''immune-suppressing drugs used for rheumatoid arthritis''', '''IVIG''', '''apheresis''', etc.

'''References''':
* (Wallukat et al) ''Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms'' https://doi.org/10.1016/j.jtauto.2021.100100 
* ''Wang, E.Y., Mao, T., Klein, J. et al. Diverse functional autoantibodies in patients with COVID-19. Nature 595, 283–288 (2021).'' https://doi.org/10.1038/s41586-021-03631-y

==Antibodies against antibodies==

It has been observed that animals generate antibodies against antibodies produced by their own immune system.  (This may be a form of down-regulation.)  Researchers refer to them as “anti-idiotype antibodies”.  If the immune system is exposed to spike protein, resulting anti-idiotype antibodies could bind to the ACE2 receptor.  A paper on the topic states:

<blockquote>This aspect of regulation of immune-cell responses [antibodies against antibodies] was postulated by Plotz in 1983 as a possible cause of autoimmunity arising after viral infection5 and has since been supported experimentally by direct transfer of anti-idiotype antibodies.</blockquote>

This theory explains why there may be auto-immunity against the ACE2 receptor (but does not explain why other auto-antibodies are common in long haulers).  It may explain a small portion of all vaccine injuries.

'''References''':
* ''A Possible Role for Anti-idiotype Antibodies in SARS-CoV-2 Infection and Vaccination'' https://doi.org/10.1056/NEJMcibr2113694

==Blood clots and microclots==

The adenovirus vector vaccines (Johnson and Johnson, AstraZeneca) have been associated with a rare blood clotting disorder called vaccine-induced immune thrombotic thrombocytopaenia (VITT).  One paper (Huynh et al.) describes how such patients have antibodies against platelet factor 4 (PF-4), which is the cause of their VITT.

Another blood clotting theory comes from Etheresia Pretorius and her colleagues.  They studied long COVID patients and found that patients’ blood still contains anomalous microclots that are resistant to fibrinolysis (a normal body process that prevents naturally-occurring blood clots from growing and causing problems).  Clinical application of their theory should provide evidence for or against the theory:
* A pre-print from Resia Pretorius' team discusses the result of a multi-drug anti-clotting intervention.  Strangely, the pre-print has very few details on patient outcomes such as what (main) symptoms resolved and the degree of mprovement.  Nonetheless, the abstract claims: “Each of the 24 treated cases reported that their main symptoms were resolved and fatigue as the main symptom was relieved, and this was also reflected in a decrease of both the fibrin amyloid microclots and platelet pathology scores.”
* Long COVID patients are currently being treated with HELP apheresis in Germany.  There are some anecdotal patient outcomes being reported in the Facebook group "Help Apheresis for Long Covid and Post Viral Syndromes".  A [https://youtu.be/C8tzTmVwEpM Youtube interview] with Resia Pretorius also contains some comments on the effectiveness of apheresis, suggesting that the treatment does not lead to instant results.

It is currently unclear if post vaccination patients also have microclots like long COVID patients.  An article in [https://www.science.org/content/article/rare-cases-coronavirus-vaccines-may-cause-long-covid-symptoms Science magazine] states:

<blockquote>The cause of the very rare but severe clotting after the AstraZeneca and Johnson & Johnson vaccines remains unknown, but Pretorius suspects all COVID-19 vaccines might also sometimes trigger subtler clotting issues. She says she has preliminary evidence that vaccination can lead to microclots, although in most cases they go unnoticed and quickly disappear—an effect she and a colleague saw in their own blood and that of eight other healthy volunteers, which they sampled after their vaccinations.</blockquote>

'''References''':
* ''Huynh, A., Kelton, J.G., Arnold, D.M. et al. Antibody epitopes in vaccine-induced immune thrombotic thrombocytopaenia. Nature 596, 565–569 (2021).'' https://doi.org/10.1038/s41586-021-03744-4 
* ''Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin'' https://doi.org/10.1186/s12933-021-01359-7 
* (Youtube) ''Interview with Dr. Resia Pretorius: LongCovid microclots (spike protein, apheresis + other topics)'' https://youtu.be/C8tzTmVwEpM
* ''Combined triple treatment of fibrin amyloid microclots and platelet pathology in individuals with Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) can resolve their persistent symptoms'' https://doi.org/10.21203/rs.3.rs-1205453/v1

==Mast cell activation syndrome (MCAS)==

MCAS resembles mastocytosis, a rare disease caused by too many mast cells. People with MCAS have a normal number of mast cells that are overly active and cause dysfunction.

Some MCAS specialists believe that long COVID is rooted in MCAS.  Other MCAS specialists note that MCAS symptoms are prevalent in long COVID patients.

'''References''':
* ''Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome'' https://doi.org/10.1016/j.ijid.2020.09.016
* ''Mast cell activation symptoms are prevalent in Long-COVID'' https://doi.org/10.1016/j.ijid.2021.09.043

==Multiple persistent infections==

Vaccine injury has similarities to other debilitating, poorly-understood illnesses:
* '''Breast implant illness'''.  Many but not all people with breast implants report significant reversal in their health problems after removing their breast implants.  The scientific literature refers to this illness as siliconosis, silicone implant incompatibility syndrome, and ASIA (autoimmune/Inflammatory syndrome induced by adjuvants).
* '''Chronic Lyme''' (“PTLDS”) and Lyme+.
* '''ME/CFS'''.
* '''Gulf War syndrome'''.
* '''HPV vaccine injury'''.
* '''Post viral syndromes''' from SARS1, MERS, Ebola, etc.
* '''Long COVID / PASC'''.

All these illnesses share common features:
* Overlapping symptoms, e.g. POTS, internal vibrations, derealization, etc.
* Patients vary widely in the symptoms that they do and don’t have.

The similarities could be explained by multiple persistent infections working together in weakening the immune system.  When the immune system is overburdened, debilitating health problems surface.  This overburdening could be triggered by stress (e.g. divorce), inorganic burdens like silicone implants, and organic sources such as new infections and S1 spike protein.

'''References''':
* ''The human microbiome and autoimmunity'' https://doi.org/10.1097/BOR.0b013e32835cedbf - This paper discusses how successive infection can drive dysbiosis, ultimately leading to autoimmunity.
* (Youtube) ''Successive infection: how pathogens support each other to drive chronic disease'' https://youtu.be/7yjh04vMe1E

=Long COVID / PASC (Post-acute Sequelae of COVID-19)=

==Viral reservoir==

Some portion of long COVID sufferers may actually have a reservoir of actively replicating virus, e.g. in the digestive system.  

'''References''':
* ''Persistence of intestinal SARS-CoV-2 infection in patients with COVID-19 leads to re-admission after pneumonia resolved'' https://doi.org/10.1016/j.ijid.2020.04.063
* ''SARS-CoV-2 infection and persistence throughout the human body and brain'' https://doi.org/10.21203/rs.3.rs-1139035/v1 - This pre-print argues that SARS-CoV-2 can persist throughout the body and in the brain.
* ''COVID-19 Endothelial Dysfunction Can Cause Erectile Dysfunction: Histopathological, Immunohistochemical, and Ultrastructural Study of the Human Penis'' https://doi.org/10.5534/wjmh.210055 - viral persistence in the penis

==Damage from acute COVID==

A COVID-19 case may have different mechanisms that may be responsible for long-term health consequences:
* The SARS-CoV-2 virus infects a wide range of human cells.
* The cytokine storm syndrome may be responsible for long-term damage.  This may also result in functional exhaustion and decreased numbers of T lymphocytes and natural killer cells.
* SARS-CoV-2 may drive multi-organ injury via stimulation of clotting cascades and related thromboinflammation, dysregulation of the renin–angiotensin–aldosterone system, and endothelial cell damage.
* Post ICU syndrome

'''References''':
* ''Immune responses to SARS-CoV-2 by Dr. Akiko Iwasaki'' https://youtu.be/D227iwnZSeA?t=2758 - This presentation by Akiko Iwasaki provides an overview of long COVID mechanisms.
* ''Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms'' https://doi.org/10.3389/fmicb.2021.698169