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 minds when the facts change.

=Post COVID vaccination syndrome (vaccine injury) or Long COVID=

==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
* ''SARS-CoV-2 S1 Protein Persistence in SARS-CoV-2 Negative Post-Vaccination Individuals with Long COVID/ PASC-Like Symptoms'' https://doi.org/10.21203/rs.3.rs-1844677/v1

==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.  He believes that atypical levels of IFN-γ, IL-2, and CCL4-MIP-1β are characteristic of 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”.

Schultheiß et al. found that the cytokines CCL2/MCP-1 and IL-8 plus long-term persistence of high IL-5 and IL-17F are characteristic of Long COVID / PASC patients.

'''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
* ''Liquid biomarkers of macrophage dysregulation and circulating spike protein illustrate the biological heterogeneity in patients with post-acute sequelae of COVID-19'' (Schultheiß et al.) - https://doi.org/10.1101/2022.09.18.22280022

==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.

A Korean research team lead by Junyoung Oh tested mice by injected S1 spike protein into their hippocampus.  While the S1 protein did not directly induce hippocampal cell death in vitro, it exerted neurotoxicity via glial cell activation, partially through interleukin-1β induction.

'''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
* ''SARS-CoV-2 spike protein induces cognitive deficit and anxiety-like behavior in mouse via non-cell autonomous hippocampal neuronal death'' https://doi.org/10.1038/s41598-022-09410-7

==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.

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DNA Damage Repair and Inhibits V(D)J Recombination In Vitro'' https://doi.org/10.3390/v13102056 - This paper has since been retracted.

==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 (Klein et al.) looked for auto-antibodies against a library of 2,770 human extracellular proteins.  They found correlations between the progression of acute COVID 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”.  However, the same lab applied version 2 of the auto-antibody panel test to Long COVID patients with different results.  The published pre-print states that "Long COVID participants did not exhibit increased autoantibodies to the extracellular proteome".
** Subsequent research (Barmada et al.) using the same REAP antibody panel suggests that auto-antibodies aren't involved in myocarditis post vaccination.  

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
* ''Klein et al. Distinguishing features of Long COVID identified through immune profiling'' https://doi.org/10.1101/2022.08.09.22278592
* ''Barmada et al.  Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine–associated myocarditis''  https://doi.org/10.1126/sciimmunol.adh3455

==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==

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.

'''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 

===Microclots===

Another blood clotting theory comes from Etheresia Pretorius and her colleagues.  The reliability of their claims is unclear.

The group has discovered microclots in the blood of patients with Type 2 Diabetes, COVID-19 (acute, including the pre-cytokine storm stage), and long COVID / PASC.  The [https://doi.org/10.1186/s12933-020-01165-7 T2DM paper published Nov 2020] states that COVID-19 patients have more microclots than diabetics, who have more microclots than healthy controls.  The paper's hypothesis was that these microclots would form into large clots that would block capillaries and cause low levels of oxygen in the blood, a characteristic symptom of acute COVID-19.

<blockquote>What we have shown here is that the clotting that is commonly seen in COVID-19 patients is in an amyloid form that forms large deposits that might be able to occlude fine capillaries. In addition, these deposits would interfere with fibrinolysis and cause the decreased ability to pass O2 into the blood that is such a feature of the disease.</blockquote>

[https://cardiab.biomedcentral.com/articles/10.1186/s12933-020-01165-7/tables/1 Table 1 in the paper] shows the range in amyloid area as measured by SEM (scanning electron microscopy).  A few COVID-19 patients had the same level of amyloid area as healthy controls and T2DM patients.

This data may be interesting because the Pretorius et al. group would later suggest that microclotting would be predictive of acute COVID-19 outcomes; it is unclear if diabetics should also experience COVID-19-like outcomes without a COVID-19 infection due to their microclots.  In [https://doi.org/10.3390/jcm10225381 the acute COVID-19 paper] published Nov 2021, the authors suggest that "the degree of platelet dysfunction and presence of microclots in circulation, together with TEG®, might be used as a guideline for disease severity". 

Near the end of the same year, the group also released a pre-print on microclots in long COVID / PASC patients.  The authors now hypothesized that microclots were responsible for long COVID symptoms:

<blockquote>Fibrin amyloid microclots that block capillaries and inhibit the transport of O2 to tissues, accompanied by platelet hyperactivation, provide a ready explanation for the symptoms of Long COVID/PASC.</blockquote>

Clinical application of their theory should provide more evidence for or against the latest hypothesis:
* [https://doi.org/10.21203/rs.3.rs-1205453/v1 Version 1] of the pre-print discussed the result of a multi-drug anti-clotting intervention.  Strangely, the pre-print had very few details on patient outcomes such as which symptoms resolved and the level of improvement.  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.”
* [https://doi.org/10.21203/rs.3.rs-1205453/v2 Version 2] of that same pre-print removes data on the 24 treated patients.  Nonetheless, the abstract calls for clinical trials ''without'' mentioning the previously-reported data: "Removal and reversal of these underlying endotheliopathies provide an important treatment option that urgently warrants controlled clinical studies to determine efficacy in patients with a diversity of comorbidities impacting on SARS-CoV-2 infection and COVID-19 severity."  It is strange for the researchers to call for RCTs while omitting their data that would be extremely relevant to their call to action.
* Version 2 also provides details on microclots in long COVID patients before treatment.  While the pre-print claims that the microclot/platelet testing is "simple and cost-effective", the paper only presents data on 30 of the 80 patients whose blood samples were analyzed.  It may be the case that data exists for all 80 patients (which the paper seems to state) and that the paper selectively presents data from 30 patients without an explanation as to why that subset was chosen.
* 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.

Constantinescu-Bercu et al. were not able to replicate the findings from Pretorius et al.  Constantinescu-Bercu et al. noted: 

<blockquote>“Seventeen of 19 (89.5%) patients had normal levels of α2-antiplasmin (Table, range: 103.8-137.1). This is in contrast with previous findings by Pretorius et al.”</blockquote>


'''References''':
* ''Prevalence of readily detected amyloid blood clots in ‘unclotted’ Type 2 Diabetes Mellitus and COVID-19 plasma: a preliminary report'' https://doi.org/10.1186/s12933-020-01165-7
* ''TEG®, Microclot and Platelet Mapping for Guiding Early Management of Severe COVID-19 Coagulopathy'' https://doi.org/10.3390/jcm10225381 - This earlier paper describes microclots in acute COVID rather than long COVID / PASC.
* ''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 - Version 1 of this pre-print describes clinical outcomes from triple anti-coag therapy.
* ''Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/ Post-Acute Sequelae of COVID-19 (PASC)'' https://doi.org/10.21203/rs.3.rs-1205453/v2  - Version 2 of this pre-print removes the clinical outcomes.  According to Resia Pretorius (personal communication), Pretorius and her team will be following up with the 24 (*they may try to increase the number) to see if they stayed reovered etc.  They will hopefully have a stronger dataset to share soon.
* ''The occurrence of hyperactivated platelets and fibrinaloid microclots in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)'' https://doi.org/10.21203/rs.3.rs-1727226/v1 - Version 1 of this pre-print reports microclots in some ME/CFS patients.
* (Youtube) ''Interview with Dr. Resia Pretorius: LongCovid microclots (spike protein, apheresis + other topics)'' https://youtu.be/C8tzTmVwEpM
* ''Analysis of thrombogenicity under flow reveals new insights into the prothrombotic state of patients with post-COVID syndrome'' https://www.jthjournal.org/article/S1538-7836(22)07182-3/fulltext

===Post COVID vaccination===

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>

==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.  More information on scientific evidence and treatment outcomes can be found on the [[Multiple_persistent_infections|multiple persistent infection]] page.

'''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

==Genetics and homozygous twins==
Some identical twin pairs report that one twin developed Long COVID (or COVID vaccine injury) while the other did not.  See [https://www.reddit.com/r/covidlonghaulers/comments/13pwe6n/identical_twin_with_long_covid_symptoms/ this Reddit thread].  As homozygous ('identical') twins have the same genetics, these anecdotes suggest that there are environment factors that play a minor or major role in the development of long haul syndromes.
# Original poster - "I am identical twin with what I believe are long covid symptoms. My twin and I both had the same virus a couple months ago but he recovered and I did not."
# mydogisfrank - "Same for me but with vax injury. My identical twin is fully vaccinated and boosted with 0 issues. I just passed my 2 year long haul anniversary."
# WhaleOnMe1989 - "Ha, I’m an identical twin in the same spot."
# Crazycattwin1986 - "Also a twin! Got long covid badly since infection (still suffering) and I thought my twin didn’t but we just realize she started having some really weird symptoms 2 months after having the vaccine. Difference is she started paxil and after some months she is completely normal. Im still fucked up and dont know if i want to take ssris."

Another poster, SanaFraley, reported that both identical twins became sick: "Me and my twin both got messed up, they couldn't care less."

=Post COVID vaccination syndrome (vaccine injury) only=

==Review paper==

* ''Adverse effects of COVID-19 mRNA vaccines: the spike hypothesis'' https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(22)00103-4

== Accidental intravenous administration instead of intramuscular administration ==

A Hong Kong research group used the Pfizer vaccine on mice.  When the vaccine was injected intravenously (rather than via the intramuscular route), the mice developed perimyocarditis.  

A German group studied IV versus IM administration of the AstraZeneca ChAdOx1 vaccine.

'''References''':
* ''Intravenous Injection of Coronavirus Disease 2019 (COVID-19) mRNA Vaccine Can Induce Acute Myopericarditis in Mouse Model'' https://doi.org/10.1093/cid/ciab707
* ''Thrombocytopenia and splenic platelet-directed immune responses after IV ChAdOx1 nCov-19 administration'' https://ashpublications.org/blood/article/140/5/478/485128/Thrombocytopenia-and-splenic-platelet-directed

== Activation of PRRs (Pattern Recognition Receptors) by PAMPs (Pathogen Associated Molecular Patterns) other than spike protein ==

Animals have specific receptors for PAMPs and DAMPs (Damage Associated Molecular Patterns).  Animal experiments demonstrate that these receptors are needed to help the immune system successfully fight off infections.  However, excessive activation of these pathways have been used to induce autoimmune disease in animal models.  Interactions with these pathways could explain why COVID vaccines lead to autoimmune conditions such as Guillain-Barre Syndrome and why certain adverse reactions (e.g. myocarditis) seem to be different between mRNA and non-mRNA vaccines.

MRNA vaccines contain multiple components that activate PRRs:
* '''The spike protein'''.  This activates the TLR2 pathways.  There is no consensus as to whether spike activates the TLR4 pathway.  See Khan et al. (DOI:[ https://doi.org/10.7554/eLife.68563  10.7554/eLife.68563]).
* '''Cationic/positively-charged LNPs'''.  
** Lipid Nano-Particles may activate TLR4.  Kedmi et al. report (DOI:[https://doi.org/10.1016/j.biomaterials.2010.05.027 10.1016/j.biomaterials.2010.05.027]): "we showed that activation of TLR4 might serve as the underlying mechanism for induction of an immune response when (þ)NPs are used."
** Abrams et al. believe that LNPs stimulate TLR2 and TLR (DOI:[https://doi.org/10.1038/mt.2009.208 10.1038/mt.2009.208]): "Immunostimulatory lipids are recognized by TLR2 and TLR4 on the cell surface of macrophages and other cells [...] The cytokine levels were comparable when animals were dosed with LNP201 containing Ssb siRNA, control siRNA, or no siRNA, suggesting that the majority of the inflammatory is induced by the lipid components"
* '''ssRNA''' - Activates TLR7 and TLR8.  Uridine is replaced with pseuodouridine to reduce stimulation of these pathways, as resulting activation of interferon I pathways will ultimately cause the immune system to shut down mRNA production of the desired antigen.
* '''dsRNA''' - Activates TLR3 and possibly other PRRs.  Double-stranded RNA may be found as an impurity from the manufacturing process used.  
** Verbeke et al. report (DOI:[https://doi.org/10.1016/j.nantod.2019.100766 10.1016/j.nantod.2019.100766]): By the formation of secondary RNA structures or through the introduction of contaminants of double-stranded (ds) RNA fragments during the IVT mRNA production process, immune activation can be triggered via the endosomal TLR3 pathway. In addition to these TLRs, dsRNA was shown to activate the cytosolic RNA sensors retinoic acid inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) [32–34].

It has also been found that empty LNPs can trigger inflammation.  Tahtinen et al. report (DOI:[https://doi.org/10.1038/s41590-022-01160-y 10.1038/s41590-022-01160-y]): "the IL-1 pathway plays a key role in triggering RNA vaccine-associated innate signaling, an effect that was unexpectedly amplified by certain lipids used in vaccine formulations incorporating N1-methyl-pseudouridine-modified RNA to reduce activation of Toll-like receptor signaling."

== LNP size can affect vaccine immunogenicity ==

An effect of LNP size was found in small mammals but not non-human primates, possibly suggesting a relationship with the diameter of blood vessels.  Because LNPs clump together due to the Oswalt effect, it is likely that LNPs can get as big as 800nm which is roughly the size of a capillary.  It is unknown if this is a problem.

'''References:'''
* ''Impact of lipid nanoparticle size on mRNA vaccine immunogenicity'' https://doi.org/10.1016/j.jconrel.2021.05.021

= ME/CFS =

== Craniocervical instability (CCI), Chiari, mechanical issues, etc. ==

The theory is that physical injury is responsible for ME/CFS (and possibly long COVID).  Such injuries can be triggered by a virus, an impact trauma, or other events.

Jen Brea and Jeff Wood are ME/CFS patients who experienced a ME/CFS following a series of surgeries.  Jen Brea has since unfortunately developed new chronic health problems following long COVID, as discussed in a [https://www.meaction.net/2020/11/12/important-news-from-jennifer-brea/ #MEAction news item].  There has also been one case of disabling results following surgery (occipitocervical fusion and posterior fossa decompression): https://www.jkrowbory.co.uk/2020/01/post-surgery-update-on-jenny/

Some patients with mechanical issues seem to see some symptom relief from neck braces, avoiding changes in barometric pressure from flying, living at lower altitudes, etc.

'''Resources''':
* Jeff Wood's website: https://www.mechanicalbasis.org/theory
* Jen Brea's medium: https://jenbrea.medium.com/health-update-3-my-me-is-in-remission-dd575e650f71
* Health rising: https://www.healthrising.org/blog/2019/05/21/jennifer-brea-chronic-fatigue-mecfs-recovering-story/

=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
* ''Persistence of residual SARS-CoV-2 viral antigen and RNA in tissues of patients with long COVID-19'' https://doi.org/10.21203/rs.3.rs-1379777/v1 - Persistence in appendix and breast tissue
* ''SARS-CoV-2 infection and persistence throughout the human body and brain'' https://doi.org/10.21203/rs.3.rs-1139035/v1 - An autopsy study found evidence of virus persisting in acute COVID patients, though it is unclear if these findings would generalize to long COVID patients.  89% of the patients died from COVID while 11% died with COVID.  13.6% of the patients had 'chronic immunosuppression' as a comorbidity, which could explain why virus was found for "up to 230 days following symptom onset".
* ''Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection'' https://doi.org/10.1016/j.medj.2022.04.001 - 4% of patients with COVID-19 shed fecal viral RNA 10 months after diagnosis.
* ''Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae'' https://www.medrxiv.org/content/10.1101/2022.06.14.22276401v1 - This paper claims to have found (full-length) spike in many long COVID patients.  However, a previous paper by co-author David Walt ([https://doi.org/10.1093/clinchem/hvaa213 Ogata et al.]) found "spike" in pre-pandemic samples.  See Figure S6 in the supplementary data.  Whereas the earlier paper discussed "assay cross-reactivity with other coronaviruses" and entertained the possibility that the Simoa assay found something other than full-length spike in post-pandemic samples, the newer paper lacks such a discussion.  Both papers discuss how full-length spike protein is often cleaved to create a S1 subunit; the newer paper provides a discussion as to why full-length spike protein is not being cleaved as expected.
* ''SARS CoV-2 detected in neonatal stool remote from maternal COVID-19 during pregnancy'' https://doi.org/10.1038/s41390-022-02266-7 - "These findings suggest in utero transmission of SARS-CoV-2 and possible persistent intestinal viral reservoirs in the newborns."
* ''Persistent SARS-CoV-2 Nucleocapsid Protein Presence in the Intestinal Epithelium of a Pediatric Patient 3 Months After Acute Infection'' https://doi.org/10.1097/PG9.0000000000000152 - Staining biopsied tissue with a rabbit monoclonal SARS-CoV-2 nucleocapsid antibody suggested the presence of mucosal SARS-CoV-2 virions.
* ''Persistent SARS-CoV-2 infection in patients seemingly recovered from COVID-19'' https://doi.org/10.1002/path.6035 - This study performed autopsies on elderly patients with some degree of pneumonia.  PCR found viral RNA in tissue lysates but not the typical nasopharyngeal swabs or bronchioalveolar lavage.  Authors noted that the "progressive worsening of clinical conditions in apparently PCR-negative patients after COVID-19 is often associated with the persistent infection of specific cell types in the lung".

===Gut bacteria reservoir?!===

One research group suggests that SARS-CoV-2 may actively replicate in gut bacteria, potentially explaining why viral RNA persists in fecal matter for several months in some patients.  Carlo Brogna [https://youtu.be/o2Y18P3TCjY?t=632 has presented his ideas at the Long Covid Coalition International Conference].  Highlights of his non-consensus ideas include:
* Toxin-like peptides are produced by gut bacteria and cause sequalae in long COVID
* SARS-CoV-2 has bacteriophage-like behaviour which allows it to infect eukaryotes and prokaryotes.
* SARS-Cov-2 replicates in human wastewater.  (This would be an observation previously unnoticed by the many organizations which regularly perform PCR screening on human wastewater.)

'''References''':
* ''Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection'' https://doi.org/10.1016/j.medj.2022.04.001 - 4% of patients with COVID-19 shed fecal viral RNA 10 months after diagnosis.
* ''Could SARS-CoV-2 Have Bacteriophage Behavior or Induce the Activity of Other Bacteriophages?'' https://doi.org/10.3390/vaccines10050708 - This study suggests that SARS-CoV-2 may have bacteriophage behavior (or bacteriophage-inducing behaviour) and that it may actually replicate in gut bacteria.

==SARS-CoV-2 has potential 'superantigenic' mechanisms==

Superantigens are potent antigens that can send the immune system into overdrive.  SARS-CoV-2 may be acting as a superantigen that leads to the depletion of naive T and B-cells in individuals with Long COVID. Superantigens are implicated in the development of autoimmune diseases and could explain why autoimmunity is so prevalent in long haulers.

Hamdy and Leonardi suggest that vaccination is a ''solution'' to superantigens as vaccination would reduce the dose of superantigen that a patient receives. They use MIS-C as an example but make no mention of MIS-V, which is MIS (multisystem inflammatory syndrome) caused by vaccination.

Rivas et al. argue that a superantigen-like motif (near the PRRA furin cleavage site) is the root cause of MIS in children (MIS-C).

'''References''':
* ''Superantigens and SARS-CoV-2'' https://doi.org/10.3390/pathogens11040390
* ''Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis'' https://doi.org/10.3389/fimmu.2022.941009

==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

=== Damage to the olfactory system (sense of smell) ===

Observational studies suggest that damage to the olfactory system is strongly associated with COVID infections.  Lasting effects on the sense of smell may be related to the initial COVID infection.

* ''Real-time tracking of self-reported symptoms to predict potential COVID-19'' https://doi.org/10.1038/s41591-020-0916-2 - Data from the Zoe app strongly suggests that loss of smell is a fairly good predictor of a future COVID infection (6.74X chance of developing COVID).
* ''Brain imaging before and after COVID-19 in UK Biobank'' https://doi.org/10.1101/2021.06.11.21258690