Our study explaining the pathophysiology of acute COVID has been published by ERJ, the flagship scientific journal of the European Respiratory Society @ERSpublications. Here, we describe how severe COVID-19 is NOT a viral pneumonia, but a post-viral autoimmune attack of the lung.
The target of this autoimmune attack is Annexin A2, a phospholipid-binding protein, which acts as a cofactor for tPA, ensuring integrity of the pulmonary vasculature and promoting lung elasticity. Antagonism of Annexin A2 would cause lung blood clots, pulmonary edema, and ARDS.
In essence, anti-Annexin A2 would cause all the hallmark pulmonary pathology already identified on autopsy among severe cases of acute COVID-19. Autoantibodies to this lung protective protein were already identified among hospitalized SARS patients. pubmed.ncbi.nlm.nih.gov/20015551/
Furthermore, Annexin A2 is also expressed in the vasculature of the brain. Therefore, antagonism of Annexin A2 can cause microvascular stroke and damage to the blood-brain barrier, which would result in neuro-inflammation and long-term neurological injury.
ncbi.nlm.nih.gov/pmc/articles/P…
The implications for acute COVID-19 are enormous. Not only would it explain why steroids work in this disease, but it would suggest that we should be treating the disease more like other autoimmune diseases of the lung. pubmed.ncbi.nlm.nih.gov/6336643/
We have misdiagnosed severe cases of acute COVID-19 as a viral pneumonia, which disregards the established evidence that shows viral load of SARS-CoV-2 is markedly diminished by the time patients develop the respiratory distress that only occurs in second stage of the disease.
We are also misdiagnosing Long COVID, which is also characterized by lung perfusion deficits, pulmonary fibrosis, and various neurologic sequelae. Our next studies will establish whether these autoantibodies are also present among patients with persistent post-COVID symptoms.
While we are just beginning to establish this evidence, prothrombotic antiphospholipid antibodies have already been well described by @jasonsknight @RayZuoMD and @YogenKanthi. Anti-Annexin A2 is a known "non-criteria" APL antibody that causes thrombosis. stm.sciencemag.org/content/12/570…
Here's our study identifying anti-Annexin A2 autoantibodies among hospitalized COVID-19 patients, which strongly predicted mortality. It's time for us to fully reassess how we define the pathophysiology of COVID-19 and consider alternative explanations. erj.ersjournals.com/content/early/…

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More from @DaveLeeERMD

May 8
Learned that there's something called type 2 asthma, which I had never heard before. It's often assigned to severe patients with poor response to standard therapy. However it's also prevalent among 50-70% of patients with asthma. Instead of "type 1" asthma, there is "non-type 2."
I see a lot of Long COVID patients get diagnosed with asthma, but then are poorly responsive to typical therapy bronchodilators. So then what is this? Type 2 asthma? I'm kind of thinking this is again our way of putting names on things that we just don't understand quite yet.
There was this recent study of CT scans demonstrating 25% of non-hospitalized Long COVID patients (versus 7% of healthy controls) having evidence of air trapping. What is seen is a mosaic pattern on CT consistent with a constrictive bronchiolitis. pubs.rsna.org/doi/10.1148/ra…
Read 6 tweets
Jan 29
Reading this article on the disordered vascular architecture of COVID-19 lungs was fascinating, but also something that I didn't know and some long harbored feelings about how doctors approached this disease caused by SARS-CoV-2. nationalgeographic.com/science/articl…
The idea that COVID-19 was a vascular disease predated so many other theories about the damage that occurred after SARS-CoV-2 infection, and that concept was published in NEJM way back in May 2020. That's right May 2020! I wasn't aware of that. nejm.org/doi/full/10.10…
Why did that idea not become more mainstream? Well plainly, the naysayers had to put their opinion in. Basically, someone had to say the standard refrain of well, actually that's not novel, we see this in ARDS all the time. nejm.org/doi/full/10.10…
Read 8 tweets
Jan 27
Cytotoxic T cells and activated B cells in the lungs of Long COVID patients that subsequently tested negative for SARS-CoV-2 by PCR on bronchoscopy samples. Sounds like a type of host versus host organ rejection. Note these markers were not in the blood but only in the tissues.
"Despite the presence of ongoing respiratory morbidity, the plasma proteins differentially expressed during acute disease appear to have returned to similar concentrations to those seen in healthy controls."
"In contrast, the post-COVID19 airways continue to display an abnormal proteome, with both distinct and shared features to that seen in acute disease."
Read 4 tweets
Dec 21, 2021
Though most people will develop a productive neutralizing anti-spike S1 immune response to SARS-CoV-2, here's more evidence that some will produce a non-neutralizing anti-spike S2 immune response that can result in loss of self-tolerance and autoimmunity. nature.com/articles/s4136…
In SARS-CoV-1, anti-spike S2 antibodies were found to be cross-reactive against lung epithelial cells, which suggested the possibility of SARS being an autoimmune attack of the lung. Notably, there is about 90% homology of S2 between SARS CoV-1 and CoV-2. ncbi.nlm.nih.gov/labs/pmc/artic…
This is critical as many studies of COVID-19 only use anti-spike S1 assays to identify cases including several studies of Long COVID. To be rigorous, every study of COVID-19 should be differentiating between neutralizing anti-spike S1 vs. non-neutralizing anti-spike S2 responses.
Read 4 tweets
Jun 29, 2021
Rheumatology consult please! When I read about Wegener’s most citations say c-ANCA antagonizes cytoplasmic proteinase 3 within neutrophils making them attack vascular walls. What about this study where proteinase 3 is expressed by the endothelium itself? sciencedirect.com/science/articl…
I guess because there were subsequent studies that showed that proteinase 3 was not expressed by endothelial cells? pubmed.ncbi.nlm.nih.gov/10792617/
Are there some c-ANCA like autoAbs yet to be discovered that activate the neutrophils leading the NETosis seen in COVID-19? Why is this neutrophil activation specific to small lung vessels in Wegener’s and to the microvasculature in COVID-19?
Read 5 tweets
Jun 26, 2021
Everyone hates math but I’m going to give it a shot and see if I can explain something about clinical trials and meta-analysis at least the way that I understand it. Say you have a rare event that you’re trying to prevent. It only happens maybe 1% but when it does it’s horrible.
Then you say there’s this incredible treatment that drops that bad outcome to 0.2% meaning in relative terms it’s effective 80% of the time when used. Based on power calculations you need a trial of 3000 patients to prove this point. Try it yourself here. clincalc.com/stats/samplesi…
Say no one has done a trial that big then are you allowed to just take 10 published studies of 300 in order to prove the same point? Can you take 100 published studies of 30? This is where people are making a statistical error in judgment because you’re ignoring publication bias.
Read 7 tweets

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