Cite this post as:
Scott Weingart, MD FCCM. EMCrit Wee – A Theoretical Model of the Pathophysiology of COVID-19 with Farid Jalali (Not a Single Thing Verified–Pure Musings). EMCrit Blog. Published on May 18, 2020. Accessed on January 20th 2025. Available at [https://emcrit.org/emcrit/pathophysiology-of-covid19/ ].
Financial Disclosures:
The course director, Dr. Scott D. Weingart MD FCCM, reports no relevant financial relationships with ineligible companies. This episode’s speaker(s) report no relevant financial relationships with ineligible companies unless listed above.
CME Review
Original Release: May 18, 2020
Date of Most Recent Review: Jul 1, 2024
Termination Date: Jul 1, 2027
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Thank you for this. I had a few questions about how this fits in with some of the other observations out there. This is more for my understanding of the disease and how it fits with the model, rather than a critique of the model itself. 1. If there is blood flow across bronchopulmonary anastomoses, and the bronchial circulation is a high pressure system, how is it that the pulmonary pressures can develop significantly enough to generate shunt, yet this disease is not associated with severe pulmonary hypertension/right heart failure? Is the proposal that these shunts are post muscular arteriole… Read more »
Hi Ryan and Thank you for your excellent questions. Some of these are my questions too. I truly meant it that this is purely a model, a framework, and lots of work is still left to get us to the true model of the disease. If I may though, I can attempt to answer some of your questions to the best of my understanding (which again, take it with a grain of salt as evidence is obviously lacking for a lot of this). 1. The proposed intrapulmonary shunts (i.e. “hyper-perfusion of gasless tissue” thru distended vessels commonly seen on CT… Read more »
Amazing explanation. I think you’re underestimating yourself; at least, no one ‘smarter than you’ seems to have appeared or come up with half of what you have. Perhaps someone within the field of PCCM will provide an alternate explanation, but for now, your model holds sway (and holds water for that matter..). You are integrating clinical observations and lab and imaging findings with the pathology and research findings in a way I haven’t seen before. Thank you for all that you are doing for people everywhere through your tireless efforts to understand, develop models, educate and discuss (in order to… Read more »
So this really makes one wonder about the efficacy of initiating a treatment with an ACEI + ARB at the earliest presentation of the disease. I’ve seen that Zhang P, Zhu L, Cai J, et al. showed survival benefit in patients who continue on a pre-existing ACEI or ARB, but I haven’t seen where anybody tried initiating them as possible treatment.. It appears that the University of Minnesota is planning a trial of Losartan initiation along these lines. (ClinicalTrials.gov identifier: NCT04311177) Does anybody know of any other evidence that might indicate STARTING an ACEI / ARB could be helpful?
Thank you for the information and things to ponder. I just have some hypothetical questions. If this is primarily a vascular issue as you propose and if this causes a vasculitis similar to Kawasaki’s disease in children Has anyone looked at Aspirin (perhaps higher dose) as a treatment strategy to prevent worsening outcomes? I can only find one trial at this point. I also suspect that many of the individuals who have died due to COVID were on aspirin 81 mg due to underlying comorbidities…. perhaps the dose needs to be higher and started early in the disease to prevent… Read more »
Ask yourself what happens with extensive hemolysis, Hypoxia drives the chain of evens leading to vasculitis, not the other way around. The Kawasaki-like syndrome is seen quite a bit AFTER hypoxia, all these kids present with igg, igm.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786764/
Covid patients’ blood contains immature, nucleated RBCs
https://health.ucdavis.edu/health-news/newsroom/what-the-blood-tests-of-a-covid-19-patient-can-tell-us/2020/03
Indicating higher erythropoiesis.
The reason you see silent/happy hypoxemia is because RBM is substantially higher, i.e. patients sought help substantially later than the onset of shortness of breath.
Children with the Kawasaki-like syndrome test negative on RT-PCR tests, i.e. have cleared the virus from their bodies, but test positive for covid-19 antibodies. Why such a delayed response? The current main stream working “theory” that it is a delayed immune response is plain wrong. Red blood cells normally live 120 days. Under hypoxia REPOS cells in kidneys overproduce erythropoietin, and cause bone marrow to pump out a lot of extra RBCs. (Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes) https://mcb.asm.org/content/35/15/2658 After sars-cov2 is cleared, and pneumonia recedes these kids end up with larger hematocrit, so their bodies start lysing… Read more »
Could you comment on this case study? https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25839 Also, would you be able to offer your opinion on respiratory distress in Neuroleptic Malignant Syndrome? My daughter suffered a case of NMS (from metoclopramide) during which she appeared to experience ‘happy hypoxia’. It seems that the currently accepted explanation for pulmonary edema in NMS is that it is due to aspiration pneumonia. However, I came across an article on dopamine and alveolar (and kidney) Na/K ATPase function, it seems the pulmonary edema in NMS could be due to suppression of Na/K ATPase activity. I only have an MSc in marine… Read more »
With this as background, what do you think of https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213974/? Are there pharmacological answers to be found in study of the kinin-kallirein system? Also, what about UPSTREAM renin, angiotensin or ACE reduction?
Concerning my second question, your references to angiotensin 1-7 and endothelial stabilization are noted. I don’t know much about those topics, so there may be something in what you’ve already said about which I just need more explanation.
Thank you for putting together something like this. Its one thing to hypothesis but quite something else to able to convey it to others. I’m an EM registrar from South Africa – and we starting to get into our peak now in Cape Town. I am interested in the low levels of PaHT in these cases. Do we have evidence to show that PA pressures aren’t really increased (as is the case for ARDS https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-014-0028-6)? Acute RV pressure overload from PE is caused by pulmonary vasoconstriction – in the absence of a significant shunt to offload the pressure? – I… Read more »
Great work you have done on your logical theory of the pathophysiology. I’m of the opinion that besides the anticoagulation you suggested, Hyperbaric oxygen therapy may save the patient by providing an extension of Henry’s law to allow oxygen to perfuse to all tissues, reduction of inflammation while allowing the compensatory physiology to do it’s intended function.
This would reduce damage caused by the ventilator peep and air hunger.
What are your thoughts?
test
Thanks Dr Jalali for your beautiful detective work. Please see: Vitamin D and Endothelial Function Do-Houn Kim et al. Nutrients 2020, 12(2), 575 https://www.mdpi.com/2072-6643/12/2/575 Vitamin D is vital for endothelial cells to produce NO for vasodilation, to protect them from inflammation and lesions and to inhibit platelet adherance and aggregation. Please also see this research from the Philippines (Mark Alipio https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3571484 ) and Indonesia (Prabowo Raharusun et al. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3585561 ). Hospital COVID-19 patients with 30ng/ml 25OHD vitamin D generally had few or mild symptoms, while those with less than 30ng/ml were at a very high risk for severe symptoms and… Read more »
An article released in the last day or so contains many details of lung pathology from COVID-19 and H1N1 influenza in 2009: Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19 Maximilian Ackermann et al. NEJM 2020-05-21 https://www.nejm.org/doi/full/10.1056/NEJMoa2015432 “The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (P<0.001). In lungs from patients… Read more »
Legit not finding this podcast on any of platforms ….was it taken down?
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I really appreciate the efforts behind this article,
I really liked reading this article.
Maybe at the end the ride on the roller coaster, maybe a disrupted center of gravity is even better than a lay on your face approach, you can tell the patient that you’re at the end of the ride, and now, maybe we can give you something that may help you!! Sorry you guys are so handcuffed. Peace!!
Excellent and rational explanation of what I have seen in patients in our ED the UK. Best and only model that makes sense to me. Amazing work. Brilliant thinker with an amazingly patient wife.
Thank you for your presentation. I agree with most of your hypothesis. Especially part with VQ mismatch, at the beginning of pandemic I came up with my theory which was based on vascular phenomenon and VQ mismatch as a main pathophysiologic mechanism of COVID19. For main cause of pulmonary vasoconstriction I had hypoxia and acidosis . I had it wrong when I thought that SARS CoV2 with it’s spike protein was causing vasodilation from the get go, of course it is causing vasoconstriction on initial stage and vasodilation on the later stage. Nevertheless you can watch my presentation, which I… Read more »