Severe cases should be treated with anticoagulants
Inhaled interferon, antivirals, and other effective treatments are probably much more effective when taken early to prevent the first few replication rounds.
A case is probably followed by a period of immune suppression, and possibly some T-cell immunity amnesia.
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The virus may be causing abnormal inflammation and a whole-body, but especially concentrated in the lungs, hyper-coagulable state that is triggering microscopic blood clots in the lungs that are one of the main contributors to morbidity and mortality and ineffectiveness of ventilation. Effective treatment of severe cases should probably include anticoagulants unless there are contraindications, and another effective treatment has been an interleukin inhibiting antibody normally reserved for severe arthritis. See the entire recent twitter diggings of @_ice9.
There have been major reports from clinicians that the lungs of COVID patients are not responding the same way as typical ARDS. The ability to get oxygen in the blood is too low compared to the amount of air they can get into them. Autopsies are revealing lots of small clots, and blood tests are finding the most predictive measurement of outcome is an indicator of blood clot dissolution (D-dimer).
Children with non-severe cases are having anomalously high rates of sores and discoloration on fingers and toes, indicative of diffuse coagulation in small vessels causing mild tissue damage that seems to heal on its own afterwards.
This hyper-coagulable state *might* explain the reports of anomalously low oxygen measurements in people that would ordinarily indicate death or unconscoiusness. They might have small clots in the finger the sensor is on triggering temporary sporadic low blood flow. It also could explain more of the fact that ventilators are less useful than they thought—some people going on them probably didn’t actually need them.
(Before anyone asks, that preprint that was making the rounds suggesting the virus was destroying hemoglobin was STUNNINGLY and EMBARRASSINGLY bad. Complete bullshit, not worth even hate-reading unless you find fantasy biochemistry from a universe in which chemical reactions have energies you normally associate with nuclear reactors and viruses do photosynthesis funny).
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Additionally, there are two bits of immunology that explain parts of this virus’s behavior and suggest ways of hurting it. First, the virus evolved in bats in which the interferon response is on an absolute hair trigger, and accordingly in human cells it almost completely escapes the interferon response. This allows it to replicate to absurd viral loads before the immune system notices it, explaining the extreme infectiousness shortly before symptoms develop. Then when the immune system notices it, it goes all out on a huge viral infection, triggering an inflammatory response that is all out of whack and can do a lot of damage. This means that it is vulnerable to inhaled interferon pretreatment (https://www.biorxiv.org/content/10.1101/2020.03.07.982264v1). On top of this, it may be that anything that reduces the replication of the virus in this period before the adaptive immune system mounts a robust response could reduce the probability of progression to severe disease. If antivirals work out or if chloroquine is effective (given the biochemistry I am very hopeful!), they will probably be most effective early via reducing the fraction of patients that progress to severe disease.
Second, there is evidence that the virus is able to enter and destroy (but not replicate within) T-cells using the same receptor it uses everywhere else, triggering immune suppression and altering the inflammatory profile (https://www.nature.com/articles/s41423-020-0424-9). It lacks HIV’s obscene dirty tricks and isn’t actually replicating within them, so this would be a temporary thing until recovery.
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That last bit may sound bad, but it is far from unique. When looking for other examples, one should look to the Measles virus. It too basically escapes the interferon response and grows to absurd highly-communicable levels (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC112268/), and it actually infects and replicates within T-cells and B-cells which it then rides throughout the body. This causes people who get the measles to basically forget 70% of their adaptive immune responses from before they were infected, and go through a period of immune suppression afterwards. I expect the loss of immune memory to be smaller in this case because the new bug doesn’t seem to infect B cells or all types of T-cells from what I have seen.
449 people. Specifically, they observed no difference in survival between heparin users/non-users overall, but in the very-high-D-dimer subset (or in people with lots of sepsis‐induced coagulopathy), survival seemed to be better with heparin.
This link carries no new information yet, but seems to be a placeholder for a future review paper on this topic.
The “blood coagulation as a major contributor to death” bit generally matches pretty well with some early results where high D-dimer predicted worse rates of mortality fairly reliably, since D-dimer is basically a problematic-blood-clot indicator.
There’s a potential complicating factor for the elderly, which is that many of them are already on anticoagulants (to mitigate stroke-risk). And going on some experiences of my grandparents, it seems to be hard to navigate the risks mitigated with anticoagulants with the risk of bleeding out unless you’re pretty careful. All the same, it looks like a promising line of improvement to treatment of severe COVID-19.
As for why blood clots are a problem in the first place… one of the hypotheses I’ve seen floating around is that it might be tied into complement system malfunction?
Warning that this is pretty speculative...
The complement system is an immune response that uses C-protein complexes to poke holes in membranes to kill cells and fight large infections.
This paper used results from 5 lung autopsies and tried to draw a link between the prolonged procoagulant state in the lungs with excessive activity of the complement system. I could barely follow it beyond that.
I had also heard before that complement system malfunctions were thought to be connected to bad vaccine response for SARS-1.
I don’t feel certainty in this at all. But it comes up semi-consistently, and I don’t have a better theory yet.
I think it’s a horse, not a zebra. ACE2 is expressed on endothelial cells lining blood vessels. If you get bad viremia the inner sheath of blood vessels, especially in heavily infected organs, probably just gets all messed up.
Claims:
Severe cases should be treated with anticoagulants
Inhaled interferon, antivirals, and other effective treatments are probably much more effective when taken early to prevent the first few replication rounds.
A case is probably followed by a period of immune suppression, and possibly some T-cell immunity amnesia.
-----
The virus may be causing abnormal inflammation and a whole-body, but especially concentrated in the lungs, hyper-coagulable state that is triggering microscopic blood clots in the lungs that are one of the main contributors to morbidity and mortality and ineffectiveness of ventilation. Effective treatment of severe cases should probably include anticoagulants unless there are contraindications, and another effective treatment has been an interleukin inhibiting antibody normally reserved for severe arthritis. See the entire recent twitter diggings of @_ice9.
There have been major reports from clinicians that the lungs of COVID patients are not responding the same way as typical ARDS. The ability to get oxygen in the blood is too low compared to the amount of air they can get into them. Autopsies are revealing lots of small clots, and blood tests are finding the most predictive measurement of outcome is an indicator of blood clot dissolution (D-dimer).
Children with non-severe cases are having anomalously high rates of sores and discoloration on fingers and toes, indicative of diffuse coagulation in small vessels causing mild tissue damage that seems to heal on its own afterwards.
This hyper-coagulable state *might* explain the reports of anomalously low oxygen measurements in people that would ordinarily indicate death or unconscoiusness. They might have small clots in the finger the sensor is on triggering temporary sporadic low blood flow. It also could explain more of the fact that ventilators are less useful than they thought—some people going on them probably didn’t actually need them.
(Before anyone asks, that preprint that was making the rounds suggesting the virus was destroying hemoglobin was STUNNINGLY and EMBARRASSINGLY bad. Complete bullshit, not worth even hate-reading unless you find fantasy biochemistry from a universe in which chemical reactions have energies you normally associate with nuclear reactors and viruses do photosynthesis funny).
-----
Additionally, there are two bits of immunology that explain parts of this virus’s behavior and suggest ways of hurting it. First, the virus evolved in bats in which the interferon response is on an absolute hair trigger, and accordingly in human cells it almost completely escapes the interferon response. This allows it to replicate to absurd viral loads before the immune system notices it, explaining the extreme infectiousness shortly before symptoms develop. Then when the immune system notices it, it goes all out on a huge viral infection, triggering an inflammatory response that is all out of whack and can do a lot of damage. This means that it is vulnerable to inhaled interferon pretreatment (https://www.biorxiv.org/content/10.1101/2020.03.07.982264v1). On top of this, it may be that anything that reduces the replication of the virus in this period before the adaptive immune system mounts a robust response could reduce the probability of progression to severe disease. If antivirals work out or if chloroquine is effective (given the biochemistry I am very hopeful!), they will probably be most effective early via reducing the fraction of patients that progress to severe disease.
Second, there is evidence that the virus is able to enter and destroy (but not replicate within) T-cells using the same receptor it uses everywhere else, triggering immune suppression and altering the inflammatory profile (https://www.nature.com/articles/s41423-020-0424-9). It lacks HIV’s obscene dirty tricks and isn’t actually replicating within them, so this would be a temporary thing until recovery.
-----
That last bit may sound bad, but it is far from unique. When looking for other examples, one should look to the Measles virus. It too basically escapes the interferon response and grows to absurd highly-communicable levels (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC112268/), and it actually infects and replicates within T-cells and B-cells which it then rides throughout the body. This causes people who get the measles to basically forget 70% of their adaptive immune responses from before they were infected, and go through a period of immune suppression afterwards. I expect the loss of immune memory to be smaller in this case because the new bug doesn’t seem to infect B cells or all types of T-cells from what I have seen.
Here’s a paper that situationally agrees with you on anticoagulants… Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy
449 people. Specifically, they observed no difference in survival between heparin users/non-users overall, but in the very-high-D-dimer subset (or in people with lots of sepsis‐induced coagulopathy), survival seemed to be better with heparin.
This link carries no new information yet, but seems to be a placeholder for a future review paper on this topic.
The “blood coagulation as a major contributor to death” bit generally matches pretty well with some early results where high D-dimer predicted worse rates of mortality fairly reliably, since D-dimer is basically a problematic-blood-clot indicator.
There’s a potential complicating factor for the elderly, which is that many of them are already on anticoagulants (to mitigate stroke-risk). And going on some experiences of my grandparents, it seems to be hard to navigate the risks mitigated with anticoagulants with the risk of bleeding out unless you’re pretty careful. All the same, it looks like a promising line of improvement to treatment of severe COVID-19.
Nitpick: __ice9 has 2 underscores, not 1.
As for why blood clots are a problem in the first place… one of the hypotheses I’ve seen floating around is that it might be tied into complement system malfunction?
Warning that this is pretty speculative...
The complement system is an immune response that uses C-protein complexes to poke holes in membranes to kill cells and fight large infections.
This paper used results from 5 lung autopsies and tried to draw a link between the prolonged procoagulant state in the lungs with excessive activity of the complement system. I could barely follow it beyond that.
I had also heard before that complement system malfunctions were thought to be connected to bad vaccine response for SARS-1.
I don’t feel certainty in this at all. But it comes up semi-consistently, and I don’t have a better theory yet.
I think it’s a horse, not a zebra. ACE2 is expressed on endothelial cells lining blood vessels. If you get bad viremia the inner sheath of blood vessels, especially in heavily infected organs, probably just gets all messed up.