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How does COVID-19 kill? Uncertainty is hampering doctors’ ability to choose treatments

RL_sparky

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https://www.nature.com/articles/d41586-020-01056-7

How does COVID-19 kill? Uncertainty over whether it is the virus itself — or the response by a person’s immune system — that ultimately overwhelms a patient’s organs, is making it difficult for doctors to determine the best way to treat patients who are critically ill with the coronavirus.

Clinical data suggest that the immune system plays a part in the decline and death of people infected with the new coronavirus, and this has spurred a push for treatments such as steroids that rein in that immune response. But some of these treatments act broadly to suppress the immune system, stoking fears that they could actually hamper the body’s ability to keep the viral infection in check.

“My greatest fear is that this gets taken to an extreme, where people are using whatever they can get their hands on to turn off the immune response,” says Daniel Chen, an immunologist and chief medical officer at IGM Biosciences in Mountain View, California. “You can’t knock down the immune system at a time when it’s battling an infection.”

Race for treatments
As coronavirus patients flood hospitals worldwide, physicians are wading through streams of incomplete data and preprints that have not been peer-reviewed, struggling to find ways to help their patients and sharing experiences on social media. Some doctors are trying cocktails of unproven therapies in a desperate bid to save lives.



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“People are watching patients deteriorate before their eyes, and there’s a very strong motivation to reach for any therapy that you think could be effective,” says Kenneth Baillie, an intensive-care anaesthetist at the University of Edinburgh, UK. “When I feel powerless at the end of a bed, I feel the same.”

Some of the earliest analyses of coronavirus patients in China suggested that it might not be only the virus that ravages the lungs and kills; rather, an overactive immune response might also make people severely ill or cause death. Some people who were critically ill with COVID-19 had high blood levels of proteins called cytokines, some of which can ramp up immune responses. These include a small but potent signalling protein called interleukin-6 (IL-6). IL-6 is a call-to-arms for some components of the immune system, including cells called macrophages. Macrophages fuel inflammation and can damage normal lung cells as well. The release of those cytokines, known as a cytokine storm, can also occur with other viruses, such as HIV.

The ideal counter, then, would be a drug that blocks IL-6 activity and reduces the flow of macrophages into the lungs. Such drugs, known as IL-6 inhibitors, already exist for the treatment of rheumatoid arthritis and other disorders. One called Actemra (tocilizumab), made by the Swiss pharmaceutical firm Roche, has been approved in China to treat coronavirus patients, and researchers around the world are working furiously to test it and other drugs of this type.

Immune challenges
But globally there is not enough of the drug to go round, and many clinicians are turning to steroids, which more broadly dampen the immune system, says James Gulley, an immuno-oncologist at the National Cancer Institute in Bethesda, Maryland. IL-6 inhibitors may suppress only those immune responses that are governed by IL-6, allowing other immune responses that might help the body fight COVID-19 to continue. But steroids and some other therapies that act more generally might significantly reduce the body’s ability to fight infection overall. These drugs will not only suppress macrophages, but also immune cells called CD4 T cells, which are crucial for initiating immune responses, and also CD8 T cells, which are the body’s antiviral assassins, capable of destroying infected cells with more precision than macrophages. “When things get really bad, they’ll throw on steroids,” says Gulley. “I am a bit worried about where some people are going.”



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Chen notes that although IL-6 levels are high in some acutely ill patients, viral loads are high as well, suggesting that the body is still fighting off an active viral infection. “You have to assume that there’s an ongoing antiviral immune response that is important to these patients,” he says. If so, then reducing CD4 and CD8 T cells could undermine that response.

Steroids and other immune suppressants are already being tested against coronavirus in clinical trials. In March, UK researchers launched the RECOVERY study, a randomized clinical trial that will evaluate the steroid dexamethasone and other potential treatments for COVID-19. This worries rheumatologist Jessica Manson at University College Hospital in London. Evidence from previous outbreaks caused by related coronaviruses suggests that steroids hold little benefit, and might even delay the time it takes for patients to rid themselves of the virus, she says. And the RECOVERY trial calls for giving the treatments before patients become critically ill and have no other recourse.

But Peter Horby, who studies infectious diseases at Oxford University in the UK and leader of the RECOVERY trial, notes that the trial will be using relatively low doses of steroid. “Higher doses are not routinely recommended, but the jury is out on lower doses,” he says. “And many authorities, including the World Health Organization, recommend a trial.”

Combination therapy
A combination of damage from both a virus and the immune response to it is not uncommon, says Rafi Ahmed, a viral immunologist at Emory University in Atlanta, Georgia. The effects of 'hit-and-run' viruses such as norovirus, which make people sick almost immediately after infection, are more probably due to the virus itself, he says. By contrast, people infected with viruses such as coronavirus do not show symptoms until several days after infection. By then, collateral damage from the immune response often contributes to the illness.

“It’s very hard to dissect what per cent of it is due to the virus itself, and what per cent is the immune response,” Ahmed says. “But it’s almost always a combination of the two.”



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In the absence of an answer, Ahmed is hopeful that researchers will arrive at a combination therapy, such as an IL-6 inhibitor that does not completely suppress the immune system, combined with an antiviral drug that directly targets the virus. Other drugs that target the immune system are also being tested, including one called anakinra, which targets a signalling protein called IL-1, and may provide a way to reduce specific immune responses without hampering CD4 and CD8 T cells, says Chen.

But Baillie says that given the widespread use of steroids to treat people with coronavirus already, it is important to collect data on the practice. And although he is also concerned about suppressing immune responses in coronavirus patients, he notes that it is still possible that the practice could hold some benefit. “The only responsible thing to do is to use them in the context of a randomized clinical trial,” he says. “There’s no other way to know if a treatment is working.”
 

Judee

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Learner1

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  1. Lack of oxygen, like high altitude sickness
  2. Damageto lung cells and heart?
  3. Cytokine storm?

Wonder if cell membranes and mitos are damaged in 2 and 3...

Wonder how Narik's C, thism7ne and steroid treatment for sepsis would work here, sling with oxygen. And maybe mito support?
 

JES

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There is so much work that could and should have been done by studying e.g. ME/CFS, Lyme or other post infectious patients, to see how the immune system goes on to respond from the point where acute infection develops to eventual recovering or to where it goes wrong and either the patient dying or becoming chronically ill. The conventional "wisdom" in medicine has always been to treat everything from acute infections to autoimmune diseases with various forms of immune suppressants, which has never been much successful other than in reducing symptoms. It seems clear to me that you need a tool set of different treatment options to tackle this virus depending on which stage of the illness the patient is in. These type of treatment options are currently completely lacking and while it's good to finally get everyone looking into this, at the point where we actually get results it might be too late to make an impact on COVID-19.
 

Diwi9

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I think the picture is going to get more complicated. The fact that people turn blue (cyanotic) before dying is a clue. It might not just be the lungs able to function properly...there may be problems with red blood cells delivering oxygen. New articles are discussing that ventilators are not necessarily helping and their extended use with COVID-19 patients may be causing more harm.
 

andyguitar

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Something that is often a cause of death among the critically ill is an 'opportunistic infection'. Baisically the body becomes so run down it is unable to stop the proliferation of bacteria and fungi (like candida) which are present in all of us. An old term for candida was 'Old mans blessing', so called as its proliferation ended the suffering of the very old and ill.
 
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It might not just be the lungs able to function properly...there may be problems with red blood cells delivering oxygen
According to the WHO, SARS punched holes in the lungs, giving them “a honeycomb-like appearance". In COVID, the effect is very similar, and is described as looking like "shattered glass". The holes are most likely created by the cytokine storm's aggressive, frenzied response, creating scar tissue that simultaneously protects and stiffens the lungs

At the same time, the inflammation created also makes the membranes between the air sacs and blood vessels more permeable, causing an effect described as "bleeding from the blood vessels", which would certainly impede effective oxygenation, and which can also fill the lungs with fluid and affect their ability to oxygenate blood, on top of losing huge quantities of it thru that leakage in a kind of perfect storm effect.
 

raghav

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https://www.researchsquare.com/article/rs-17806/v1

Withanone from Withania somnifera May Inhibit Novel Coronavirus (COVID-19) Entry by Disrupting Interactions between Viral S-Protein Receptor Binding Domain and Host ACE2 Receptor

Background

Newly emerged COVID-19 has been shown to engage the host cell ACE2 through its spike protein receptor binding domain (RBD). Here we show that natural phytochemical from a medicinal herb, Withania somnifera, have distinct effects on viral RBD and host ACE2 receptor complex.

Methods

We employed molecular docking to screen thousands of phytochemicals against the ACE2-RBD complex, performed molecular dynamics (MD) simulation, and estimated the electrostatic component of binding free energy, along with the computation of salt bridge electrostatics.

Results

We report that W. somnifera compound, Withanone, docked very well in the binding interface of AEC2-RBD complex, and was found to move slightly towards the interface centre on simulation. Withanone significantly decreased electrostatic component of binding free energies of ACE2-RBD complex. Two salt bridges were also identified at the interface; incorporation of Withanone destabilized these salt bridges and decreased their occupancies. We postulate, such an interruption of electrostatic interactions between the RBD and ACE2 would block or weaken COVID-19 entry and its subsequent infectivity.

Conclusion

Our data, for the first time, show that natural phytochemicals could well be the viable options for controlling COVID-19 entry into host cells, and W. somnifera may be the first choice of herbs in these directions to curb the COVID-19 infectivity.
 

andyguitar

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Could that mean it is possible to build up "herd immunity" to this thing?
Yes it does. However the burning question that needs to be answered is how long does the immunity last? I have seen reports saying some people have been re-infected. My own personal opinion is that is unlikely and it may just be a false positive test result.
 

ljimbo423

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According to the WHO, SARS punched holes in the lungs, giving them “a honeycomb-like appearance". In COVID, the effect is very similar, and is described as looking like "shattered glass". The holes are most likely created by the cytokine storm's aggressive, frenzied response, creating scar tissue that simultaneously protects and stiffens the lungs
What I don't understand is why the elderly, with the weakest immune systems are dying, if it's really a cytokine storm doing it. Why would weak immune systems cause the strongest immune system reactions, through a massive increase in cytokines?

This has been bugging me for a couple of weeks now.
 

ljimbo423

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Yes it does. However the burning question that needs to be answered is how long does the immunity last? I have seen reports saying some people have been re-infected. My own personal opinion is that is unlikely and it may just be a false positive test result.
I read 2-3 articles last night that said they think that some people are not being re-infected but instead, were still infected but had a false negative test, even though the virus was still active in them.

I don't know how long immunity will last either, my hope is at least until they can make vaccine. I had the virus, I'm pretty sure and it was very mild but I don't know if I get it again, I will be so fortunate.
 

andyguitar

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Why would weak immune systems cause the strongest immune system reactions, through a massive increase in cytokines?
Yes it does look strange, but I am wondering if when the immune system is weak the mechanisms for damping down an immune response are also weak. Look at it like this: If an immune response is weak would'nt it make sense that nature tries to compensate by trying to stop that response being switched off?
 

ljimbo423

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Yes it does look strange, but I am wondering if when the immune system is weak the mechanisms for damping down an immune response are also weak. Look at it like this: If an immune response is weak would'nt it make sense that nature tries to compensate by trying to stop that response being switched off?
I think you might be onto something. The antiviral immune response (the TH1 arm) is pro-inflammatory and is first to attack viruses. The adaptive immune system (the TH2 arm) is anti-inflammatory and where antibodies to viruses are made.

It could be that the pro-inflammatory response (th1 immunity) becomes out of control from fighting the virus, because of a weak or lacking th2 response or anti-inflammatory response. Leading to out of control inflammation, from a cytokine storm.

This might be at least one scenario.
 

ljimbo423

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One thing that suggests this is how common RA is in the elderly.
You're pretty sharp today Andy! :thumbsup: This says that RA patients immune systems are skewed toward TH1 immunity, which is pro-inflammatory and would cause there TH2-anti-inflammatory immunity to be weak-

The results illustrated RA patients were characterized by a disruption of Th1/Th2 balance towards Th1.
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