COVID-19 Cytokine Storm Syndrome. Therapy options before it’s too late. 4

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What are the treatment options for cytokine storm syndrome and what drugs were tried in other diseases that manifest with the cytokine storm? What medications have already been used to treat COVID-19 Coronavirus patients with a cytokine storm? It’s a great question. So it’s easy to speak about what has been used in other cytokines storms. And then the tougher question is this. Do we use those same types of therapies for COVID-19 coronavirus? Because COVID-19 is so novel in many ways. So it depends, right? So now we go back to these different names of cytokine storm: the macrophage activation syndrome, the HLH, the cytokine release syndrome. This cytokine storm we see in leukemia patients who are refractory to chemotherapy. These patients get these fancy CAR-T cell approaches to therapy. But in a subset of leukemia patients, they also get a cytokine storm syndrome. Interleukin six tends to be a dominant cytokine, maybe interleukin one too. And so, these treatments vary. We don’t have real randomized trials for any of these. We have one clinical trial here in Birmingham that we started before COVID-19. But it’s a very small clinical trial. And we only enrolled eight or nine patients at this point. But there aren’t randomized trials with the current exception. And it’s not published yet, but it’s FDA approved. We have an antibody against interferon gamma. It was used to try to treat infants who get a familial form of HLH or hemophagocytic lymphohistiocytosis. From what I hear, it worked very well. And these were patients who were not doing well. They had issues with the chemotherapeutic protocol, which is pretty aggressive. But these children would die without it. So that’s the one FDA approved drug we have for the genetic or familial form of cytokine syndrome. It’s not approved for these secondary forms of cytokine syndrome that happen in older children or adults later in life. And whether you’d want to be targeting interferon gamma in a viral-induced cytokine storm is another question. It worked in the mice, actually. But you’re balancing any of these approaches. But particularly with anti-gamma interferon, the ability to control the virus is important. At the same time, if it’s the immune system that’s killing you, that may dominate. So the treatment may improve that aspect of your care relative to maybe not controlling the virus well. Then that may be a reasonable trade-off if the alternative is mortality. But a long time ago, people learned something important early on for various subtypes of a cytokine storm, including macrophage activation syndrome. In some of the rheumatologic diseases corticosteroids are these broadly immunosuppressive drugs. Steroids are our best friend and our worst enemy. They do fabulous things when you need them. But steroids have lots and lots of side effects, both short and long term. Steroids have saved lots of lives of the people who have had cytokine storm syndromes over the years. Corticosteroids are very broad, they attack essentially every aspect of immune system, at least the cellular aspects of it. And steroids work quickly, and they tend to work well when they work. But people worry about steroids. Let’s get back to SARS specifically. Then I’ll come back to the general cytokine storms. In the past, steroids were tried in SARS in 2003, the MERS epidemic, or even in some bad strains of influenza. The data on steroids efficacy is all over the map. They’re not perfectly controlled trials, most of them. But there was a Cochrane analyses of the influenza trials. It’s very hard to conclude anything from steroid treatment clinical trials basically. But there is concern that they don’t help or they although some say they do and others say steroids don’t work. Steroids may cause more harm than provide benefits. The World Health Organization is made it clear that we should not be using corticosteroids for COVID-19 coronavirus. That’s on most people’s radars, with the exception of, for example, patients with asthma who may need it for an asthmatic flare control. Even if they have COVID-19. But anyway, corticosteroids were kind of our first big gun drugs against cytokine storm syndrome. Steroids are often still used for many cytokine storm syndromes. Other kind of broad immunosuppressive types of agents are these things called calcineurin inhibitors, and there they go by names like cyclosporine or tacrolimus. And they are not as broad as is corticosteroids. They tend to attack more these adaptive immune cells, the lymphocytes, which often are the problematic one of the problematic cells and cytokine storm syndrome. They have side effects too, right. And so there is No suppressive. And if you’re in a hospital setting, particularly the ICU setting, yet, maybe a lot of different lines coming in out of your body, you know, you worry about infection. And so both of those types of drugs, you worry a lot about infection cyclosporine, and medicines like that you worry about kidney function and blood pressure. So there’s a variety of things, you know, to be concerned about. But once again, depending on how ill you are, you have to weigh that against the potential benefit of treating the cytokine storm that’s making you sick. But recently, in the last couple decades, we’ve had the benefit of more targeted approaches, and in that instead of having to be so broadly immunosuppressive, and these drugs can be used with the more broadly immunosuppressive drugs as well. We have these novel biologic agents, many of them are kind of engineered agents, whether they’re monoclonal antibodies, or even recombinant human proteins that are proteins that normally dampen the immune response that we can just make more of and get back as medicine. That target very specific side kinds like interleukin one r IO one or interleukin six or gamma interferon or interleukin 18. And TNF, which you know, those drugs I think a lot of people are familiar with because they’re used to treat rheumatoid arthritis and juvenile arthritis and oh, and inflammatory bowel disease, psoriasis, a whole variety of excuse me, autoimmune diseases, and they’ve revolutionized care for a lot of people. Now, they’re, they’re not the cheapest drugs in the world, but they’re, they tend to work rather well. And their side effect profile is tolerable. They mean there’s some risk of infection, possibly some malignancies, but overall they’re they’re very widely used and they work when they, they, they work well often and beside a kind of storm syndromes. They’re kind of hit and miss the TNF inhibitors particularly. Sometimes they work sometimes they’re considered a trigger it’s very hard to know but what any of these drugs will do in in the COVID-19 cytokine storm is is completely unknown. But the beauty of some of these targeted approaches is you, you still are at risk for infections, some of these more than others. But they don’t target cells in your body. No, almost all the drugs we take out set up like antibiotics, antivirals target cells in your body. they do a pretty good job, you know, hopefully, of targeting the cells that you want them to target, but they have off-target effects. And that’s the reason we get some of the side effects we see and various therapies. But these don’t do that. They target these inflammatory proteins or cytokines that are circulating throughout the body during these cytokines storms and try to dampen them down and bring the immune system back under control. There are even medicines now that target downstream of these inflammatory cytokines because they’re they work by binding to receptors on cells and then signaling in those cells. And there are these small molecule inhibitors of proteins called Janice kinase and stat proteins that are associated with many of these receptors. And so by targeting certain jak stat combinations, you often end up targeting several cytokines that signal through those receptors. So as opposed to going after one side of a kind of two cytokines, you may be targeting three or four. But once again, you know, then you’re making a trade-off of, you know, you may want to focus one, but maybe not the other. And so, and it’s hard to know, but I think those are also out there as potential options. But these are kind of the things that we’ve been using over the years including chemotherapy, for severe cases of cytokine storm that have shown promise then, you know, it saved lives.