Transcript of video
Professor Cron, you are an expert in cytokine storm syndrome, cytokine storm syndrome. What is cytokine storm syndrome? How does cytokine storm syndrome become relevant for COVID-19 coronavirus patients? Cytokine storm syndrome is a an umbrella term. We like to use it to cover a group of hyperactive immune responses. There is some type of trigger in cytokine storm syndrome. Whether it’s an infection or a complication of a autoimmune or autoinflammatory disease. Or sometimes cytokine storm is a complication of cancer. It can be a complication of even the therapy for cancer. Under that umbrella there are multiple different named entities. That makes cytokine storm syndrome somewhat confusing. But it is also important because cytokine storms are not all identical. So we have to treat cytokine storm patients somewhat differently. Fortunately, in the end a lot of our therapies work. Many cytokine storm variants have some nuances. But in rheumatology cytokine storm syndrome has been named macrophage activation syndrome. These are complications of systemic lupus erythematosus or lupus. Still’s disease is an uncommon inflammatory arthritis that children and adults can develop. The original names for cytokine storm syndrome was hemophagocytic lymphohistiocytosis. It is more than the mouthful to say. HLH for short term. That’s a genetic disease that affects one in fifty thousand live births. Hemophagocytic lymphohistiocytosis is typically autosomal recessive. So both chromosomes are mutated for the same protein typically. We know a fair amount about the pathophysiology from these genetic conditions. We studied cytokine storm syndrome both in humans and in mice. Because these proteins that have been studied are involved in the immune process. There are certain white blood cells: lymphocytes, such as CD8 cytotoxic T-cells, or T lymphocytes, and NK or natural killer cells. One of their rules is killing infected target cells or antigen presenting cells. In the familial form of Hemophagocytic lymphohistiocytosis these immune cells have defects in that pathway. aIt could be in the protein perforin. Perforin was the first gene discovered for this cytokine storm disease. It was published in 1999, so not all that long ago. Perforin punches a hole directly in the target cell. But perforin itself has to be delivered to this synapse or connection between the killing cell and its target cell. That’s an infected cell. There are many proteins involved in transport process. They all have unusual names like RAB27A or Munc13-4. But if you are homozygous and deficient in those proteins, you will get this familial form of cytokine storm syndrome. HLH is a name of a subset of these cytokine storm syndromes. Then there are a lot of what we call secondary forms of that Hemophagocytic lymphohistiocytosis. In rheumatologic diseases where we call it macrophage activation syndrome. There are also a whole slew of infections that have been associated with cytokine storm syndromes. Many are viral infections but not all. They are bacterial, fungal, parasite infections. But many of them are viral infections particularly members of the herpes virus family member. So these are large DNA viruses, like Epstein-Barr virus. It causes mononucleosis. It’s probably the most notorious infection for causing a cytokine storm. But other members of that virus family including cytomegalovirus or CMV, herpes simplex viruses also can cause cytokine storm. Influenza virus can trigger a cytokine storm as well. Some influenza strains are more likely to cause a cytokine storm than others. The 2009 h1n1 strain pandemic. Now we know that this nasty COVID-19 coronavirus SARS-CoV-2 seems to be capable of causing a cytokine storm syndrome too. So a cytokine storm – this is a long explanation – it could be any of these syndromes. What happens is the immune system is no longer able to balance out the inflammatory response to whatever triggered it in the first place. In a normal situation, if you’re a normal host or a normal individual, and you get infected with the flu virus. Your immune system appropriately responds to infection and tries to clear it from the body. But your immune system is also designed to shut itself down after removing infectious pathogen. So that we’re not living in a chronic state of inflammation. But if you have a partial defect in immune system. Or a complete defect in the familial form of cytokine storm syndrome. Then you may have a problem with killing the virally infected cell. Then the lymphocyte that’s trying to kill target cell is actually spending more time engaged with the target cell. And that interaction increases levels of these cytokines. Cytokines are proteins or a kind of hormones of the immune system. Cytokines signal other immune cells to come over and help or to do other functions. When these cytokines keep getting increased and nothing stops them. Because these immune cells and target cells keep talking to each other instead of one cell killing the other and then leaving to go somewhere else. This is when patients get into trouble. So it’s really a dysfunctional immune response to whatever triggers it. But in case of COVID-19 coronavirus infection, it’s an appropriate response initially. Ultimately these pro-inflammatory cytokines get increased beyond levels that can be balanced by other cytokines. In our immune system we have pro-inflammatory cytokines that heat things up. But we also have cytokines that cool things down at the appropriate time. But in cytokine storm syndrome the pro-inflammatory cytokines are winning. They are dominating things that are supposed to keep them under control. Cytokines ultimately lead to multi-organ failure in many diseases with a cytokine storm. Whether it’s the liver being attacked or other organs, central nervous system. But in this case of COVID-19 coronavirus it’s a relatively unique cytokine storm. It really focuses on the lung. You can get this acute respiratory distress syndrome in other types of cytokine storm syndromes. But they tend not to be the initial inciting event. There are other features of the cytokine storm. It’s laboratory markers or other clinical features of COVID-19 coronavirus. They all seem to be a little bit different than our typical cytokine storm. But it shows enough features including the acute respiratory distress syndrome that we see in other types of cytokine storms. So we know that’s likely what’s going on. It may ultimately be what’s causing a lot of the pathology and death from this COVID-19 coronavirus pandemic. We get these viruses and we need to be able to treat the virus. For example we don’t know yet if we have any great therapies for COVID-19 coronavirus. Hopefully we well do. Therapy is being trialled in many places around the world. But if there’s an overly exuberant immune response to the COVID-19 coronavirus. We also have to be cognizant of that. We have to not only recognize it but do something about it. Because if it’s a cytokine storm killing you, then we need to respond to that too.