How to diagnose Cytokine Storm Syndrome in COVID-19 patients? (4)

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How to diagnose a cytokine storm syndrome in a COVID-19 coronavirus patients? Can a diagnosis of cytokine storm be made before it manifests clinically? Cytokine storm can dramatically cause acute respiratory failure. I think that’s really the million dollar question. If we can we recognize cytokine storm before people get deadly ill. We talked about this umbrella of cytokine storm syndromes. So we’ve been trying as a community of researchers to develop criteria for diagnosing many cytokine storm syndromes. Some of these criteria that we’ve generated over the years are very broad. So potentially we could diagnose any type of cytokine storm. Some diagnostic criteria are very specific for the diseases where cytokine storm occurs. Most commonly, for example, in children with systemic juvenile idiopathic arthritis. It is a type of arthritis with high fevers and chronic inflammation. So we can use these prior criteria for cytokine storm. Some diagnostic tests were better than others for different types of cytokine storms. None of tests are perfect. But we know there are signs that are commonly shared. That helps us diagnostically with many of these cytokine storms. A simple, quick and cheap, and readily available test that is often used is a serum ferritin test. Ferritin test existed for a long time. If your ferritin value is low, that’s often an indication of iron deficiency anemia. So blood ferritin test is run frequently for those health problems. But if someone is very sick and has fever. Blood ferritin test can be a quick and fast early screen for a cytokine storm syndrome. Normal blood ferritin is 200 nanogram per milliliter. Ferritin is not often much lower than that in normal healthy individuals. But in inflammation ferritin can increase. Ferritin is not specific at low to moderate levels for a cytokine storm. The higher the ferritin value goes, the more specific ferritin becomes to predict a likely cytokine storm. This is particularly true in a previously healthy individual who doesn’t have chronic liver disease. Or who gets repeated transfusions for anemia. But this is where COVID-19 coronavirus makes things tricky. Take a typical cytokine storm in someone with macrophage activation syndrome, for example. Serum ferritin level can get very high very fast. Ferritin level can be in the tens of thousands or even hundreds of thousands nanogram per milliliter. It’s not really a question of what’s going on at that point. No matter what other clinical information you have. With COVID-19 coronavirus ferritin definitely gets elevated in a majority of people. Although I’ve even heard about a patient where they were pretty clear there was a cytokine storm. But blood ferritin level was normal. But for the most part, instead of being in the ten thousand or higher range, ferritin tends to run in the 1,000 to 2,000 to 3,000 range. Ferritin can go higher than that. I’ve heard of COVID-19 coronavirus patients with ferritin levels even in the 10,000 range. But for the vast majority of COVID-19 coronavirus patients ferritin is moderately high. Even in patients who are really sick with the cytokine storm, ferritin is elevated in 1,000 to 2,000 range. In a setting of someone with COVID-19 coronavirus. You may suspect COVID-19 either diagnostically based on the the chest imaging. Or a patient has a positive COVID-19 coronavirus genetic test, a PCR test, and a fever. Then a ferritin alone may not quite let you diagnose a cytokine storm syndrome. But ferritin test will certainly help you to move in that direction. There are other laboratory tests that may help you predict a cytokine storm. A lot of times the liver is a target in cytokine storm syndromes. Once again for this COVID-19 coronavirus live is a target. But usually liver is damaged in less degree compared with other cytokine storms. So you can measure liver enzymes. They will go up when the liver is unhappy or sick. Particularly an enzyme lactate dehydrogenase gets pretty high. Lactate dehydrogenase can go up for variety reasons. But that one at least gets high. This is according to some of my colleagues in Italy. They are suffering through COVID-19 coronavirus crisis right now. Liver enzyme LDH gets pretty high. It is a good sign that you have a cytokine storm ongoing. Because one of the consequences of cytokine storms in general is a coagulopathic state. Blood is clotting too much. Or you bleed too much. Typically bleeding too much is more frequent. Although this COVID-19 coronavirus once again is different. We’re starting to see that a lot of patients are having blood clots. Whether it’s pulmonary emboli or thrombi in their central nervous system. It’s unusual in that way. We often see central nervous system involvement in cytokine storm. Even up to a half the patients with cytokine storm syndrome. But this blood clotting is very unusual. Nevertheless, there’s a test called a D-dimer. D-dimer is breakdown products of the fibrinogen clotting cascade. D-dimer often become very elevated. It is also a very nonspecific marker of inflammation. But D-dimer seems to be very high in many of COVID-19 coronavirus patients. C-reactive protein level also increases. That’s another potential tool to use to help diagnose cytokine storm syndrome in COVID-19. C-reactive protein is a cheaper equivalent of interleukin 6. Interleukin 6 is a pro-inflammatory cytokine. But it doesn’t perfectly correlate with cytokine storm syndrome either. Interleukin 6 sometimes gives you an excuse me indication that interleukin 6 is elevated. You can measure interleukin 6. But that’s not typically readily available in the average laboratory. Once again in many cytokine storms interleukin 6 can be very high. In COVID-19 coronavirus interleukin 6 is high. But it tends not to be as high. Occasionally there are patients where C -reactive protein gets very high. So there are several methods of getting lab tests that will confirm a cytokine storm. Another important test is the complete blood count. It is going to give you you white blood cells and your distribution of white blood cells, your red cells, and your platelet (thrombocyte) counts. COVID-19 virus has a strong propensity to decrease your lymphocyte count. Lymphocytes could all just hide in the lung. Or lymphocytes are destroyed. No one at this point really knows. But your lymphocytes in general tend to go under 1000 per cubic millimeter. So they get pretty low in this disease. So that’s also another good sign for COVID-19 coronavirus that you likely have a cytokine storm brewing. The platelet (thrombocyte) count can also get low. It is increased when you have inflammation in general. it tends to go up so even account of maybe 180, which would normally be considered normal. It maybe can be considered abnormal in the setting of a lot of inflammation. But platelet numbers can also get below normal values as well. There are a number of factors, a lot of them are acute reactants. These laboratory indicators are known as acute reactants. But if a person is admitted to hospital, but not in a state that requires the ICU level care. What tests would clinical team be doing right away, upon admission, daily or twice daily? The goal is to predict cytokine storm. Because that’s a very important thing – predicting who can deteriorate. Because some of the physicians who are treating patients in the ER, they really struggle with decisions where to move the patients. Doctors are appropriately worried that if they put the patient onto the normal ward, the patient might not get enough of the care. Patient might not get enough vigilance. So acute deterioration of breathing can be missed. So what would be your best guess as to how these tests can be performed on patients who are not yet in acute overt respiratory failure? Yeah, I think that’s really one of the hallmarks of getting through this pandemic. It is really diagnosing cytokine storm early. Making a Diagnosis early. It’s important. But then you have to decide, what am I going to do about it? That gets complicated, and we can talk about that a little bit. But yeah, I would say if you test positive for COVID-19 coronavirus. If you have a fever and any degree of respiratory distress. Whether it’s breathing over 30 times a minute, or having an oxygen saturation below 93% on room air. This, for example, shows you’re starting to struggle with your breathing. And from talking and listening to our colleagues and reading reports on this, it’s at that point where not everyone, but a subset of patients can crash and burn within 24 to 48 hours. These patients will require mechanical ventilation very quickly with this lung inflammation and fluid that builds up in the acute respiratory distress. So that’s the point where I think if you’re sick enough to be admitted. And we have to recognize that kind of a moving target these days, because hospitals are getting overwhelmed. So what patients may have admitted two weeks ago, they may be trying to deal with at home. But in general, if you’re sick enough to be admitted to the hospital, with this virus and you have a fever. That would be the time at a minimum to get maybe a ferritin, a complete blood count, maybe some of the liver enzyme tests I talked about. A C-reactive protein, for example. And maybe the D-dimer. I think would be another kind of valuable test. And you’re right. So if you admit them, and they’re not kind of quickly headin, you know, it’s hard to know, into trouble, then you may want to certainly check it again. I don’t know, I don’t know what the answer is. Maybe do these tests every 24 hours, maybe 12 hours, maybe 36 hours. No one really knows. And you’d have to use your clinical judgment for the that individual patient again. And if you see things going in the wrong direction, then maybe that’s the time where you need to do something. But I do think this concept of treating patients for a cytokine storm, before they require mechanical ventilation. Before patients need intubation or any type of ICU care. Whether it’s blood pressor support to keep your blood pressure up, for example. It is the time that you’re more likely to get best results out of any therapy you use. Because by the time you get that sick, it’s very hard to reverse it. That’s not to say that we should give up on treating the cytokine storm. But I think treatment is much more likely to be beneficial the earlier you treat. And we know that actually even from some of our data on other cytokine storm syndromes, the earlier treat, the better you do. It’s kind of a no brainer, maybe. But it’s nice to have some of that diagnostic test data to support that concept.