Feature

Weathering the cytokine storm in COVID-19: Telltale signs, therapeutic hope on the horizon

Randy Q. Cron

Good news about COVID-19 is at a premium these days. Encouraging reports about therapeutic options or vaccine development usually are either overly optimistic or entirely spurious. But scientific advancement is as relentless as the virus itself, and this is exemplified by a growing body of research into a potential association between cytokine storm syndrome and COVID-19.

Randy Q. Cron, MD, PhD, of the Children’s Hospital of Alabama and the University of Alabama at Birmingham, described cytokine storm syndrome as an “overly exuberant” immune response to something like a viral infection or cancer. While it is not currently known why some patients with COVID-19 demonstrate this response and others do not, plenty is known about these inflammatory immunologic proteins and how they have reacted in other disease states, many of them rheumatologic conditions.

This puts rheumatologists in the unique position of being able to instruct colleagues in infectious diseases and intensive care how to manage this severely impacted subpopulation of individuals with COVID-19. In an interview with Healio Rheumatology, Cron shared his insights on how cytokine storm may be contributing to the current pandemic, telltale symptoms to watch for and possible treatments on the horizon.

Q. How might cytokine storm be related to increased severity of COVID-19 found among some patients?

 
Cytokine storm may be contributing to the COVID-19 pandemic, according to Cron, a development that may bring rheumatologists to the forefront of this evolving field.
Source: Adobe

Cron: We started thinking about this after reading some of the earliest case reports from the literature about patients in China. The reports showed many of the clinical features and lab values that we of see in cytokine storm syndrome.

Q. Can you zero in on some of the similarities between cytokine storm syndrome and the COVID-19 patients you saw in the literature?   

Cron: The signals were very strong that the subset of patients who had the most severe form of COVID-19 were likely experiencing some kind of cytokine storm. Now, it is important to note that there is context for this. We had similar thoughts a decade ago with the Ebola outbreak, and this can also be seen in some patients who develop dengue fever. Doctors have been trying to target the cytokine storm in these patients for a long time, so, it is not too crazy of an idea. We are attuned to it.

Q. What were the lessons you learned from those other outbreaks and infections?

Cron:In short, it seems like what was killing some of these patients was not just the virus, but the body’s immune response to the virus. This puts clinicians in a very delicate position. Of course, it is important to treat the virus, you also have to consider whether treating the immune response could also mitigate fatalities in some of the most serious patients. There are no home run therapies for this disease yet, so we are trying to consider all of our options.

Q. How can physicians, particularly ICU doctors who are on the front lines and dealing with these sickest patients, identify patients with COVID-19 who may have this cytokine storm?   

Cron: By necessity, we have been looking at how ICU doctors have been managing patients in the places that have been hit the hardest, including Italy, New York City and Philadelphia. Ideally, any time you have a patient who comes into the ICU with a serious condition like this, you take a slew of labs, you have pathology findings, some of which might take a week or 2 to get back.

However, because they are so overwhelmed, in terms of practicality, our colleagues in Italy are looking at a few key parameters in the most serious COVID patients, including serum ferritin and C-reactive protein (CRP). The ferritins go up when you have a cytokine storm. Now, they do not go up screaming high like they do in a condition like macrophage activation syndrome (MAS), but they may go into the thousands of nanograms per mL. As for CRP, they are using low thresholds.

Q. How can this information inform clinical decision making for those ICU doctors?   

Cron: If you have patient with COVID-19 who has a high fever and respiratory distress, elevated ferritin and/or CRP may be used as surrogate decision-making criteria to determine if the patient has cytokine storm syndrome. On top of that, simple turnaround labs such as a complete blood count can also help to confirm that this is happening. These patients can become lymphopenic or thrombocytopenic. Liver enzymes can also be elevated, but not screaming high like in MAS. Lactate dehydrogenase tends to go up in a cytokine storm. Coagulopathy can also be present. I would look at D-dimers. All of these are signals that ICU doctors can be on the lookout for.

Q. How can understanding of these lab parameters improve patient outcomes?   

Cron: This is my personal opinion, but the goal is to treat the cytokine storm right away, prior to admission to the ICU and before they need intubation. I want to stress that this intervention is not everyone with COVID-19. I would not recommend this for anyone who is asymptomatic, of course, or even patients who are at home with a high fever and a cough. I am talking about patients who are severe enough to be hospitalized, and I would recommend acting on this within the first 24 hours of admission.

Reducing the number of patients who are admitted to the ICU is going to have a number of benefits, including reducing the number of health care workers who are required to be there on the front lines.

Q. Once patients with cytokine storm syndrome have been identified, how can they be treated?   

Cron: Before I talk about treatments, I want to make an important clarification. No one wants to watch patients die without doing anything. But, of course, we do not want to mistreat patients and do harm, either. This raises the conundrum of whether we wait for clinical trials to emerge, showing, conclusively, the safety and efficacy of these medications, or whether we look at the anecdotal evidence that is emerging in real time, and try to treat them as best we can. I do not envy our colleagues in hard hit areas who have to make these choices every day.

However, we are starting to see one clear trend: These doctors are not waiting. This is an unprecedented time. People are dying. We should not just try any random idea that pops into our head, but if there is rationale for an idea — and I believe there is rationale for the treatments I am going to discuss — we should be aware of it. And it probably goes without saying, but I will say it anyway, in big, bold letters: Do not try this at home. These treatments are for patients being treated by experts in a hospital setting.

Q. Understandable. Can you discuss some of the treatments you think will be effective?   

Cron: The first agent to consider is the IL-1 inhibitor, anakinra (Kineret, Sobi). It is remarkably safe, it has a large therapeutic window, it has a short half-life and it works quickly when it works. If a patient is not responding, you can just take them off of it as though it was never in their system. We have a fair amount of experience with it, and hopefully clinical trials will bear it out.

Regarding other therapies, IL-6 inhibition also makes sense. There are two approaches to IL-6 inhibition. One is using antibodies to block IL-6 directly, and one is to block its receptor. Both can work. As far as other targets go, interferon-gamma, along with janus kinase (JAK) and signal transducers and activators of transcription (STAT) inhibitors can be effective. Regarding the JAK/STAT pathway, these target cytokine receptors downstream. In addition, they are often not just targeting one cytokine, but many. There are a lot of potential modalities out there — we simply do not have the trial results.

Q. Are the ICU doctors aware of a) the possibility of the cytokine storm and b) the potential utility of these therapies to treat it?

Cron: Many are aware, in general. But you have to understand that infectious disease and intensive care doctors, because they regularly see patients dying from sepsis, are very cautious about immunomodulatory therapies.

Q. What are some of the potential risks involved in the treatments you mentioned?   

Cron: It is important to understand that the risks are very different for these treatments. In my opinion, anakinra is likely the safest. It can cause liver enzyme elevations and platelets to go down but using it at lower doses can be remarkably safe and effective otherwise. Anecdotally, it seems to be working in COVID-19. The issue at the moment is that I do not think we will have enough of that to go around.

Q. Are there concerns about immunosuppression in these patients?

Cron: Most of the targeted approaches I discussed are more immunomodulatory than immunosuppressive. But here is something else to consider, and something that may be the most controversial, in terms of the opinions I have expressed: If any of these immunomodulatory approaches work in the subset of patients who have cytokine storm syndrome, it is likely that corticosteroids will work as well.

However, the WHO is recommending — strongly, strongly, strongly — against them, largely because of experiences with SARS and MERS. But I wonder if steroids were simply given to the wrong subset of patients with those infections. I am not saying we should just throw steroids at everyone, but we may end up relying on them. And this is not just a hunch. This is based on what I have been talking about. I believe they might help keep the case/fatality rate lower.

In the end, though, we have to respect each other’s knowledge. It is my opinion that ICU doctors are heroes every day. They save lives as part of their daily routine, and of course I trust their knowledge. But given the information that we are seeing, they may also need to trust rheumatologists and oncologists who treat cytokine storms regularly. – by Rob Volansky

For more information:
Randy Q. Cron, MD, PhD, can be reached at 1825 University Blvd., Shelby Building, 306 UAB Birmingham, AL 35294; email: bshep@uab.edu.

Disclosures: Cron reports consulting fees, and investigator-initiated clinic trial support, from Sobi.

Randy Q. Cron

Good news about COVID-19 is at a premium these days. Encouraging reports about therapeutic options or vaccine development usually are either overly optimistic or entirely spurious. But scientific advancement is as relentless as the virus itself, and this is exemplified by a growing body of research into a potential association between cytokine storm syndrome and COVID-19.

Randy Q. Cron, MD, PhD, of the Children’s Hospital of Alabama and the University of Alabama at Birmingham, described cytokine storm syndrome as an “overly exuberant” immune response to something like a viral infection or cancer. While it is not currently known why some patients with COVID-19 demonstrate this response and others do not, plenty is known about these inflammatory immunologic proteins and how they have reacted in other disease states, many of them rheumatologic conditions.

This puts rheumatologists in the unique position of being able to instruct colleagues in infectious diseases and intensive care how to manage this severely impacted subpopulation of individuals with COVID-19. In an interview with Healio Rheumatology, Cron shared his insights on how cytokine storm may be contributing to the current pandemic, telltale symptoms to watch for and possible treatments on the horizon.

Q. How might cytokine storm be related to increased severity of COVID-19 found among some patients?

 
Cytokine storm may be contributing to the COVID-19 pandemic, according to Cron, a development that may bring rheumatologists to the forefront of this evolving field.
Source: Adobe

Cron: We started thinking about this after reading some of the earliest case reports from the literature about patients in China. The reports showed many of the clinical features and lab values that we of see in cytokine storm syndrome.

Q. Can you zero in on some of the similarities between cytokine storm syndrome and the COVID-19 patients you saw in the literature?   

Cron: The signals were very strong that the subset of patients who had the most severe form of COVID-19 were likely experiencing some kind of cytokine storm. Now, it is important to note that there is context for this. We had similar thoughts a decade ago with the Ebola outbreak, and this can also be seen in some patients who develop dengue fever. Doctors have been trying to target the cytokine storm in these patients for a long time, so, it is not too crazy of an idea. We are attuned to it.

PAGE BREAK

Q. What were the lessons you learned from those other outbreaks and infections?

Cron:In short, it seems like what was killing some of these patients was not just the virus, but the body’s immune response to the virus. This puts clinicians in a very delicate position. Of course, it is important to treat the virus, you also have to consider whether treating the immune response could also mitigate fatalities in some of the most serious patients. There are no home run therapies for this disease yet, so we are trying to consider all of our options.

Q. How can physicians, particularly ICU doctors who are on the front lines and dealing with these sickest patients, identify patients with COVID-19 who may have this cytokine storm?   

Cron: By necessity, we have been looking at how ICU doctors have been managing patients in the places that have been hit the hardest, including Italy, New York City and Philadelphia. Ideally, any time you have a patient who comes into the ICU with a serious condition like this, you take a slew of labs, you have pathology findings, some of which might take a week or 2 to get back.

However, because they are so overwhelmed, in terms of practicality, our colleagues in Italy are looking at a few key parameters in the most serious COVID patients, including serum ferritin and C-reactive protein (CRP). The ferritins go up when you have a cytokine storm. Now, they do not go up screaming high like they do in a condition like macrophage activation syndrome (MAS), but they may go into the thousands of nanograms per mL. As for CRP, they are using low thresholds.

Q. How can this information inform clinical decision making for those ICU doctors?   

Cron: If you have patient with COVID-19 who has a high fever and respiratory distress, elevated ferritin and/or CRP may be used as surrogate decision-making criteria to determine if the patient has cytokine storm syndrome. On top of that, simple turnaround labs such as a complete blood count can also help to confirm that this is happening. These patients can become lymphopenic or thrombocytopenic. Liver enzymes can also be elevated, but not screaming high like in MAS. Lactate dehydrogenase tends to go up in a cytokine storm. Coagulopathy can also be present. I would look at D-dimers. All of these are signals that ICU doctors can be on the lookout for.

PAGE BREAK

Q. How can understanding of these lab parameters improve patient outcomes?   

Cron: This is my personal opinion, but the goal is to treat the cytokine storm right away, prior to admission to the ICU and before they need intubation. I want to stress that this intervention is not everyone with COVID-19. I would not recommend this for anyone who is asymptomatic, of course, or even patients who are at home with a high fever and a cough. I am talking about patients who are severe enough to be hospitalized, and I would recommend acting on this within the first 24 hours of admission.

Reducing the number of patients who are admitted to the ICU is going to have a number of benefits, including reducing the number of health care workers who are required to be there on the front lines.

Q. Once patients with cytokine storm syndrome have been identified, how can they be treated?   

Cron: Before I talk about treatments, I want to make an important clarification. No one wants to watch patients die without doing anything. But, of course, we do not want to mistreat patients and do harm, either. This raises the conundrum of whether we wait for clinical trials to emerge, showing, conclusively, the safety and efficacy of these medications, or whether we look at the anecdotal evidence that is emerging in real time, and try to treat them as best we can. I do not envy our colleagues in hard hit areas who have to make these choices every day.

However, we are starting to see one clear trend: These doctors are not waiting. This is an unprecedented time. People are dying. We should not just try any random idea that pops into our head, but if there is rationale for an idea — and I believe there is rationale for the treatments I am going to discuss — we should be aware of it. And it probably goes without saying, but I will say it anyway, in big, bold letters: Do not try this at home. These treatments are for patients being treated by experts in a hospital setting.

Q. Understandable. Can you discuss some of the treatments you think will be effective?   

Cron: The first agent to consider is the IL-1 inhibitor, anakinra (Kineret, Sobi). It is remarkably safe, it has a large therapeutic window, it has a short half-life and it works quickly when it works. If a patient is not responding, you can just take them off of it as though it was never in their system. We have a fair amount of experience with it, and hopefully clinical trials will bear it out.

PAGE BREAK

Regarding other therapies, IL-6 inhibition also makes sense. There are two approaches to IL-6 inhibition. One is using antibodies to block IL-6 directly, and one is to block its receptor. Both can work. As far as other targets go, interferon-gamma, along with janus kinase (JAK) and signal transducers and activators of transcription (STAT) inhibitors can be effective. Regarding the JAK/STAT pathway, these target cytokine receptors downstream. In addition, they are often not just targeting one cytokine, but many. There are a lot of potential modalities out there — we simply do not have the trial results.

Q. Are the ICU doctors aware of a) the possibility of the cytokine storm and b) the potential utility of these therapies to treat it?

Cron: Many are aware, in general. But you have to understand that infectious disease and intensive care doctors, because they regularly see patients dying from sepsis, are very cautious about immunomodulatory therapies.

Q. What are some of the potential risks involved in the treatments you mentioned?   

Cron: It is important to understand that the risks are very different for these treatments. In my opinion, anakinra is likely the safest. It can cause liver enzyme elevations and platelets to go down but using it at lower doses can be remarkably safe and effective otherwise. Anecdotally, it seems to be working in COVID-19. The issue at the moment is that I do not think we will have enough of that to go around.

Q. Are there concerns about immunosuppression in these patients?

Cron: Most of the targeted approaches I discussed are more immunomodulatory than immunosuppressive. But here is something else to consider, and something that may be the most controversial, in terms of the opinions I have expressed: If any of these immunomodulatory approaches work in the subset of patients who have cytokine storm syndrome, it is likely that corticosteroids will work as well.

However, the WHO is recommending — strongly, strongly, strongly — against them, largely because of experiences with SARS and MERS. But I wonder if steroids were simply given to the wrong subset of patients with those infections. I am not saying we should just throw steroids at everyone, but we may end up relying on them. And this is not just a hunch. This is based on what I have been talking about. I believe they might help keep the case/fatality rate lower.

In the end, though, we have to respect each other’s knowledge. It is my opinion that ICU doctors are heroes every day. They save lives as part of their daily routine, and of course I trust their knowledge. But given the information that we are seeing, they may also need to trust rheumatologists and oncologists who treat cytokine storms regularly. – by Rob Volansky

For more information:
Randy Q. Cron, MD, PhD, can be reached at 1825 University Blvd., Shelby Building, 306 UAB Birmingham, AL 35294; email: bshep@uab.edu.

Disclosures: Cron reports consulting fees, and investigator-initiated clinic trial support, from Sobi.

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