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The Storm Brewing Inside: Immune Systems Go Wild During SARS-CoV-2 Infection

Despite an unprecedented volume of research, there are still many unanswered questions on COVID-19, especially regarding the extremely varied clinical course the disease takes, ranging from asymptomatic to severe, even fatal. The evidence collected so far points to the so called “cytokine storm” as a major factor determining the final outcome. 

Given the large volume of knowledge accumulated to date, Dr. Luis Montaner, director of Wistar’s HIV Immunopathogenesis laboratory, vice president of Scientific Operations, the Herbert Kean, M.D., Family Endowed Chaired Professor, and editor-in-chief of the Journal of Leukocyte Biology, teamed up with other editors to prepare a comprehensive review of COVID-19 publications from around the world with a focus on obtaining a better understanding of what creates a cytokine storm in some people and not others when infected with SARS-CoV-2. Here’s the conversation.

Define a cytokine storm.

Montaner: A person’s uncontrolled inflammatory response to a pathogen, which causes a cascade of negative events that may lead to multiple organ failure and premature death.

Break down and define in simple terms leukocytes and cytokines. 

Montaner: Leukocyte, or white blood cells, are immune cells in the blood that also go into tissues. Cytokines are the messenger proteins made by leukocytes to communicate with other leukocytes and other cell types in the body. Both leukocytes and their cytokines are being evaluated as triggering factors contributing to disease severity and death in COVID-19.

What role do leukocytes and cytokines play in the immune response and disease progression?

Montaner: After a person becomes infected, leukocytes are the first cells to respond through the production of cytokines. This is a normal occurrence that is meant to jump start your immune response, but it becomes abnormal as the magnitude and rate of a person’s response to the infection increases.

Why does the immune system go wild and create a cytokine storm with COVID-19?

Montaner: That’s what this review is probing at by putting forth potential mechanisms that may trigger a cytokine storm. We are trying to understand what is changing with this disease and piece the moving parts together. We don’t know what the key triggers are for a cytokine storm or the quick onset of organ failure and death or in what order they act, but we are putting these pieces together.

Is this unique to SARS-CoV-2? If not, what other diseases bring this reaction on?

Montaner: Autoimmune diseases and other diseases can cause cytokine storms. Other coronaviruses like SARS and MERS also increase immune activation.

How did you come to study the data of 3939 patients from China? Tell me about this collaboration.

Montaner: As editor-in-chief of the Journal of Leukocyte Biology, I work closely with editors across the globe. Editors from China wanted to review the data and include integration of immune changes together with therapies being tested in the U.S. and China.

Did you find potential treatments that could be useful to dampen the storm?

Montaner: All of the strategies we reviewed are under analysis, as no FDA (or foreign equivalent) approved therapies are yet available. Clinical studies are now testing immune modulation, transfer of immunosuppressive stem cells, convalescent plasma transfusion, steroids, and traditional medicinal treatments.

What was the goal of your review?

Montaner: There have been numerous independent discussions of specific leukocytes or cytokines but no single, comprehensive review of all leukocytes and what their collective role in disease progression. I think this Review will serve to help define the clearest path forward for defining future research efforts to be explored in this global effort to create vaccines, therapeutics and diagnostics for SARS-CoV-2.

What were your final conclusions?

Montaner: While we all want to find a medicine that will be a “magic bullet” to treat all – the data indicates that the disease, leukocytes and the type of trigger for a cytokine storm may not be the same for all. In addition, diagnosis efforts to predict the risk of a cytokine storm and multi organ failure may require monitoring how the person is responding to infection as opposed to monitoring the amount of virus alone. Accordingly, our COVID-19 Wistar research is developing separate therapies to control the virus and the host response during a cytokine storm.