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Managing cytokine storm requires ‘important dialogue’ among rheumatologists, specialists

Last updated: 07-15-2020

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Managing cytokine storm requires ‘important dialogue’ among rheumatologists, specialists

Rheumatologists are familiar with the enhanced inflammatory response seen in the most severe patients with COVID-19 and could play a key role in the fight against the virus, according to a presenter at the 2020 Interdisciplinary Autoimmune Summit.

“Ninety percent of people with COVID-19 get better without much to do of anything, so we will focus on the most severe form of the disease,” Leonard H. Calabrese, DO, chief medical editor of Healio Rheumatology, and professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, said in his presentation.

Calabrese noted that 10% of patients with COVID-19 have risk factors that predispose them to more serious disease and 5% experience critical illness. He added that the overall mortality rate seems to hover between 1% and 2%.

Age, sex, diabetes mellitus, obesity, cardiovascular disease and chronic liver disease are among the main factors that push patients from asymptomatic to symptomatic COVID-19, according to Calabrese. Understanding how these and other factors impact immunity is critical.

The course of the virus can be broken down into three phases, which Calabrese described as “innate immune activation, adaptive immune activation and cytokine release syndrome.”

The first stage is marked by viral engagement of pathogen-associated molecular pattern and low type 1 IFN, while the second involves generation of specific antibody and T cell responses along with release of damage-associated molecular patterns.

In the third stage, IL-6, IL-1, TNF, granulocyte-macrophage colony-stimulating factor, interferon and IFN coagulopathy may occur.

Most patients only go through the first two phases, where IgG response occurs, and CD-4 T-cells lead to “ejection and recovery,” Calabrese said. “Stage three is where we cannot parse the virus adequately.”

The cytokine release is marked by elevation of coagulation markers, multi-organ dysfunction, respiratory failure and death.

It is important for experts who work in the realm of immunology to recognize the relationship between the cytokine storms seen in COVID-19 and those observed under the rheumatology umbrella, Calabrese noted. Clinicians who have dealt with macrophage activation syndrome, hemophagocytic lymphohistiocytosis (HLH), systemic juvenile idiopathic arthritis or adult-onset Still’s disease may have valuable input for the intensivists and ICU doctors on the front lines of the COVID battle.

Those who are not familiar with these conditions can look for elevated cytokines, IL-1,TNF, IL-6, IL-8, ferritin, CRP and D-Dimers, according to Calabrese.

All of that said, Calabrese stressed that there are “qualitative and quantitative differences” between the cytokine storms seen in these other syndromes and the end stages of COVID-19. Clinicians should pay attention to emerging data on this topic. “We have tried to learn some lessons,” he said.

To that point, Calabrese highlighted findings published in Cell from Blanco-Melo and colleagues, who showed that SARS-CoV-2 infection induces low IFN 1 and 3 levels with a moderate ISG response, strong chemokine expression, and low innate antiviral defenses and high pro-inflammatory cues. “This study has shown two features happening at the molecular level,” Calabrese said. “One is that the interferon type 1 and 3 response are defective. The second is that there is an enhanced inflammatory response.”

Importantly, this culminates in disruption of the checks and balances leading to down-regulation of the inflammatory response, allowing the immune system to turn on itself.

“There is an important dialogue that needs to take place between intensivists, immunologists and infectious diseases doctors dealing with this, and us, who know how to treat the cytokine release syndrome,” Calabrese said.


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