Siltuximab as an immune therapy to tackle severe COVID-19

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In March 2020, the Papa Giovanni XXIII Hospital in Bergamo, in northern Italy, experienced the first surge in COVID-19 cases in Western countries—and it was one of the worst. 

The pandemic brought uncertainty not only for individuals afflicted with COVID-19, but also for physicians with regard to how to respond to this unprecedented threat. We were unprepared—lacked personal protective equipment and had test supply shortages—but our determination to save humanity remained persistent. This was the first time in our careers we had seen thousands of patients at the emergency department with respiratory failure, rapidly overwhelming the hospital’s capacity and forcing a major reorganization. There was a lack of treatments available for patients with severe COVID-19.

Physicians treating a patient with severe COVID-19 and acute respiratory distress syndrome in an intensive care unit at Papa Giovanni XXIII Hospital in Bergamo, northern Italy.

Physicians treating a patient with severe COVID-19 and acute respiratory distress syndrome in an intensive care unit at Papa Giovanni XXIII Hospital in Bergamo, northern Italy.

Severe COVID-19 is characterized by acute respiratory distress syndrome and hyperinflammation, with elevated levels of cytokines such as interleukin-6. This cytokine is associated with mortality and patients requiring respiratory support. In early March 2020, we designed an observational cohort study at the start of the pandemic to devise an effective treatment for patients with severe COVID-19. Siltuximab, which is an inhibitor of interleukin-6, was supplied by EUSA Pharma under a compassionate-use program for the emergency treatment of 30 patients with severe COVID-19. We measured a plethora of cytokines in the blood to understand predictors of COVID-19 severity. Using regression modeling, we found that siltuximab caused the downregulation of cytokines interleukin-8 and pentraxin 3—this implies that siltuximab mediates its beneficial effects by reducing local and systemic inflammation. The siltuximab-mediated downregulation of cytokines was associated with improved survival and respiratory function in patients with severe COVID-19.

Schematic demonstrating siltuximab-mediated inhibition of local and systemic inflammation prognostic of improved respiratory function and survival.

Schematic demonstrating siltuximab-mediated inhibition of local and systemic inflammation prognostic of improved respiratory function and survival. 

The landscape of the world we live in has now been rocked by COVID-19. The healthcare system has been rapidly reconfigured to prioritize COVID-19 care. With severe COVID-19 cases rapidly rising, helped by the emergence of new variants of concern on a global scale, siltuximab may be an interesting therapeutic option to weather the uncontrolled cytokine storm. Our findings underscore the importance of profiling of early immune response to better understand the effect of therapies, and the importance of timely therapeutic intervention to improve respiratory function and survival. A randomized clinical trial informed by the accumulating clinical and biological findings in the field would be informative to confirm the efficacy of siltuximab in severe COVID-19.      

We have witnessed emotional and physical turmoil due to the rapidity and severity of COVID-19 infections. In the three COVID-19 waves we faced in the past year, we continued to work intensively in an attempt to save the lives of our patients. Although we are in more control of the situation now, the threat of COVID-19 is imminent and real, and is a minefield waiting to explode. As clinicians/scientists, from the rise of the pandemic we were determined to contribute to the medical research to fight COVID-19, and we are confident that the efforts of the scientific community will pave the way to develop the necessary therapeutics to combat COVID-19.

Through our concerted efforts, we hope to avoid a second wave of the lost days that made Bergamo a coronavirus tragedy.

To all of you, thank you!

Giuseppe Gritti

Hematologist, ASST Papa Giovanni XXIII