Targeting the catecholamine-cytokine axis to prevent SARS-CoV-2 cytokine storm syndrome

Maximilian F Konig; Mike Powell; Verena Staedtke; Ren-Yuan Bai; David L Thomas; Nicole Fischer; Sakibul Huq; Adham M Khalafallah; Allison Koenecke; Nickolas Papadopoulos; Kenneth W Kinzler; Bert Vogelstein; Joshua T Vogelstein; Susan Athey; Shibin Zhou; Chetan Bettegowda

In Coronavirus disease 2019 (COVID-19), the initial viral-replication phase is often followed by a hyperinflammatory reaction in the lungs and other organ systems that leads to acute respiratory distress syndrome (ARDS), the need for mechanical ventilation, and death despite maximal supportive care. As no antiviral treatments have yet proven effective, efforts to prevent progression to the severe stages of COVID-19 without inhibiting antiviral immune responses are desperately needed. We have previously demonstrated that a common, inexpensive, and well-tolerated class of drugs called alpha-1 adrenergic receptor (⍺1-AR) antagonists can prevent hyperinflammation ("cytokine storm") and death in mice. We here present clinical data that supports the use of ⍺1-AR antagonists in the prevention of severe complications of pneumonia, ARDS, and COVID-19. Emerging evidence suggests that a subset of COVID-19 is characterized by the development of a cytokine storm syndrome (CSS) that resembles cytokine release syndrome (CRS) in chimeric antigen receptor (CAR)-T cell therapy (2, 4, 5) . Hyperinflammation in COVID-19 is associated with elevation of pro-inflammatory cytokines including interleukin (IL)-6, IL-2R, IL-8, tumor necrosis factor-α, and granulocyte-colony stimulating factor (4, 6) , similar to the exuberant cytokine production by lunginfiltrating monocytes/macrophages and pneumocytes observed in SARS-CoV-1 and MERS-CoV infection (7) . Alveolar inflammation and diffuse alveolar damage impair the infected lungs' local ability to participate in gas exchange, culminating in ARDS and necessitating mechanical ventilation (8) . ARDS is the main driver of mortality of COVID-19. Thus, preventing the hyperinflammation in COVID-19 is critical for avoiding this progression.