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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.
Acceso Abierto
The mortality of Coronavirus disease 2019 (COVID-19) appears to be driven by acute respiratory distress syndrome (ARDS) and a dysregulated immune response to SARS-CoV-2. Emerging evidence suggests that a subset of COVID-19 is characterized by the development of a cytokine storm syndrome (CSS), and interleukin (IL)-6 levels are predictors of COVID-19 severity and in-hospital mortality. Targeting hyper-inflammation in COVID-19 may be critical for reducing mortality. Catecholamines enhance inflammatory injury by augmenting the production of IL-6 and other cytokines through a self-amplifying feed-forward loop in immune cells that requires alpha-1 adrenergic receptor (1-AR) signaling. Prophylactic inhibition of catecholamine synthesis with the 1-AR antagonist prazosin reduced catecholamines and cytokine responses in mice, and resulted in markedly increased survival following various hyper-inflammatory stimuli. These findings offer a rationale for studying 1-AR antagonists in the prophylaxis of patients with COVID-19-CSS and ARDS. As high infection rates threaten to overwhelm hospital capacity during this pandemic, preventative approaches that ameliorate COVID-19 severity and reduce excessive mortality are desperately needed. We hypothesize that treatment with prazosin of individuals who test positive for SARS-CoV-2 could reduce catecholamine surges, secondary cytokine dysregulation, and mortality. To investigate a potential role for 1-AR antagonists in preventing poor outcomes in ARDS, we conducted a retrospective analysis of hospitalized patients diagnosed with ARDS. Using data from the Truven Health MarketScan Research Database (2010-2017), we identified 12,673 men (age 45-64) with ARDS, of whom 1,189 patients (9.4%) were prescribed 1-AR antagonists in the previous year. Applying logistic regression models, we found that patients with prior use of 1-AR antagonists had lower odds of the composite of need for invasive mechanical ventilation and mortality compared to non-users (AOR 0.80, 95% CI 0.69-0.94, p=0.008). Mirroring findings from pre-clinical models, these data support a clinical rationale to study 1-AR antagonists in the prophylaxis of ARDS and states of local and systemic immune dysregulation. Prospective, randomized clinical trials of alpha-1 receptor antagonists (e.g. prazosin) administered prior to the onset of severe symptoms are needed to assess their efficacy in preventing CSS and reducing mortality in COVID-19.
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