key: cord-303232-0lwmzjxz
authors: Konig, Maximilian F; Powell, Mike; Staedtke, Verena; Bai, Ren-Yuan; Thomas, David L; Fischer, Nicole; Huq, Sakibul; Khalafallah, Adham M; Koenecke, Allison; Xiong, Ruoxuan; Mensh, Brett; Papadopoulos, Nickolas; Kinzler, Kenneth W; Vogelstein, Bert; Vogelstein, Joshua T; Athey, Susan; Zhou, Shibin; Bettegowda, Chetan
title: Targeting the catecholamine-cytokine axis to prevent SARS-CoV-2 cytokine storm syndrome
date: 2020-04-08
journal: nan
DOI: 10.1101/2020.04.02.20051565
sha: 
doc_id: 303232
cord_uid: 0lwmzjxz

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 (α1-AR) signaling. Prophylactic inhibition of catecholamine synthesis with the α1-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 α1-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 α1-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 13,125 men (age 45-64) with ARDS, of whom 655 patients (5.0%) were prescribed α1-AR antagonists in the previous year. Applying logistic regression models, we found that patients with prior use of α1-AR antagonists had lower odds of invasive mechanical ventilation compared to non-users (adjusted OR=0.75, 95% CI 0.59-0.95, p=0.019). Perhaps more importantly, those patients had a ~36% lower incidence of both being ventilated and dying in the hospital (adjusted OR=0.59, 95% CI 0.34-0.95, p=0.042). By contrast, prior use of beta-adrenergic receptor (β-AR) antagonists was not correlated with either outcome. We extended these analyses to patients admitted with pneumonia. Of 108,956 subjects in this cohort, 5,498 patients (5.0%) were taking α1-AR antagonist. Similar to ARDS, patients with pneumonia on α1-AR antagonists (but no β-AR antagonists) had a lower odds of mechanical ventilation (adjusted OR=0.83, 95% CI 0.75-0.92, p<0.001) and of both being ventilated and dying in the hospital (adjusted OR=0.77, 95% CI 0.62-0.94, p=0.014) compared to non-users. Mirroring findings from pre-clinical models, these data support a clinical rationale to study α1-AR antagonists in the prevention of severe complications of pneumonia, ARDS, and COVID-19. 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.

to be driven by acute respiratory distress syndrome (ARDS) and a dysregulated immune response to SARS-CoV-2 2-4 .

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 . Hyper-inflammation in COVID-19 is associated with elevation of proinflammatory cytokines including interleukin (IL)-6, IL-2R, IL-8, tumor necrosis factor-α, and granulocytecolony stimulating factor 4,6 . This is similar to the exuberant cytokine production by lung-infiltrating monocytes/macrophages and pneumocytes observed in SARS-CoV and MERS-CoV infection 7 .

Targeting the hyper-inflammation in COVID-19 may be critical for reducing mortality. IL-6 levels diverge profoundly between non-survivors and survivors in the third week after symptom onset and are predictors of COVID-19 severity and in-hospital mortality 1, 8, 9 . Tocilizumab, a monoclonal antibody targeting the IL-6 receptor, is currently being investigated for the treatment of patients with COVID-19-CSS (ChiCTR2000029765, NCT04306705, NCT04310228) [10] [11] [12] . Pending data from randomized controlled trials, retrospective data from 21 patients with severe or critical COVID-19 treated with tocilizumab suggests that inhibition of the IL-6 signaling axis is highly effective 13 . However, given the cost, immunosuppression, and potential adverse reactions of tocilizumab, this strategy will likely be restricted to select patients in developed countries.

We have recently shown that CRS observed with bacterial infections, CAR-T cells, and other T cell-activating therapies is accompanied by a surge in catecholamines 14 . 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 14 .

Prophylactic inhibition of catecholamine synthesis with metyrosine, a tyrosine hydroxylase antagonist, reduced levels of catecholamines and cytokine responses and resulted in markedly increased survival following various inflammatory stimuli in mice. Similar protection against a hyper-inflammatory stimulus was observed with prazosin, demonstrating that ⍺1-AR antagonists can also prevent cytokine storm 14 .

. CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The findings discussed herein offer a rationale for studying ⍺1-AR antagonists in the prophylaxis of COVID-19-CSS. However, all drugs can have unanticipated side effects, and the incompletely understood relationship between hypertension and COVID-19 suggests caution in using any agent that impacts blood pressure 15 . Prospective, double-blinded clinical trials of ⍺1-AR antagonists in high-risk patients, when administered prior to symptom onset, will therefore be required to assess their utility in preventing COVID-19-CSS. Prazosin is inexpensive and safe, as has been documented by long-term . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.04.02.20051565 doi: medRxiv preprint treatment of millions of patients with benign prostatic hyperplasia, hypertension, and other conditions. We emphasize that the extensive experience with using prazosin for other indications should prioritize -not obviate -rigorous, controlled clinical research rather than indiscriminate off-label use in patients exposed to SARS-CoV-2. Such trials could be expeditiously implemented in areas suffering from high infection rates that threaten to overwhelm hospital capacity. We encourage readers to recommend specific populations and trial designs to test the hypothesis proposed herein. *adjusted for comorbid hypertension, ischemic heart disease, acute myocardial infarction, heart failure, chronic obstructive pulmonary disease, diabetes mellitus, benign prostatic hyperplasia, and post-traumatic stress disorder identified from health care encounters in the prior year as well as age and year. A . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint .

COI: In 2017, Johns Hopkins University filed a patent application on the use of various drugs to prevent cytokine release syndromes, on which V.S., R.B., B.V., K.W.K., and S.Z. are listed as inventors.

. CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.04.02.20051565 doi: medRxiv preprint

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