Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection

Allison Koenecke; Michael Powell; Ruoxuan Xiong; Zhu Shen; Nicole Fischer; Sakibul Huq; Adham M. Khalafallah; Marco Trevisan; Pär Sparen; Juan J. Carrero; Akihiko Nishimura; Brian Caffo; Elizabeth A. Stuart; Renyuan Bai; Verena Staedtke; David L. Thomas; Nickolas Papadopoulos; Ken W. Kinzler; Bert Vogelstein; Shibin Zhou; Chetan Bettegowda; Maximilian F. Konig; Brett D. Mensh; Joshua T. Vogelstein; Susan Athey

doi:10.7554/eLife.61700

Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection

Allison Koenecke, Michael Powell, Ruoxuan Xiong, Zhu Shen, Nicole Fischer, Sakibul Huq, Adham M. Khalafallah, Marco Trevisan, Pär Sparen, Juan J. Carrero, Akihiko Nishimura, Brian Caffo, Elizabeth A. Stuart, Renyuan Bai, Verena Staedtke, David L. Thomas, Nickolas Papadopoulos, Ken W. Kinzler, Bert Vogelstein, Shibin ZhouChetan Bettegowda, Maximilian F. Konig, Brett D. Mensh, Joshua T. Vogelstein, Susan Athey

Research output: Contribution to journal › Article › peer-review

Abstract

In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replica-tion phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor (⍺₁-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n = 18,547) and three cohorts with pneumonia (n = 400,907). Federated across two ARD cohorts, we find that patients exposed to ⍺₁-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR = 0.70, p = 0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of ⍺₁-AR antagonists ameliorates lower respiratory tract infection-associated hyper-inflammation and death, as observed in COVID-19.

Original language	English (US)
Article number	e61700
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/eLife.61700
State	Published - Jun 2021

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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10.7554/eLife.61700

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Koenecke, A., Powell, M., Xiong, R., Shen, Z., Fischer, N., Huq, S., Khalafallah, A. M., Trevisan, M., Sparen, P., Carrero, J. J., Nishimura, A., Caffo, B., Stuart, E. A., Bai, R., Staedtke, V., Thomas, D. L., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., ... Athey, S. (2021). Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection. eLife, 10, Article e61700. https://doi.org/10.7554/eLife.61700

Koenecke, A, Powell, M, Xiong, R, Shen, Z, Fischer, N, Huq, S, Khalafallah, AM, Trevisan, M, Sparen, P, Carrero, JJ, Nishimura, A , Caffo, B , Stuart, EA , Bai, R , Staedtke, V , Thomas, DL , Papadopoulos, N , Kinzler, KW , Vogelstein, B , Zhou, S , Bettegowda, C , Konig, MF, Mensh, BD, Vogelstein, JT & Athey, S 2021, 'Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection', eLife, vol. 10, e61700. https://doi.org/10.7554/eLife.61700

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title = "Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection",

abstract = "In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replica-tion phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor (⍺1-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n = 18,547) and three cohorts with pneumonia (n = 400,907). Federated across two ARD cohorts, we find that patients exposed to ⍺1-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR = 0.70, p = 0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of ⍺1-AR antagonists ameliorates lower respiratory tract infection-associated hyper-inflammation and death, as observed in COVID-19.",

author = "Allison Koenecke and Michael Powell and Ruoxuan Xiong and Zhu Shen and Nicole Fischer and Sakibul Huq and Khalafallah, {Adham M.} and Marco Trevisan and P{\"a}r Sparen and Carrero, {Juan J.} and Akihiko Nishimura and Brian Caffo and Stuart, {Elizabeth A.} and Renyuan Bai and Verena Staedtke and Thomas, {David L.} and Nickolas Papadopoulos and Kinzler, {Ken W.} and Bert Vogelstein and Shibin Zhou and Chetan Bettegowda and Konig, {Maximilian F.} and Mensh, {Brett D.} and Vogelstein, {Joshua T.} and Susan Athey",

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year = "2021",

month = jun,

doi = "10.7554/eLife.61700",

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AU - Koenecke, Allison

AU - Powell, Michael

AU - Xiong, Ruoxuan

AU - Shen, Zhu

AU - Fischer, Nicole

AU - Huq, Sakibul

AU - Khalafallah, Adham M.

AU - Trevisan, Marco

AU - Sparen, Pär

AU - Carrero, Juan J.

AU - Nishimura, Akihiko

AU - Caffo, Brian

AU - Stuart, Elizabeth A.

AU - Bai, Renyuan

AU - Staedtke, Verena

AU - Thomas, David L.

AU - Papadopoulos, Nickolas

AU - Kinzler, Ken W.

AU - Vogelstein, Bert

AU - Zhou, Shibin

AU - Bettegowda, Chetan

AU - Konig, Maximilian F.

AU - Mensh, Brett D.

AU - Vogelstein, Joshua T.

AU - Athey, Susan

PY - 2021/6

Y1 - 2021/6

N2 - In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replica-tion phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor (⍺1-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n = 18,547) and three cohorts with pneumonia (n = 400,907). Federated across two ARD cohorts, we find that patients exposed to ⍺1-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR = 0.70, p = 0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of ⍺1-AR antagonists ameliorates lower respiratory tract infection-associated hyper-inflammation and death, as observed in COVID-19.

AB - In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replica-tion phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor (⍺1-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n = 18,547) and three cohorts with pneumonia (n = 400,907). Federated across two ARD cohorts, we find that patients exposed to ⍺1-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR = 0.70, p = 0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of ⍺1-AR antagonists ameliorates lower respiratory tract infection-associated hyper-inflammation and death, as observed in COVID-19.

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Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection

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ASJC Scopus subject areas

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