All Publications

  • Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection. eLife 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., Zhou, S., Bettegowda, C., Konig, M. F., Mensh, B. D., Vogelstein, J. T., Athey, S. 2021; 10

    Abstract

    In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication 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 hyperinflammation and death, as observed in COVID-19.

    View details for DOI 10.7554/eLife.61700

    View details for PubMedID 34114951

  • The Association Between Alpha-1 Adrenergic Receptor Antagonists and In-Hospital Mortality From COVID-19. Frontiers in medicine Rose, L., Graham, L., Koenecke, A., Powell, M., Xiong, R., Shen, Z., Mench, B., Kinzler, K. W., Bettegowda, C., Vogelstein, B., Athey, S., Vogelstein, J. T., Konig, M. F., Wagner, T. H. 2021; 8: 637647

    Abstract

    Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed, and pre-clinical data suggest alpha-1 adrenergic receptor antagonists (alpha1-AR antagonists) may be effective in reducing mortality related to hyperinflammation independent of etiology. Using a retrospective cohort design with patients in the Department of Veterans Affairs healthcare system, we use doubly robust regression and matching to estimate the association between baseline use of alpha1-AR antagonists and likelihood of death due to COVID-19 during hospitalization. Having an active prescription for any alpha1-AR antagonist (tamsulosin, silodosin, prazosin, terazosin, doxazosin, or alfuzosin) at the time of admission had a significant negative association with in-hospital mortality (relative risk reduction 18%; odds ratio 0.73; 95% CI 0.63-0.85; p ≤ 0.001) and death within 28 days of admission (relative risk reduction 17%; odds ratio 0.74; 95% CI 0.65-0.84; p ≤ 0.001). In a subset of patients on doxazosin specifically, an inhibitor of all three alpha-1 adrenergic receptors, we observed a relative risk reduction for death of 74% (odds ratio 0.23; 95% CI 0.03-0.94; p = 0.028) compared to matched controls not on any alpha1-AR antagonist at the time of admission. These findings suggest that use of alpha1-AR antagonists may reduce mortality in COVID-19, supporting the need for randomized, placebo-controlled clinical trials in patients with early symptomatic infection.

    View details for DOI 10.3389/fmed.2021.637647

    View details for PubMedID 33869251

  • The Association Between Alpha-1 Adrenergic Receptor Antagonists and In-Hospital Mortality from COVID-19. medRxiv : the preprint server for health sciences Rose, L. n., Graham, L. n., Koenecke, A. n., Powell, M. n., Xiong, R. n., Shen, Z. n., Kinzler, K. W., Bettegowda, C. n., Vogelstein, B. n., Athey, S. n., Vogelstein, J. T., Konig, M. F., Wagner, T. H. 2020

    Abstract

    Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed, and preclinical data suggest alpha-1 adrenergic receptor antagonists (α 1 -AR antagonists) may be effective in reducing mortality related to hyperinflammation. Using a retrospective cohort design with patients in the Department of Veterans Affairs healthcare system, we use doubly robust regression and matching to estimate the association between use of α 1 -AR antagonists at time of hospitalization and likelihood of death due to COVID-19 during an inpatient stay. Having an active prescription for an α 1 -AR antagonist (tamsulosin, silodosin, prazosin, terazosin, doxazosin, or alfuzosin) at the time of admission had a significant negative association with in-hospital mortality (relative risk reduction 14%; odds ratio 0.75; 95% CI 0.66 to 0.86; p ≤ 0.001). These effects were also found in an expanded cohort of suspected COVID-19 patients, supporting the need for clinical trials.

    View details for DOI 10.1101/2020.12.18.20248346

    View details for PubMedID 33398294

    View details for PubMedCentralID PMC7781337

https://orcid.org/0000-0003-4564-5438