Studying ways to reduce hyperinflammation and death in COVID-19

 

In a subset of patients with COVID-19, an abnormal immune response —hyperinflammation— can develop that worsens disease, leading to organ failure and mortality. Catecholamines (hormones like adrenaline and noradrenaline) can enhance inflammatory injury by dramatically increasing the production of cytokines. This self-amplifying feed-forward loop depends on signaling through alpha-1 adrenergic receptors on the surface of immune cells.

In animal models, blocking catecholamine production prevents abnormal cytokine responses and results in markedly increased survival in response to severe inflammatory insults (for example, sepsis or cytokine release syndrome). A similar protection is also observed in animals that are treated early with alpha-1 adrenergic receptor antagonists (“alpha-1 blockers”), a class of drugs that act on this type of receptor.

Alpha-1 blockers (e.g., prazosin and doxazosin) inhibit signaling through alpha-1 adrenergic receptors and are used in clinical practice to treat common conditions such as hypertension and prostate hyperplasia. We are investigating whether these drugs can prevent severe disease and mortality when given early in patients with COVID-19.

Model of the catecholamine-mediated feed-forward loop in immune cells that amplifies cytokine production during hyperinflammation. Graphic © Maximilian Konig

 

In large collaborative efforts, our groups have found evidence that patients who are taking alpha-1 blockers have a significantly lower risk of dying when hospitalized with COVID-19 or pneumonia (see selected publications below). These large retrospective studies have now paved the way to test whether early treatment with alpha-1 blockers can prevent hospitalization, severe disease, and death in patients with COVID-19. Three investigator-initiated randomized controlled clinical trials testing the therapeutic efficacy and safety of the alpha-1 blockers doxazosin or prazosin are currently being conducted to answer this question definitively.

If successful, early treatment with this cheap, generic, and widely available class of drugs would provide the first approach to prevent hyperinflammation — rather than treat it when organ damage has already developed. Different from other drugs that have and are being tested to treat COVID-19-associated hyperinflammation, alpha-1 blockers are not immunosuppressive but modulate immune responses to prevent them from becoming abnormal in the first place.

We hope that the first clinical translation of this therapeutic strategy to human disease will offer an immediate opportunity to treat patients who develop COVID-19 due to lack of vaccines across the world, vaccine failure (such as in patients on immunosuppressive drugs), or potential lack of vaccine efficacy in the light of evolving SARS-CoV-2 variants.

Beyond COVID-19, alpha-1 blockers have potential to treat other common and uncommon inflammatory diseases such as pneumonia or cytokine release syndrome in patients receiving CAR T cell therapy.

 

Explore the Data

Early treatment with alpha-1 blockers in COVID-19: Summary of our rationale

 

Alpha-1 blockers show up to 74% reduced mortality in COVID-19: Department of Veterans Affairs

The Association Between Alpha-1 Adrenergic Receptor Antagonists and In-Hospital and 28-Day Mortality from COVID-19. Forest plots show the odds ratios (OR) for in-hospital mortality based on prior use of any a1-AR antagonists (i.e., tamsulosin, silodosin, prazosin, terazosin, doxazosin, or alfuzosin; dark green) or only doxazosin (light green) in each panel. Unadjusted (square), adjusted model (triangle), and matched model (circle) analyses are shown for each sample group. Filled symbols reflect the odds of death within 28 days from index hospital admission (including deaths after discharge), whereas empty symbols reflect odds of death during the index admission. Relative risk reduction (RRR), odds ratios (ORs) for death, 95% confidence intervals (CI), p-values, and sample size (n) for each analysis are shown on the right.

 

Inpatient use of alpha-1 blockers reduced mortality in COVID-19

 

Alpha-1 blockers show reduced mortality in pneumonia

 

Alpha-1 blockers show reduced mortality in pneumonia: Denmark

 
 

Clinical Trials in COVID-19

  • Baltimore

    Johns Hopkins Hospital, Baltimore, Maryland. PREVENT-COVID Trial: Testing prazosin versus standard of care in hospitalized patients with COVID-19 (PI: Chetan Bettegowda, M.D., Ph.D.)

    More: https://clinicaltrials.gov/ct2/show/NCT04365257

  • Brazil

    Pontifical Catholic University of Minas Gerais, Brazil. TOGETHER Trial: Testing doxazosin versus placebo in non-hospitalized patients with COVID-19 who have mild disease.

    More: https://www.togethertrial.com

  • India

    Bangalore, India and other centers. CALM-COVID Trial: Testing doxazosin versus placebo in non-hospitalized patients with COVID-19 who have mild disease.

    (coming soon)

 Team and Collaborators

Chetan Bettegowda, M.D., Ph.D.; Ludwig Center for Cancer Genetics and Therapeutics

Bert Vogelstein, M.D.; Ludwig Center for Cancer Genetics and Therapeutics

Kenneth Kinzler, Ph.D.; Ludwig Center for Cancer Genetics and Therapeutics

Shibin Zhou, M.D., Ph.D.; Ludwig Center for Cancer Genetics and Therapeutics

Nickolas Papadopoulos, Ph.D.; Ludwig Center for Cancer Genetics and Therapeutics

Joshua Vogelstein, Ph.D.; Whiting School of Engineering, The Johns Hopkins University

Michael Powell; Whiting School of Engineering, The Johns Hopkins University

Susan Athey, Ph.D.; Stanford University

Allison Koenecke, Ph.D.; Stanford University

Todd Wagner, Ph.D.; Department of Veterans Affairs Health

Liam Rose, Ph.D.; Department of Veterans Affairs Health

Verena Staedtke, M.D., Ph.D.; Department of Neurology, The Johns Hopkins University

Renyuan Bai, M.B.B.S., Ph.D.; Department of Neurosurgery, The Johns Hopkins University

Antony Rosen, M.B.Ch.B., M.S.; Division of Rheumatology, The Johns Hopkins University

Gilmar Reis M.D., Ph.D.; Pontifícia Universidade Católica de Minas Gerais, Brazil

The Ludwig Center for Cancer Genetics and Therapeutics

Please see publications above for a list of all collaborators.

 

We are incredibly grateful to those (named and unnamed) who are supporting our investigator-initiated clinical trials in COVID-19. In the hope that we will find a solution to this pandemic— and the next.

If you would like to donate to this cause and help finance our clinical trials in Brazil and India, please contact us.

 
 

Stay safe.