Summary: Early treatment with alpha-1 adrenergic receptor antagonists (alpha blockers) may reduce the risk of cytokine storm in some COVID-19 patients. These drugs appear to interrupt the inflammatory signaling that can lead to runaway immune responses. Animal studies showed reduced cytokine release and lower mortality when alpha blockers were administered to infected mice, and retrospective human data suggest a potential protective effect in respiratory illness.
Source: HHMI
Why some COVID-19 cases become life-threatening
In a subset of patients, the immune system’s response to SARS-CoV-2 becomes excessively aggressive, producing very high fevers, acute respiratory distress, and extensive lung damage. These symptoms reflect a hyperinflammatory state often referred to as a cytokine storm, in which immune cells release large quantities of signaling proteins (cytokines) that cause widespread tissue injury.
Researchers at Johns Hopkins University School of Medicine, led by Howard Hughes Medical Investigator Bert Vogelstein, are initiating a clinical trial to evaluate whether alpha blockers can prevent or reduce this dangerous overreaction. The study is currently recruiting participants aged 45 to 85 who are hospitalized at Johns Hopkins Hospital with COVID-19 but are not yet in the intensive care unit or on mechanical ventilation.
Alpha blockers are commonly prescribed for conditions such as high blood pressure and benign prostatic hyperplasia. The investigators hypothesize these medications may halt the cascade of immune and adrenergic signaling that amplifies cytokine release, potentially preventing the progression to severe disease.
How cytokine storms develop
Cytokine storms are not unique to COVID-19; they can occur in autoimmune diseases and as a side effect of some cancer immunotherapies. When macrophages and other immune cells detect viral particles, they secrete cytokines that summon additional immune cells to contain infection. This inflammatory response is beneficial at moderate levels, but it can escalate when macrophages also produce catecholamines—chemical messengers that further amplify cytokine production. The result is a self-reinforcing loop of inflammation that becomes difficult to control.
“Once this process begins, it can be hard to switch off,” says Maximilian Konig, a rheumatologist at Johns Hopkins helping to coordinate the trial.
Preclinical and retrospective evidence
Before the COVID-19 pandemic, Vogelstein’s team investigated strategies to reduce hyperinflammation in cancer patients undergoing immunotherapy. In laboratory studies and mouse models, alpha blockers reduced the magnitude of cytokine storms and lowered mortality without appearing to impair other essential immune functions. These preclinical results were published in Nature in 2018.
As COVID-19 cases surged, the team also conducted a retrospective analysis of medical claims data for patients hospitalized with pneumonia or acute respiratory distress from various causes. Their review suggested that patients who were already taking alpha blockers for other conditions had lower rates of ventilation and death compared with non-users. While these observational findings cannot establish cause and effect on their own, they provided supportive rationale for moving ahead with a prospective clinical trial.
Design of the clinical trial
The trial will test prazosin, an alpha-1 adrenergic receptor antagonist commonly marketed under the name Minipress. Enrolled COVID-19 patients will receive gradually increasing doses of prazosin over six days. Investigators, including neurosurgeon Chetan Bettegowda, will compare the rate of ICU admission and ventilator use among trial participants versus those receiving standard care. Each patient will be followed for 60 days, and preliminary safety and efficacy data may become available within weeks to months after enrollment begins.
If results indicate that alpha blockers are both safe and effective, the research team plans to expand testing to non-hospitalized patients who have tested positive for COVID-19 but are not yet severely ill. They are also inviting collaboration from other hospitals to accelerate data collection and broaden the study population.
Vogelstein emphasizes that this approach represents secondary prevention: reducing the risk of severe symptoms after infection has occurred, rather than preventing infection itself. Vaccination remains the primary goal for stopping disease transmission, but secondary prevention strategies can help reduce hospitalizations and preserve intensive care resources while vaccines are distributed.
About this coronavirus research article
Source: HHMI
Media contacts:
Meghan Rosen – HHMI
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Image credited to scientificanimations.com / Wikimedia Commons.
Original research and preprints (titles only)
“Preventing cytokine storm syndrome in COVID-19 using α-1 adrenergic receptor antagonists” — authors include Maximilian F. Konig, Michael A. Powell, Verena Staedtke, Ren-Yuan Bai, David L. Thomas, Nicole M. Fischer, Sakibul Huq, Adham M. Khalafallah, Allison Koenecke, Ruoxuan Xiong, Brett Mensh, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Joshua T. Vogelstein, Susan Athey, Shibin Zhou, Chetan Bettegowda.
“Alpha-1 adrenergic receptor antagonists for preventing acute respiratory distress syndrome and death from cytokine storm syndrome” — authors include Joshua T. Vogelstein, Michael Powell, Allison Koenecke, Ruoxuan Xiong, Nicole Fischer, Sakibul Huq, Adham M. Khalafallah, Brian Caffo, Elizabeth A. Stuart, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Shibin Zhou, Chetan Bettegowda, Maximilian F. Konig, Brett Mensh, Susan Athey.
Key takeaway
Medications that inhibit catecholamine-associated inflammation—specifically alpha-1 adrenergic receptor antagonists—may offer a practical and widely available strategy to prevent or reduce cytokine storm syndrome in COVID-19 and other conditions marked by dangerous hyperinflammation. Ongoing clinical trials will determine whether these drugs can safely lower the risk of respiratory failure and death among infected patients.
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