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 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.

α1 adrenoreceptor antagonism mitigates extracellular mitochondrial DNA accumulation in lung fibrosis models and in patients with IPF

“…Additional work using transgenic mouse modeling and dedicated in vitro studies will be required to more fully explore this connect, as will larger prospective studies of patients with IPF. Nevertheless, these findings carry significance for the relatively rare condition of IPF as well as for numerous cross organ conditions of adrenergic overactivation, inflammatory remodeling and mtDNA such as non-alcoholic hepatic steatosis (33, 49), cardiac fibrosis (50), obesity (51, 52), ARDS (43, 53), and COVID-19 (46, 54), and suggest a convergent mechanism for divergent disease states.…”

“…α1 adrenoreceptor antagonism is emerging as a potential treatment for diseases characterized by inflammatory remodeling such as ARDS and COVID-19 (11, 42, 43) and we have previously shown that IPF patients taking these agents experienced preserved lung function and improved survival (11). In an attempt to link these clinical observations to the basic science studies shown above, we evaluated the relationship between plasma mtDNA concentrations – a reproducible biomarker of both fibroblast activation and mortality in the IPF disease state (21, 44, 45) – and α1 adrenoreceptor antagonism t in a longitudinal cohort of IPF patients followed at the Yale ILD Center of Excellence.…”

“…The present study also raises the exciting possibility of repurposing orally available α1 adrenoreceptor antagonists that are FDA approved for other indications for the treatment of IPF. While studies have demonstrated its therapeutic potential of this drug class for the treatment of acute inflammatory lung diseases (43, 46), its benefit for chronic fibrotic conditions such as IPF has yet to be explored. In our work we show that αSMA+ fibroblasts express ADRA1D and are reduced by terazosin treatment in the bleomycin mouse model and in cultured human cells.…”

Hold Breath: Autonomic Neural Regulation of Innate Immunity to Defend Against SARS-CoV-2 Infection

“…Although nicotine is suggested to alleviate immune dysregulation and inhibit cytokine storm, inhalation of nicotine from tobacco could increase the risk of SARS-CoV-2 infection due to upregulation of ACE2. Two population-based clinical cohort studies revealed and analyzed that treatment of influenza, pneumonia, or ARDS patients with α1-adrenergic blockers could reduce 30-day mortality, risk of intensive care unit admission, mechanical ventilation, and death ( Koenecke et al, 2021 ; Thomsen et al, 2021 ). In future studies, research and development of therapeutic strategies or drugs that can inhibit and counterbalance inflammatory cytokine secretion through adrenergic and cholinergic pathways are considered that may play an important role in helping us bring some enlightenment for treating COVID-19.…”

Ten Rules for Conducting Retrospective Pharmacoepidemiological Analyses: Example COVID-19 Study

“…Here we introduce a potential COVID-19 pharmaceutical treatment to discuss the 10 rules more concretely. Prior work indicates that certain alpha-1 adrenergic receptor antagonists (alpha blockers) disrupt cytokine storm syndromes, a pathological hyperinflammatory response associated with respiratory infection and other diseases (Staedtke et al, 2018;Koenecke et al, 2021;Thomsen et al, 2021). Subsequently, others determined that hyperinflammation is implicated in morbidity and mortality in COVID-19 patients (Mehta et al, 2020;Li et al, 2021).…”