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, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Shibin Zhou, Chetan Bettegowda, Maximilian F. Konig, Brett Mensh, Joshua T. Vogelstein, Susan Athey
Alpha-1 adrenergic receptor antagonists for preventing acute respiratory distress syndrome and death from cytokine storm syndrome
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 Department of Biomedical Engineering, Institute of Computational Medicine, The Johns Hopkins University, Baltimore, MD, USA Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health at Johns Hopkins University, Baltimore, MD, USA Institute for Computational & Mathematical Engineering, Stanford University, Stanford, CA, USA Management Science and Engineering, Stanford University, Stanford, CA, USA The Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Ludwig Center, Lustgarten Laboratory, and the Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA and Optimize Science Stanford Graduate School of Business, Stanford University, Stanford, CA, USA † Equal contribution. *To whom correspondence should be addressed.
Abstract
In severe viral pneumonias, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by a hyperinflammatory reaction (‘cytokine storm syndrome’) that leads to acute respiratory distress syndrome and death, despite maximal supportive care. Preventing hyperinflammation is key to avoiding these outcomes. We previously demonstrated that alpha-1 adrenergic receptor antagonists ( ⍺ -blockers) can prevent cytokine storm syndrome and death in mice. Here, we conduct a retrospective analysis of patients with acute respiratory distress or pneumonia (n = 13,125 and n = 108,956, respectively) from all causes; patients who were incidentally taking ⍺ -blockers had a reduced risk of requiring ventilation (by 35% and 16%, respectively), and a reduced risk of being ventilated and dying (by 56% and 20%, respectively), compared to non-users. Beta-adrenergic receptor antagonists had no significant effects. These results highlight the urgent need for prospective trials testing whether prophylactic ⍺ -blockers improve outcomes in diseases with a prominent hyperinflammatory component such as COVID-19. Introduction
Each year ~300 million people contract bacterial or viral pneumonia [1] , which is usually overcome by a local immune/inflammatory response. In severe cases (Figure 1A), the pathogen overwhelms host defenses, causing massive lung damage and compromising other organs. In some patients, pathological immune activation (‘hyperinflammation') occurs in the lungs and systemically [2] . Infection and immune-mediated damage can compromise gas exchange, leading to acute respiratory distress syndrome (ARDS) and the need for mechanical ventilation; other organ systems may also fail. Dysregulated immune responses contribute substantially to the global pneumonia death toll of 3 million per year [3] . The clinical picture is similar in Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, including hyperinflammation in the lungs and other organs, ultimately compromising function and causing high morbidity and mortality [4–7] . Disease-modifying strategies for these conditions include targeting the virus, such as with antivirals, and preventing hyperinflammation with immunomodulators or immunosuppressors. Here, we propose an approach using the latter strategy of hyperinflammation prevention [8,9] . Specialized cells of the immune/inflammatory response communicate with each other by secreting peptides called cytokines, which amplify the response and restore homeostasis after the threat has receded. However, in hyperinflammation, cytokines and other molecules trigger immune cells to produce even more cytokines, forming a ‘cytokine storm’ that can damage healthy tissue and overwhelm the host. Some patients with COVID-19 experience cytokine storm syndrome (CSS), which is characterized by elevated pro-inflammatory cytokines, including interleukin (IL)-6, IL-2R, tumor necrosis factor-α, and granulocyte-colony stimulating factor, among others [5,7,10–13] . One proposed immunosuppressive approach to ameliorating CSS is blocking IL-6 signaling. IL-6 levels predict COVID-19 severity and in-hospital mortality [4,13,14] ; monoclonal antibodies against IL-6 (siltuximab) and its receptor (tocilizumab and sarilumab) are in clinical trials for COVID-19-induced CSS [15–26] . However, the utility of antibodies is likely to be restricted by their prohibitive costs and the risks of suppressing antiviral host responses, which include prolonged immunosuppression and potential adverse reactions. Another potential target for preventing hyperinflammation is the catecholamine system. Catecholamine release precedes hyperinflammation and enhances inflammatory injury by augmenting cytokine production via a self-amplifying process that requires alpha-1 adrenergic receptor ( ⍺ -AR) signaling [27] . In mice, catecholamine synthesis inhibition reduced cytokine responses and increased survival after inflammatory stimuli. The ⍺ -AR antagonist prazosin (at clinically realistic dosages)—but not beta-adrenergic receptor (β-AR) antagonists—offered similar protection, showing that this drug class can prevent cytokine storm syndrome [27] . These preclinical findings provide a rationale for clinical studies that assess whether ⍺ -AR antagonists can prevent CSS and its sequelae. Methods and Results
To date, no controlled trials have studied whether ⍺ -AR antagonism reduces CSS, ARDS, or mortality in patients with acute respiratory distress or pneumonia. We therefore conducted a retrospective analysis of two cohorts of hospitalized patients from the MarketScan Research Database (2007-2015). Some patients were taking ⍺ -AR antagonists (doxazosin, alfuzosin, prazosin, silodosin, terazosin, or tamsulosin) to treat chronic conditions unrelated to ARDS, such as benign prostatic hyperplasia (BPH), hypertension, or post-traumatic stress disorder (PTSD). A medication was considered to be in active use on the admission date if the drug’s medication possession ratio was ≥50% in the year prior to the admission. Due to transitions to Medicare coverage at age 65, and because over 90% of ⍺ -AR antagonist users are male (due to BPH), we studied 45- to 64-year-old men. We estimated odds ratios (OR) and adjusted odds ratios (AOR) using logistic regression to relate receipt of ⍺ -AR antagonists to two outcome measures: progression to mechanical ventilation and further progression to in-hospital death. We used profile maximum likelihood to estimate confidence intervals (CI) [28] . Reported p -values use a one-sided Wald statistic test with the alternative hypothesis that the treatment reduces risk. Models were adjusted for age, fiscal year, prior inpatient admissions, total prior days as an inpatient, and comorbidities identified from healthcare encounters in the prior year: hypertension, ischemic heart disease, acute myocardial infarction, heart failure, chronic obstructive pulmonary disease, diabetes mellitus, and PTSD. The first cohort comprised 13,125 patients diagnosed with acute respiratory distress (ICD-9 code 518.82), which is often a precursor to ARDS (Figure 1B). In this cohort, taking ⍺ -AR antagonists, compared to non-users, was associated with a 22% lower incidence (relative risk reduction) of mechanical ventilation (p ≤ 0.009), and a 38% lower incidence of ventilation and death (p ≤ 0.023). We next specifically assessed the most commonly used ⍺ -AR antagonist, tamsulosin, which is selective for ⍺ and ⍺ receptor subtypes. Tamsulosin is used almost exclusively for BPH, thus reducing the likelihood of confounding by indication. Acute respiratory distress patients taking tamsulosin had a 35% lower incidence of mechanical ventilation and a 55% lower incidence of ventilation and death (p ≤ 0.002 and p ≤ 0.015, respectively). In contrast, β-AR antagonist use did not affect either clinical outcome. Figure 1 . ( A ) Model of clinical progression of COVID-19 from local infection to systemic hyperinflammation (“cytokine storm”). The timing and relation of hyperinflammation to specific organ manifestations of severe COVID-19 are areas of uncertainty and investigation. ( B ) Patients from MarketScan Research Database with acute respiratory distress. (B.i) For those who required ventilation: (left) number and proportion of patients taking medications, (right) odds ratios and confidence intervals (unadjusted and adjusted) and p-values. (B.ii) Same for those who experienced ventilation and death. ( C ) Same as (B) but for those patients with pneumonia (AHRQ category code). The results from (B) and (C) are qualitatively similar: ⍺ -AR antagonist users, and specifically tamsulosin users, have a significantly reduced likelihood of progression to death, whereas β-AR antagonists have no meaningful impact. The second cohort was 108,956 patients diagnosed with pneumonia, identified by the Agency for Healthcare Research and Quality’s (AHRQ) pneumonia category (Figure 1C). We found that taking ⍺ -AR antagonists, compared to non-users, was associated with a 13% lower incidence of mechanical ventilation (p ≤ 0.001), and a 16% lower incidence of ventilation and death (p ≤ 0.040). Pneumonia patients taking tamsulosin specifically had a 16% lower incidence of mechanical ventilation compared to non-users (no ⍺ -AR antagonist), and a 20% lower incidence of ventilation and death (p ≤ 0.001 and p ≤ 0.042, respectively). As above, β-AR antagonist use did not affect either clinical outcome. All stated results were robust to multiple alternative analysis approaches, including 5:1 propensity score matching [30] , restricting the sample to the range with propensity score overlap [29], using a Cochran–Mantel–Haenszel test, and using non-parametric causal forests [31,32] . Discussion
The results of this retrospective clinical study extend preclinical findings to support the hypothesis that ⍺ -AR antagonists may reduce morbidity and mortality in patients at risk for developing cytokine storm syndrome [33] . The fact patients were generally on ⍺ -AR antagonists for reasons unrelated to ARDS, and our ability to match the groups on a set of observed characteristics, leads to a particularly strong retrospective design. We believe the consequences of an unobserved confounder would be minimal, but it is possible that there are unobserved factors that differ between the exposure groups. Thus, randomized prospective trials will be needed to further test this hypothesis, specifically in patients at risk of cytokine storm due to COVID-19. In such trials, early administration of ⍺ -AR antagonists prior to development of severe symptoms is required because the goal is to prevent, rather than treat, hyperinflammation. ⍺ -AR antagonists with various receptor subtype specificities have been used to treat millions of patients with benign prostatic hyperplasia, hypertension, and other disorders. This history supports their safety profile [34] , although caution is warranted in using any medication for the first time in a new disease such as COVID-19. Given the poorly understood relationship between COVID-19 and hypertension [33] , it is important to note that non-receptor-subtype selective ( ⍺ = ⍺ = ⍺ ) ⍺ -ARs, such as prazosin, are used to reduce blood pressure, whereas receptor-subtype selective drugs such as tamsulosin ( ⍺ = ⍺ > ⍺ ) have fewer hemodynamic effects. ⍺ -AR antagonists are inexpensive and administered orally, enabling widespread use if prospective trials support their efficacy and safety. Beyond COVID-19 and other pneumonias, ⍺ -AR antagonists may also reduce cytokine storms and their sequelae in adoptive cell therapy and autoimmune rheumatic disease. Acknowledgments:
We thank Adam Sacarny (Columbia University) for advice on processing and analyzing health care claims data. Dr. Sacarny was not compensated for his assistance. We thank Sandra Aamodt for reviewing and editing the manuscript, and Julia Kuhl and Eric Bridgeford for help generating the figure. Research, including data analysis, was partially supported by funding from Microsoft Research and Fast Grants. The work of Allison Koenecke is supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE – 1656518. Any opinion, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. Dr. Konig was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award no. T32AR048522. Dr. Bettegowda was supported by the Burroughs Wellcome Career Award for Medical Scientists. Dr. Stuart was supported by the National Institute of Mental Health under Grant R01MH115487. This work was further supported by The Virginia and D.K. Ludwig Fund for Cancer Research, The Lustgarten Foundation for Pancreatic Cancer Research, and the BKI Cancer Genetics and Genomics Research Program. Study approval : This study used the MarketScan Research Databases. Access was granted through the Stanford Center for Population Health Sciences. Research activity on population health on de-identified data has been judged exempt by the Stanford IRB. This research is covered under Stanford PHS protocol 40974. Disclosures:
In 2017, The Johns Hopkins University (JHU) filed a patent application on the use of various drugs to prevent cytokine release syndromes, on which V.S., R.B., N.P., B.V., K.W.K., and S.Z. are listed as inventors. JHU will not assert patent rights from this filing for treatment related to COVID-19.
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