Statins as an adjunctive therapy for COVID-19: the biological and clinical plausibility

References

• Coronavirus. World Health Organization [Internet]. Who.int.; 2020; [cited 2020 Sep 6]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019
   Google Scholar
• Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620–2629.
   PubMed Web of Science ®Google Scholar
• Zhang W, Zhao Y, Zhang F, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the perspectives of clinical immunologists from China. Clin Immunol. 2020;214:108393.
   PubMed Web of Science ®Google Scholar
• Tay MZ, Poh CM, Rénia L, et al. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020;20(6):363–374.
   PubMed Web of Science ®Google Scholar
• Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endothelialitis in COVID-19. Lancet. 2020;395(10234):1417–1418.
   PubMed Web of Science ®Google Scholar
• Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19. N Engl J Med. 2020;383(2):120–128.
   PubMed Web of Science ®Google Scholar
• Mehta N, Kalra A, Nowacki AS, et al. Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(9):e201855.
   Web of Science ®Google Scholar
• Reynolds HR, Adhikari S, Pulgarin C, et al. Renin–angiotensin– aldosterone system inhibitors and risk of covid-19. N Engl J Med. 2020;382(25):2441–2448.
   PubMed Web of Science ®Google Scholar
• The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19): China, 2020. China CDC Weekly. 2020;2(8):113–122.
   PubMedGoogle Scholar
• Mancia G, Rea F, Ludergnani M, et al. Renin–angiotensin– aldosterone system blockers and the risk of Covid-19. N Engl J Med. 2020;382(25):2431–2440.
   PubMed Web of Science ®Google Scholar
• Kang Y, Chen T, Mui D, et al. Cardiovascular manifestations and treatment consideration in covid-19. Heart. 2020;106(15):1132–1141.
   PubMed Web of Science ®Google Scholar
• Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061–1069.
   PubMed Web of Science ®Google Scholar
• Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(7):e201017.
   Web of Science ®Google Scholar
• Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult patients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–1062.
   PubMed Web of Science ®Google Scholar
• Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. 2020;5(7):e200950.
   Web of Science ®Google Scholar
• Santoso A, Pranata R, Wibowo A, et al. Cardiac injury is associated with mortality and critically ill pneumonia in COVID-19: a meta-analysis. Am J Emerg Med. 2020.
   Google Scholar
• Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507–513.
   PubMed Web of Science ®Google Scholar
• National Health Commission of People’s Republic of China. Chinese clinical guidance for COVID-19 pneumonia diagnosis and treatment. 7th ed.; 2020. Available from: http://kjfy.meetingchina.org/msites/news/show/cn/3337.html
   Google Scholar
• Chen C, Zhou Y, Wang DW. SARS-CoV-2: a potential novel etiology of fulminant myocarditis. Herz. 2020;45(3):230–233.
   PubMed Web of Science ®Google Scholar
• Inciardi RM, Lupi L, Zaccone G, et al. Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(7):819.
   PubMed Web of Science ®Google Scholar
• Tian S, Xiong Y, Liu H, et al. Pathological study of the 2019 novel coronavirus disease (COVID-19) through post-mortem core biopsies. Mod Pathol. 2020;1–8.
   Google Scholar
• Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020.
   Google Scholar
• Stefanini GG, Montorfano M, Trabattoni D, et al. ST-elevation myocardial infarction in patients with COVID-19: clinical and angiographic outcomes. Circulation. 2020;141(25):2113–2116.
   PubMed Web of Science ®Google Scholar
• Vaughan CJ, Gotto AM, Basson CT. The evolving role of statins in the management of atherosclerosis. J Am Coll Cardiol. 2000;35(1):1–10.
   PubMed Web of Science ®Google Scholar
• Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373(9670):1175–1182.
   PubMed Web of Science ®Google Scholar
• Ridker PM, Morrow DA, Rose LM, et al. Relative efficacy of atorvastatin 80 mg and pravastatin 40 mg in achieving the dual goals of low-density lipoprotein cholesterol <70 mg/dl and C-reactive protein <2 mg/l: an analysis of the PROVE-IT TIMI-22 trial. J Am Coll Cardiol. 2005;45:1644–1648.
   PubMed Web of Science ®Google Scholar
• Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol. 2006;6(5):358–370.
   PubMed Web of Science ®Google Scholar
• Oesterle A, Laufs U, Liao JK. Pleiotropic effects of statins on the cardiovascular system. Circ Res. 2017;120(1):229–243.
   PubMed Web of Science ®Google Scholar
• Banach M, Penson PE, Fras Z, et al. Brief recommendations on the management of adult patients with familial hypercholesterolemia during the COVID-19 pandemic. Pharmacol Res. 2020;158:104891.
   PubMed Web of Science ®Google Scholar
• Stancu C, Sima A. Statins: mechanism of action and effects. J Cell Mol Med. 2001;5(4):378–387.
   PubMed Web of Science ®Google Scholar
• Nakayama H, Nagafuku M, Suzuki A, et al. The regulatory roles of glycosphingolipid-enriched lipid rafts in immune systems. FEBS Lett. 2018;592(23):3921–3942.
   PubMed Web of Science ®Google Scholar
• Redondo-Morata R, Sanford RL, Andersen OS, et al. Effect of statins on the nanomechanical properties of supported lipid bilayers. Biophys J. 2016;111(2):363–372.
   PubMed Web of Science ®Google Scholar
• Matzinger P. The danger model: a renewed sense of self. Science. 2002;296(5566):301–305.
   PubMed Web of Science ®Google Scholar
• Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol. 2014;5:1–8.
   PubMed Web of Science ®Google Scholar
• Zelvyte I, Dominaitiene R, Crisby M, et al. Modulation of inflammatory mediators and PPARgamma and NFkappaB expression by pravastatin in response to lipoproteins in human monocytes in vitro. Pharmacol Res. 2002;45(2):147–154.
   PubMed Web of Science ®Google Scholar
• Niessner A, Steiner S, Speidl WS, et al. Simvastatin suppresses endotoxin-induced upregulation of toll-like receptors 4 and 2 in vivo. Atherosclerosis. 2006;189(2):408–413.
   PubMed Web of Science ®Google Scholar
• Moutzouri E, Tellis CC, Rousouli K, et al. Effect of simvastatin or its combination with ezetimibe on Toll-like receptor expression and lipopolysaccharide-induced cytokine production in monocytes of hypercholesterolemic patients. Atherosclerosis. 2012;225(2):381–387.
   PubMed Web of Science ®Google Scholar
• Ascer E, Bertolami MC, Venturinelli ML, et al. Atorvastatin reduces proinflammatory markers in hypercholesterolemic patients. Atherosclerosis. 2004;177(1):161–166.
   PubMed Web of Science ®Google Scholar
• Satoh M, Tabuchi T, Itoh T, et al. NLRP3 inflammasome activation in coronary artery disease: results from prospective and randomized study of treatment with atorvastatin or rosuvastatin. Clin Sci (Lond). 2014;126(3):233–241.
   PubMed Web of Science ®Google Scholar
• Chakrabarti R, Engleman EG. Interrelationships between mevalonate metabolism and the mitogenic signaling pathway in T lymphocyte proliferation. J Biol Chem. 1991;266:12216–12222.
   PubMed Web of Science ®Google Scholar
• Cuthbert JA, Lipsky PE. A product of mevalonate proximal to isoprenoids is the source of both a necessary growth factor and an inhibitor of cell proliferation. Trans Assoc Am Physicians. 1991;104:97–106.
   PubMedGoogle Scholar
• Kwak B, Mulhaupt F, Myit S, et al. Statins as a newly recognized type of immunomodulator. Nat Med. 2000;6(12):1399–1402.
   PubMed Web of Science ®Google Scholar
• Yilmaz A, Reiss C, Tantawi O, et al. HMG-CoA reductase inhibitors suppress maturation of human dendritic cells: new implications for atherosclerosis. Atherosclerosis. 2004;172(1):85–93.
   PubMed Web of Science ®Google Scholar
• Youssef S, Stüve O, Patarroyo JC, et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 2002;420(6911):78–84.
   PubMed Web of Science ®Google Scholar
• Bath PMW, Hassall DG, Gladwin A-M, et al. Nitric oxide and prostacyclin. Divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro. Arterioscler Thromb. 1991;11(2):254–260.
   PubMedGoogle Scholar
• Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A. 1991;88(11):4651–4655.
   PubMed Web of Science ®Google Scholar
• Sasidhar MV, Chevooru SK, Eickelberg O, et al. Downregulation of monocytic differentiation via modulation of CD147 by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. PLoS One. 2017;12(12):e0189701.
   PubMed Web of Science ®Google Scholar
• Yurchenko V, Constant S, Eisenmesser E, et al. Cyclophilin-CD147 interactions: a new target for anti-inflammatory therapeutics. Clin Exp Immunol. 2010;160(3):305–317.
   PubMed Web of Science ®Google Scholar
• Jin R, Xiao AY, Chen R, et al. Inhibition of CD147 (cluster of differentiation 147) ameliorates acute ischemic stroke in mice by reducing thromboinflammation. Stroke. 2017;48(12):3356–3365.
   PubMed Web of Science ®Google Scholar
• Lu Y, Liu DX, Tam JP. Lipid rafts are involved in SARS-CoV entry into Vero E6 cells. Biochem Biophys Res Commun. 2008;369(2):344–349.
   PubMed Web of Science ®Google Scholar
• Wang H, Yuan Z, Pavel MA, et al. The role of high cholesterol in age-related COVID-19 lethality. bioRxiv. Preprint; 2020.
   Google Scholar
• Glende J, Schwegmann-Wessels C, Al-Falah M, et al. Importance of cholesterol-rich membrane microdomains in the interaction of the S protein of SARS-coronavirus with the cellular receptor angiotensin-converting enzyme 2. Virology. 2008;381(2):215–221.
   PubMed Web of Science ®Google Scholar
• Reiner Ž, Hatamipour M, Banach M, et al. Statins and the COVID-19 main protease: in silico evidence on direct interaction. Arch Med Sci. 2020;16(3):490–496.
   PubMed Web of Science ®Google Scholar
• Müller C, Hardt M, Schwudke D, et al. Inhibition of cytosolic phospholipase A(2)a impairs an early step of coronavirus replication in cell culture. J Virol. 2018;92(4):e01463-17.
   PubMed Web of Science ®Google Scholar
• Moscardó A, Vallés J, Latorre A, et al. Reduction of platelet cytosolic phospholipase A2 activity by atorvastatin and simvastatin: biochemical regulatory mechanisms. Thromb Res. 2013;131(4):e154–e159.
   PubMed Web of Science ®Google Scholar
• Cui L, Zhang X, Yang R, et al. Neuroprotection of early and short-time applying atorvastatin in the acute phase of cerebral ischemia: down-regulated 12/15-LOX, p38MAPK and cPLA2 expression, ameliorated BBB permeability. Brain Res. 2010;1325:164–173.
   PubMed Web of Science ®Google Scholar
• Wang K, Chen W, Zhou YS, et al. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein. BioRxiv Preprint; 2020.
   Google Scholar
• Jacobson JR, Barnard JW, Grigoryev DN, et al. Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol. 2005;288(6):L1026–L1032.
   PubMed Web of Science ®Google Scholar
• Fessler MB, Young SK, Jeyaseelan S, et al. A role for hydroxy-methylglutaryl coenzyme a reductase in pulmonary inflammation and host defense. Am J Respir Crit Care Med. 2005;171(6):606–615.
   PubMed Web of Science ®Google Scholar
• Kim JW, Rhee CK, Kim TJ, et al. Effect of pravastatin on bleomycin-induced acute lung injury and pulmonary fibrosis. Clin Exp Pharmacol Physiol. 2010;37(11):1055–1063.
   PubMed Web of Science ®Google Scholar
• Siempos II, Maniatis NA, Kopterides P, et al. Pretreatment with atorvastatin attenuates lung injury caused by high-stretch mechanical ventilation in an isolated rabbit lung model. Crit Care Med. 2010;38:1321–1328.
   PubMed Web of Science ®Google Scholar
• Müller HC, Hellwig K, Rosseau S, et al. Simvastatin attenuates ventilator-induced lung injury in mice. Crit Care. 2010;14(4):R143.
   PubMed Web of Science ®Google Scholar
• Bao XC, Mao AR, Fang YQ, et al. Simvastatin decreases hyperbaric oxygen-induced acute lung injury by upregulating eNOS. Am J Physiol Lung Cell Mol Physiol. 2018;314(2):L287–L297.
   PubMed Web of Science ®Google Scholar
• Shyamsundar M, McKeown ST, O'Kane CM, et al. Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers. Am J Respir Crit Care Med. 2009;179(12):1107–1114.
   PubMed Web of Science ®Google Scholar
• O’Neal HR Jr., Koyama T, Koehler EA, et al. Prehospital statin and aspirin use and the prevalence of severe sepsis and acute lung injury/acute respiratory distress syndrome. Crit Care Med. 2011;39:1343–1350.
   PubMed Web of Science ®Google Scholar
• Craig TR, Duffy MJ, Shyamsundar M, et al. A randomized clinical trial of hydroxymethylglutaryl-coenzyme a reductase inhibition for acute lung injury (The HARP Study). Am J Respir Crit Care Med. 2011;183(5):620–626.
   PubMed Web of Science ®Google Scholar
• Calfee CS, Delucchi KL, Sinha P, et al. Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomized controlled trial. Lancet Respir Med. 2018;6(9):691–698.
   PubMed Web of Science ®Google Scholar
• Kruger P, Bailey M, Bellomo R, et al. A multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis. Am J Respir Crit Care Med. 2013;187(7):743–750.
   PubMed Web of Science ®Google Scholar
• Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomized controlled trials. Lancet. 2019;393(10170):407–415.
   PubMed Web of Science ®Google Scholar
• Kunutsor SK, Seidu S, Khunti K. Statins and primary prevention of venous thromboembolism: a systematic review and meta-analysis. Lancet Haematol. 2017;4(2):e83–e93.
   PubMed Web of Science ®Google Scholar
• Fedson DS. Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola. Ann Transl Med. 2016;4(21):421.
   PubMed Web of Science ®Google Scholar
• Mehrbod P, Omar AR, Hair-Bejo M, et al. Mechanisms of action and efficacy of statins against influenza. Biomed Res Int. 2014;2014:872370.
   PubMed Web of Science ®Google Scholar
• Bifulco M, Gazzerro P. Statins in coronavirus outbreak: it's time for experimental and clinical studies. Pharmacol Res. 2020;156:104803.
   PubMed Web of Science ®Google Scholar
• San-Juan-Vergara H, Sampayo-Escobar V, Reyes N, et al. Cholesterol-rich microdomains as docking platforms for respiratory syncytial virus in normal human bronchial epithelial cells. J Virol. 2012;86(3):1832–1843.
   PubMed Web of Science ®Google Scholar
• Chang TH, Segovia J, Sabbah A, et al. Cholesterol-rich lipid rafts are required for release of infectious human respiratory syncytial virus particles. Virology. 2012;422(2):205–213.
   PubMed Web of Science ®Google Scholar
• Bajimaya S, Frankl T, Hayashi T, et al. Cholesterol is required for stability and infectivity of influenza A and respiratory syncytial viruses. Virology. 2017;510:234–241.
   PubMed Web of Science ®Google Scholar
• Hui KP, Kuok DI, Kang SS, et al. Modulation of sterol biosynthesis regulates viral replication and cytokine production in influenza A virus infected human alveolar epithelial cells. Antiviral Res. 2015;119:1–7.
   PubMed Web of Science ®Google Scholar
• Episcopio D, Aminov S, Benjamin S, et al. Atorvastatin restricts the ability of influenza virus to generate lipid droplets and severely suppresses the replication of the virus. FASEB J. 2019;33(8):9516–9525.
   PubMed Web of Science ®Google Scholar
• Carette JE, Raaben M, Wong AC, et al. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature. 2011;477(7364):340–343.
   PubMed Web of Science ®Google Scholar
• Shrivastava-Ranjan P, Flint M, Bergeron E, et al. Statins suppress Ebola virus infectivity by interfering with glycoprotein processing. mBio. 2018;9(3):e00660-18.
   PubMed Web of Science ®Google Scholar
• Waheed AA, Freed EO. Lipids and membrane microdomains in HIV-1 replication. Virus Res. 2009;143(2):162–176.
   PubMed Web of Science ®Google Scholar
• Osuna-Ramos JF, Reyes-Ruiz JM, Del Ángel RM. The role of host cholesterol during flavivirus infection. Front Cell Infect Microbiol. 2018;8:388.
   PubMed Web of Science ®Google Scholar
• Zhu Q, Li N, Han Q, et al. Statin therapy improves response to interferon alfa and ribavirin in chronic hepatitis C: a systematic review and meta-analysis. Antiviral Res. 2013;98(3):373–379.
   PubMed Web of Science ®Google Scholar
• Whitehorn J, Nguyen CVV, Khanh LP, et al. Lovastatin for the treatment of adult patients with dengue: a randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2016;62(4):468–476.
   PubMed Web of Science ®Google Scholar
• Blanc M, Hsieh WY, Robertson KA, et al. Host defense against viral infection involves interferon mediated down-regulation of sterol biosynthesis. PLoS Biol. 2011;9(3):e1000598.
   PubMed Web of Science ®Google Scholar
• Nagase T, Uozumi N, Aoki-Nagase T, et al. A potent inhibitor of cytosolic phospholipase A2, arachidonyl trifluoromethyl ketone, attenuates LPS-induced lung injury in mice. Am J Physiol Lung Cell Mol Physiol. 2003;284(5):L720–L726.
   PubMed Web of Science ®Google Scholar
• Uozumi N, Shimizu T. Roles for cytosolic phospholipase A2alpha as revealed by gene-targeted mice. Prostaglandins Other Lipid Mediat. 2002;68–69:59–69.
   PubMed Web of Science ®Google Scholar
• Kor DJ, Iscimen R, Yilmaz M, et al. Statin administration did not influence the progression of lung injury or associated organ failures in a cohort of patients with acute lung injury. Intensive Care Med. 2009;35(6):1039–1046.
   PubMed Web of Science ®Google Scholar
• McAuley DF, Laffey JG, O'Kane CM, et al. Simvastatin in the acute respiratory distress syndrome. N Engl J Med. 2014;371(18):1695–1703.
   PubMed Web of Science ®Google Scholar
• Sinha P, Delucchi KL, Thompson BT, et al. Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study. Intensive Care Med. 2018;44(11):1859–1869.
   PubMed Web of Science ®Google Scholar
• Rogers AJ, Guan J, Trtchounian A, et al. Association of elevated plasma interleukin-18 level with increased mortality in a clinical trial of statin treatment for acute respiratory distress syndrome. Crit Care Med. 2019;47:1089–1096.
   PubMed Web of Science ®Google Scholar
• Papazian L, Roch A, Charles PE, et al. Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial. JAMA. 2013;310(16):1692–1700.
   PubMed Web of Science ®Google Scholar
• Nagendran M, McAuley DF, Kruger PS, et al. Statin therapy for acute respiratory distress syndrome: an individual patient data meta-analysis of randomised clinical trials. Intensive Care Med. 2017;43(5):663–671.
   PubMed Web of Science ®Google Scholar
• Tleyjeh IM, Kashour T, Hakim FA, et al. Statins for the prevention and treatment of infections: a systematic review and meta-analysis. Arch Intern Med. 2009;169(18):1658–1667.
   PubMed Web of Science ®Google Scholar
• Khan AR, Riaz M, Bin Abdulhak AA, et al. The role of statins in prevention and treatment of community acquired pneumonia: a systematic review and meta-analysis. PLoS One. 2013;8(1):e52929.
   PubMed Web of Science ®Google Scholar
• Pertzov B, Eliakim-Raz N, Atamna H, et al. Hydroxymethylglutaryl-CoA reductase inhibitors (statins) for the treatment of sepsis in adults – a systematic review and meta-analysis. Clin Microbiol Infect. 2019;25(3):280–289.
   PubMed Web of Science ®Google Scholar
• Sapey E, Patel JM, Greenwood H, et al. Simvastatin improves neutrophil function and clinical outcomes in pneumonia. A pilot randomized controlled clinical trial. Am J Respir Crit Care Med. 2019;200(10):1282–1293.
   PubMed Web of Science ®Google Scholar
• Lee CC, Lee MG, Hsu TC, et al. A population-based cohort study on the drug-specific effect of statins on sepsis outcome. Chest. 2018;153(4):805–815.
   PubMed Web of Science ®Google Scholar
• Bryan-Marrugo OL, Arellanos-Soto D, Rojas-Martinez A, et al. The anti-dengue virus properties of statins may be associated with alterations in the cellular antiviral profile expression. Mol Med Rep. 2016;14(3):2155–2163.
   PubMed Web of Science ®Google Scholar
• De Spiegeleer A, Bronselaer A, Teo JT, et al. The effect of ARBs, ACEIs and statins on clinical outcomes of COVID-19 infection among nursing home residents. J Am Med Dir Assoc. 2020.
   Google Scholar
• Zhang X-J, Qin J-J, Cheng X, et al. In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19. Cell Metab. 2020;32(2):176–187.e4.
   PubMed Web of Science ®Google Scholar
• Tikoo K, Patel G, Kumar S, et al. Tissue specific up regulation of Ace2 in rabbit model of atherosclerosis by atorvastatin: role of epigenetic histone modifications. Biochem Pharmacol. 2015;93(3):343–351.
   PubMed Web of Science ®Google Scholar
• BinAbdulhak A, Kashour T, Tlayjeh H, et al. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers and outcome of COVID-19: a systematic review and meta-analysis. medRxiv; 2020.
   Google Scholar
• Sheahan T, Morrison TE, Funkhouser W, et al. MyD88 is required for protection from lethal infection with a mouse-adapted SARS-CoV. PLoS Pathog. 2008;4(12):e1000240.
   PubMed Web of Science ®Google Scholar
• Totura AL, Whitmore A, Agnihothram S, et al. Toll-like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection. mBio. 2015;6(3):e00638–e00615.
   PubMed Web of Science ®Google Scholar
• Xu JF, Washko GR, Nakahira K, et al. Statins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation. Am J Respir Crit Care Med. 2012;185(5):547–556.
   PubMed Web of Science ®Google Scholar
• Takahashi HK, Mori S, Iwagaki H, et al. Simvastatin induces interleukin-18 production in human peripheral blood mononuclear cells. Clin Immunol. 2005;116(3):211–216.
   PubMed Web of Science ®Google Scholar
• Takahashi HK, Mori S, Iwagaki H, et al. Differential effect of LFA703, pravastatin, and fluvastatin on production of IL-18 and expression of ICAM-1 and CD40 in human monocytes. J Leukoc Biol. 2005;77(3):400–407.
   PubMed Web of Science ®Google Scholar
• Lane J, van Eeden SF, Obeidat M, et al. Impact of statins on gene expression in human lung tissues. PLoS One. 2015;10(11):e0142037.
   PubMed Web of Science ®Google Scholar
• Wibaut-Berlaimont V, Randi AM, Mandryko V, et al. Atorvastatin affects leukocyte gene expression in dyslipidemia patients: in vivo regulation of hemostasis, inflammation and apoptosis. J Thromb Haemost. 2005;3(4):677–685.
   PubMed Web of Science ®Google Scholar