key: cord-0749567-mji1l1u4 authors: Chatterjee, Subhankar; Vardhan, Bhagya; Singh, Deepa Kumari; Maitra, Abhishek; Ojha, Umesh Kumar title: Should statins be considered for the management of mucormycosis in COVID-19? date: 2021-06-05 journal: Diabetes Metab Syndr DOI: 10.1016/j.dsx.2021.05.035 sha: f718f8cbceef50091ae47a31119b3c98338b9ef4 doc_id: 749567 cord_uid: mji1l1u4 nan Authors: Subhankar Chatterjee 1 , Bhagya Vardhan 2 , Deepa Kumari Singh 3 patients [1] . Among 101 worldwide mucormycosis cases, 81.2% were from India alone during COVID-19 [2] . Hypoxia, hyperglycemia, acidosis, hyperferritinemia, and rampant steroid use create a fertile soil for Rhizopus to grow [2] . While diabetes and COVID-19 form unholy association since inception [3] , advent of mucormycosis forms the deadly trinity (mortality rate ~30.7%) [2] . Hyperglycemia, found in 83.3% cases, is the single most important risk factor for developing mucormycosis among COVID-19 patients [2] . Prompt diagnosis, normoglycemia, tapering of glucocorticoids, anti-fungals and surgical debridement are the cornerstones of management [4] . While amphotericin-B is the drug of choice, posoconazole and isavucoanzoleare alternatives [5]. Due to upsurge of both COVID-19 and mucormycosis, scarcity of these drugs has raised concern [6]. Authorities have cautioned against the use of prophylactic antifungals to curb mucormycosis [7] . Thus, there is urgent requirement of alternative,cheaper medications. In this context we examine whether statins can be repurposed as potential anti-COVID-19-cum-anti-Rhizopus therapy to combat mucormycosis. There is growing interest regarding statins to be deployed against COVID-19 because of their multifaceted pleiotropic effects [8, 9] . Multiple studies and meta-analyses have shown improved outcome among COVID-19 patients with history of taking statins [10] [11] [12] [13] . Unfortunately, there is no randomized control trial available to explore the efficacy and benefits of statins in COVID-19 at present.Anti-fungal potential of statins is well-known and widespread use of statins is one of the reasons behind the lesser incidence of zygomycosis among diabetics since 1990s [14] . Lovastatin caused apoptosis of Mucor racemosus [15] . Amphotericin-B in combination with atorvastatin or lovastatin against Rhizopus oryzae was more effective than amphotericin-B alone [16] . Similar success has been noticed with fluvastatin and rosuvastatin against Rhizomucor and Rhizopus [17] .I nvestigators showed statins impaired fungal morphogenesis by inhibiting isoprenylation of vital cell wall proteins, decreased germination, induced DNA fragmentation, increased susceptibility to oxidative stress, attenuated fungal virulence and prevented endothelial invasion (independent of GRP78/CotH interactions) [18] . Although these data from cellbasedand animal studies are encouraging, real world clinical data and human studies are needed J o u r n a l P r e -p r o o f to know whether statins reach enough tissue concentration to exert their antifungal activity when administered in usual therapeutic dosage. Diabetic patients, commonly being dyslipidemic should be screened for it and statins should be started without delay. Whether normolipdemic patients with diabetes on steroids are potential candidates for statin to prevent mucormycosis is to be explored. Although statins have been found to be safe among COVID-19 patients, their side effects and drug interactions with antifungals should be considered. Post COVID-19 Mucormycosis -from the Frying Pan into the Fire Mucormycosis in COVID-19: A Systematic Review of Cases Reported Worldwide and in India COVID-19: the endocrine opportunity in a pandemic When Uncontrolled Diabetes Mellitus and Severe COVID-19 Converge: The Perfect Storm for Mucormycosis Evidence based advisory in the time of COVID-19 COVID-19: Direct and Indirect Mechanisms of Statins Statins as Adjuvant Therapy for COVID-19 to Calm the Stormy Immunothrombosis and Beyond Association between antecedent statin use and decreased mortality in hospitalized patients with COVID-19 Decreased Mortality Rate Among COVID-19 Patients Prescribed Statins: Data From Electronic Health Records in the US Inhospital use of statins is associated with a reduced risk of mortality in coronavirus-2019 (COVID-19): systematic review and meta-analysis Association between antecedent statin use and severe disease outcomes in COVID-19: A retrospective study with propensity score matching Decrease in the number of reported cases of zygomycosis among patients with diabetes mellitus: a hypothesis Lovastatin triggers an apoptosis-like cell death process in the fungus Mucor racemosus In Vitro Activity of Amphotericin B in Combination with Statins against Clinical and Environmental Rhizopus oryzae Strains Antifungal activity of statins and their interaction with amphotericin B against clinically important Zygomycetes Statin Concentrations Below the Minimum Inhibitory Concentration Attenuate the Virulence of Rhizopus oryzae Mechanisms by which statins act against deadly duo of COVID-19 and mucormycosis (TLR-Toll like receptor, TNF-Tumor necrosis factor, IL-Interleukin, TGF-Transforming TLR-4, TNFalfa