key: cord-0946499-5s5qhm4u authors: Karampoor, Sajad; Hesamizadeh, Khashayar; Shams, Zinat; Ghafari Novin, Arefeh; Farahmand, Mohammad; Zahednasab, Hamid; Mirzaei, Rasoul; Zamani, Farhad; Hajibaba, Marzieh; Bouzari, Behnaz; Laali, Azadeh; Tabibzadeh, Alireza; Hadi Karbalaie Niya, Mohammad; Keyvani, Hossein title: The Role of Lovastatin in the Attenuation of COVID-19 date: 2021-09-24 journal: Int Immunopharmacol DOI: 10.1016/j.intimp.2021.108192 sha: 9cf08be2e311da17fdf2b2792a256584026d4fb1 doc_id: 946499 cord_uid: 5s5qhm4u The mounting evidence regarding the pathogenesis of COVID-19 indicated that the cytokine storm has an axial role in the severity of this disease, which may lead to thrombotic complications, acute respiratory distress syndrome (ARDS), and myocardial damage, among other consequences. It has recently been demonstrated that statins are known to have anti-viral, anti-inflammatory, anti-thrombotic, and immunomodulatory features; however, their advantage has not been evaluated in COVID-19. This study aimed to investigate the protective effects of lovastatin in intensive care unit (ICU) patients with COVID-19. The case-control study consists of 284 ICU patients, which classified into three groups as follows: 1) the patients who no received lovastatin as a control (92 patients), 2) patients received 20 mg per day lovastatin (99 patients), and 3) patients received 40 mg per day lovastatin (93 patients). Each group's demographic and clinical parameters, along with CRP, interleukin (IL)-6, IL-8 levels, and mortality rate, were studied in three-time points. The results showed that there was no statistically significant difference between our study groups in terms of age and sex. (P > 0.05). Besides, in patients, receiving lovastatin the CRP, IL-6, IL-8 levels were significantly decreased from T1 to T3 than to the control group. Our results also showed that the use of lovastatin in COVID-19 patients significantly reduced the length of hospitalization in the ICU compared with the control group. In addition, our results showed that the mortality rate in patients receiving lovastatin was lower when compared to the control group; however, this difference was not statistically significant. Since the cytokine storm is a significant factor in the pathology of SARS-CoV-2, our findings highlighted the potential use of lovastatin to mitigate the inflammatory response induced by SARS-CoV-2 infection. In December 2019, the novel pathogen was called SARS-CoV-2, the etiologic agent of COVID- 19 , which emerged in Wuhan, China, representing a pandemic warning to global health [1] [2] [3] [4] [5] . This pandemic can overcome national healthcare policies and significantly influence the world economy if SARS-CoV-2 extension and virulence are not included, or efficient medications are not generated [6] [7] [8] . The cellular receptor involving in entering the SARS-CoV-2 to the host cells is angiotensin-converting enzyme 2 [9, 10] . The renin-angiotensin-aldosterone system (RAAS) is dysregulated after interaction between SARS-CoV-2 and ACE-2, which might ac as a possible mechanism contributing to this pathogen's virulence [10] . The blend of direct and indirect pathogenic effects of the SAES-CoV-2, such as uncontrolled inflammation and thrombosis, and impaired regulation of RAAS may underlie the severe form of COVID-19, which can emerge with ARDS, myocardial injury, and thrombotic results [11] . According to the available evidence of many anti-inflammatory agents, anti-thrombosis and immunomodulatory drugs can be promising in treating COVID-19 patients [12] ; among these drugs, statins are one of the drug classes with anti-inflammatory effects, anti-thrombotic, immunomodulatory, and antiviral properties. Statins act as an inhibitor of the key enzyme in cholesterol biosynthesis called hydroxyl methylglutaryl-coenzyme A (HMG-CoA) reductase [13] . Statins have pleiotropic effects via targeted HMG-CoA reductase, an enzyme that limits the pathway of mevalonate and cholesterol [14] . Recently, it has been appreciated that statins (including lovastatin) have an anti-viral [15] [16] [17] , antithrombotic and anti-inflammatory features address them as an engaging class of medications in the context of COVID-19 [18, 19] . Moreover, statins can influence viral transmission and infectivity in cellular membranes through the effect on lipid rafts [19] [20] [21] [22] . Statins appear to potentially alleviate the influence of myocardial damage and thrombotic effects correlated with critical COVID-19 manifestations [13] . In this case-control investigation, we evaluated the impacts of lovastatin on the dynamic changes in the levels of selected inflammatory markers, including CRP, IL-6, and IL-8, and the outcome of COVID-19 patients, including mortality rate. This case-control study aimed to evaluate lovastatin's protective effect in ICU patients with The study was performed at three-time points (T1-T3). At each time point, 5 ml peripheral blood was collected from each patient and quickly following sample gathering, the serum was isolated by centrifugation and put at −70C° up to use. The serum's routine biochemical parameters from confirmed COVID-19 patients were done on the day of admission by standard automated methods in a Technicon Dax autoanalyzer (Technicon Instruments, CO, USA). According to the manufacturer's structure, CRP levels were assayed using BOSTER cases (P > 0.05). Also, in order to determine the role of gender in the clinical outcome of patients with COVID-19, we analyzed patients treated with lovastatin by sex ( Table 2 ). As shown in Table 2 , the statistically significantly different factors between men and women include age and IL-6 (T1) levels; more details are displayed in Table 2 3. As presented in Table 1 and Figure 1 , the CRP levels were significantly higher in cases who will receive 20 mg/day lovastatin than other groups on the day of admission (P <0.05). Also, the levels of IL-8 were significantly higher in the control group when compared with other study groups (P <0.05). After receiving lovastatin, inflammatory cytokine including CRP, IL-6, and IL-8 were significantly reduced in cases receiving lovastatin than in the control group (P <0.05). CRP levels were gradually decreased; in a way, in the groups receiving 20 and 40 mg/day of lovastatin, CRP levels were significantly reduced when compared to the control group (P <0.05). There was no statistically significant difference in serum levels of IL-6 on the day of hospitalization between the three groups. However, after receiving lovastatin, the IL-6 levels significantly declined in patients receiving lovastatin than the control group (P <0.05). The reduction in IL-6 was dose-dependent manner; in this way, the 40 of IL-6 was reduced more significantly than the 20 mg dose. In the same way, administration of lovastatin leads to a significant decline in IL-8 levels in cases receiving lovastatin than the control group (P <0.05), like the effect of lovastatin on IL-6 in this case, the dose-dependent manner reduced the decrease in serum IL-8. As shown in Table 1 and Table 3 , in patients receiving lovastatin, the length of hospitalization was significantly diminished than in the control group (P <0.05). As illustrated in Table 3 , the factors involved in death include heart disease and IL-6, which were statistically significant compared to survivors (P <0.05). Our results also showed that the mortality rate in patients receiving lovastatin was reduced than in the control group, but this reduction was not statistically meaningful (P >0.05). To date, our understanding regarding the pathogenicity of SARS-CoV-2 remains incomplete. However, the rapid expansion of our finding regarding SARS-CoV-2 pathogenesis indicated that critical mechanisms that may contribute to the pathophysiology of multi-organ damage to infection with SARS-CoV-2 hold endothelial cell damage and thrombosis, inflammation, dysregulation of the immune response, and dysregulation of the RAAS [23] . Since many anti-inflammatory, immunomodulatory, and anti-thrombotic drugs may hold a potential role in treating and preventing COVID-19 [12] , statins with these properties are among the available potential drugs to prevent or treat COVID-19 patients. Previous reports demonstrated that the use of statins such as lovastatin (inhibitor of HMG-CoA reductase) could inhibit replication of respiratory viral infections such as RSV [24, 25] and influenza [26] . In this case-control investigation, we evaluated the efficacy of lovastatin in alleviating inflammation, duration time of hospitalization, and mortality incidence in ICU cases with COVID-19. Our study results indicated that lovastatin might have a beneficial function in cases with COVID-19, which agrees with the previous investigations that indicated that receiving statin might have a beneficial effect in COVID-19 patients [27] [28] [29] [30] [31] . The vast majority of the investigation indicated that the excess inflammatory response or cytokine storm has an axial determinant in the pathogenesis of SARS-CoV-2 [32] [33] [34] [35] . The study result showed that the administration of lovastatin could attenuate the inflammatory response due to SARS-CoV-2 infection. The study results are under previous studies, indicating that CRP levels were raised in cases with COVID-19 [8, 36, 37] . Our result agrees with the previous study, which indicated that statins could decrease CRP [35, 38, 39] . The previous investigation indicated that after interaction between SARS-CoV-2 and its receptor ACE2, CRP is produced [40] [41] [42] , which is a marker of the acute phase of inflammation and has been correlated to prognosis mortality and severity of COVID-19 [42] [43] [44] . Also, the crucial stage in CRP biology is complement activation that has a pathogenic effect in [63, 64] , coagulation [65, 66] , tissue damage [67, 68] . In sum, IL-6 levels were elevated in all cases with COVID-19; therefore, it may be considered a potential therapeutic target for investigators. Regarding IL-8 levels, our finding agrees with previous research that displayed that IL-8 levels were elevated in patients with COVID-19 [69] [70] [71] . Recently, the accumulating evidence points out the significant function of neutrophils in the pathophysiology of SARS-CoV-2, especially in those with critical disease courses [72] [73] [74] . Also, IL-8 is a pro-inflammatory cytokine that may recruit neutrophils to the infected areas by act as neutrophil-activating chemokine (61 [27, 28] ; however, this finding was not statistically significant. Due to the small sample size, to better evaluate the role of lovastatin in reducing COVID-19 mortality, it is recommended to use a high sample size in future studies to interpret the results. It is also recommended that future studies will be performed as a prospective cohort study. In the present work, we provide evidence for the possible beneficial role of lovastatin in ICU cases with COVID-19. Our findings divulged that lovastatin might have a protecting role in COVID-19 patients by reducing inflammatory markers, including CRP, IL-6, and IL-8. However, further investigations are needed concerning evaluating the effect of lovastatin on the COVID-19 cases, and more clinical trials are required to declare lovastatin as a beneficial option for the help to the treatment of COVID-19 patients The authors declare that they have no competing interests. Legends to the tables and figures. Table 3 . Demographic and clinical parameters of dead patients versus alive patients. The laboratory finding and dynamic changes in CRP, IL-6, and IL-8 levels in different study groups. All authors read and approved the final version of the revised manuscript. 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