key: cord-266113-3fp46sov authors: Dashti‐Khavidaki, Simin; Khalili, Hossein title: Considerations for Statin Therapy in Patients with COVID‐19 date: 2020-05-04 journal: Pharmacotherapy DOI: 10.1002/phar.2397 sha: doc_id: 266113 cord_uid: 3fp46sov Current coronavirus pandemic named coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is the third coronavirus outbreak during the current century after severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses.1 Acute respiratory distress syndrome (ARDS) is an immunopathologic event and main cause of death following COVID-19. The main mechanism of ARDS is uncontrolled systemic inflammatory response and cytokine storm following release of proinflammatory cytokines (such as interferons (IFN), interleukines (IL), tumor necrosis factor (TNF)-α) and chemokines.2-3 So, some Chinese researchers proposed or used anti-inflammatory agents in the treatment regimen of patients with COVID-19.3-4. The current coronavirus pandemic is an outbreak of coronavirus disease 2019 (COVID- 19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is the third coronavirus outbreak during the current century, after the outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses. 1 Acute respiratory distress syndrome (ARDS) is an immunopathologic event and the main cause of death following COVID-19. The main mechanism of ARDS is uncontrolled systemic inflammatory response and cytokine storm following the release of proinflammatory cytokines (e.g., interferons [IFNs], interleukins [ILs], tumor necrosis factor [TNF]-a) and chemokines. 2, 3 Therefore, some Chinese researchers proposed or used anti-inflammatory agents in the treatment regimen of patients with COVID-19. 3, 4 Statins are well known for their anti-inflammatory effects, 5 and some hospitals included them in the COVID-19 treatment protocol. 6 Here, we summarize the main points that should be considered before incorporating this class of drugs in a COVID-19 treatment regimen. Toll-like receptors (TLRs), a family of sensor proteins, assist the immune system to discriminate between "self" and "non-self." In a mice model, researchers demonstrated that TLR signaling through TRIF adaptor protein mitigate ARDS as a main cause of death in SARS-CoV disease. 7 Gene expression of myeloid differentiation primary response 88 (MyD88) acts downstream of TLRs and is induced by SARS-CoV infection. 7 Both overexpression 7 and underrexpression of MyD88 gene 8 were related to increased mortality after MERS-CoV infection. Downstream of TLRs-MyD88 pathways, NF-jB is activated by coronavirus infections. In a mice model, inhibition of NF-jB improved lung infection and survival after SARS-CoV infection. 9 Statins preserve MyD88 at normal levels during hypoxia 10 and mitigate NF-jB activation, 11 so some investigators hypothesized the idea of using statins for the treatment of MERS-CoV infection 12 and COVID-19. 13 But animal studies have shown that aberrant inhibition of TLR adaptor TRIF or MyD88 signals results in severe lung damage and death. 7, 14 This may be due to the compensatory activation of other innate immune factors. In addition, animal studies on SARS-CoV and MERS-CoV infections revealed that abolished TLR pathway leads to increased viral load that persists for a longer time and increases the risk of human-to-human transmission. 7, 14 Therefore, statins, by the potential to stop TLR and NF-jB signaling, carry the potential risk of exacerbating compensatory immune signals and poor disease outcome. Although some human and animal studies have shown lung injury improvement of statins via their anti-inflammatory effects, 15 and mortality in statin-treated patients. 17 The findings on the effects of statin on communityacquired 18 and ventilator-associated pneumonia 19, 20 are conflicting as well. Finally, for the COVID-19 outbreak, although some US hospitals included statins in COVID-19 treatment 6 and some proposed their use for this condition, 13 some others worry regarding statininduced increase in IL-18 and deterioration of SARS-CoV-2-induced ARDS and mortality. 21 We have to notice that patients with common comorbidities, including hypertension, cardiovascular diseases, and diabetes, are at greater risk for SARS-CoV-2 infection and its related ARDS and mortality. 22 Most of these patients are taking statins routinely based on diabetes and cardiovascular guidelines. There is no evidence for discontinuing statins in these patients during the COVID-19 episode. Although usually well tolerated, statins may cause myotoxicity in some patients. Features of statin-induced myotoxicity differ from those of myalgia (more common) to myopathies and rarely rhabdomyolysis. Rhabdomyolysis can cause acute kidney injury. 23 Myalgia, increased creatine phosphokinase, rhabdomyolysis, and acute kidney injury occur in patients with COVID-19 as well. 2 In addition, some risk factors such as advanced age and liver and kidney impairments are common between statininduced myopathies and infection with SARS-CoV-2. 2, 23 Thus, initiating statins in patients with COVID-19 may increase the risk and severity of myopathies and acute kidney injury. Furthermore, statin therapy and COVID-19 both increase liver enzymes that are hard to differentiate from each other, if statin therapy starts at the episode of COVID-19. 2 Most available statins are substrate for the cytochrome P450 (CYP) system, especially 3A isoenzymes and P-glycoproteins (P-gp). Protease inhibitors (e.g., lopinavir, darunavir) and their pharmacokinetic enhancers (ritonavir and cobicistat) are potent inhibitors of both CYP3A and P-gp, and their concomitant administration results in markedly increased statin exposure and adverse effects. Coadministration of simvastatin or lovastatin with ritonavir/cobicistat-boosted protease inhibitors should be avoided. Maximum daily doses of 20 mg for atorvastatin and 10-20 mg for rosuvastatin have been proposed in patients receiving ritonavir/cobicistat-boosted protease inhibitors. 24, 25 Conclusion Taken together, although there is an urgent need for finding safe and available options for treatment of COVID-19 and its related fatal ARDS, we must balance our expectation from these immunomodulatory drugs against the potential of disease exacerbation by these agents. We recommend guideline-directed continuation of statin therapy among COVID-19 patients with a history of atherosclerotic cardiovascular disease or diabetes. We recommend guidancedirected initiation of statin in patients with COVID-19 who show acute cardiac injury. But, de novo initiation of statin therapy for management of COVID-19 episode can be done only as a clinical trial, not routinely. Molecular immune pathogenesis and diagnosis of COVID-19 Clinical characteristics of coronavirus disease 2019 in China Induction of proinflammatory cytokines (IL-1 and IL-6) and lung inflammation by coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the experience of immunologists from China Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents? Massachusetts General Hospital COVID-19 Treatment Guidance Version 1.0 3/17/2020. Available at: https://medtube.net/ infectious-diseases/medical-documents/26086-covid19-treatmentguidelines-by-massachusetts-general-hospital Toll-like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection MyD88 is required for protection from lethal infection with a mouseadapted SARS-CoV Inhibition of NF-jB-mediated inflammation in severe acute respiratory 485 syndrome coronavirus-infected mice increase survival Atorvastatin attenuates myocardial remodeling induced by chronic intermittent hypoxia in rats: partly involvement of TLR4/MYD88 pathway Atorvastatin attenuates TLR-4-mediated NF-kappa B activation in a MyD88-dependent pathway Statins may decrease the fatality rate of Middle East respiratory syndrome infection Hiding in plain sight: an approach to treating patients with severe COVID-19 infection Reply to "statins may decrease fatality rate of MERS infection Simvastatin decreases lipopoly-saccharide-induced pulmonary inflammation in healthy volunteers Role of claudin-5 in the attenuation of murine acute lung injury by simvastatin Association of elevated plasma interleukin-18 level with increased mortality in a clinical trial of statin treatment for acute respiratory distress syndrome Mart ın-Loeches I. 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