key: cord-0867760-cska35ia authors: Cour, Martin; Ovize, Michel; Argaud, Laurent title: Cyclosporine A: a valid candidate to treat COVID-19 patients with acute respiratory failure? date: 2020-06-02 journal: Crit Care DOI: 10.1186/s13054-020-03014-1 sha: 3023b02167636a151ea4e15e5e4a32581d7a4db4 doc_id: 867760 cord_uid: cska35ia nan binding to cyclophilin-A (Cyp-A) which prevents the nuclear factor of activated T cell (NF-AT) activation and the transcription of genes required for T cell proliferation, notably interleukin-2 ( Fig. 1) [3, 4] . Interestingly, SARS-CoV non-structural protein 1 was found to induce the expression of interleukin-2 via NF-AT activation [5, 6] , which might trigger the cytokine storm seen in patients with severe COVID-19 [1] . Consequently, it is tempting to use CsA to dampen the dysregulated immune response in the setting of COVID-19-related ARF. In addition, a major advantage of CsA over most anti-inflammatory drugs lies in its potent antiviral activity against coronaviruses (Fig. 1) . Indeed, at low micromolar and non-cytotoxic concentrations, CsA blocks the replication of all coronavirus genera (including SARS-CoV-1) in cell cultures [5, 6] . This antiviral property is thought to be mediated by the inhibition of Cyp-A-dependant viral assembly as well as inhibition of the NF-AT pathway [5, 6] . Finally, equally important, CsA binds to Cyp-D, which inhibits opening of the mitochondrial permeability transition pore (mPTP), a pathophysiological event triggered by injury (e.g., oxidative stress, hypoxia, and ischemia/reperfusion) that may compromise cell function or survival ( Fig. 1 ) [3] . In addition to preventing cell death under stress conditions [3] , genetic or pharmacological specific inhibition of Cyp-D has the potential to hinder viral replication [6] . In experimental models of sepsis and/or inflammationinduced acute lung injury, CsA has been consistently reported to improve lung function via mitochondrial processes, including PTP inhibition [7, 8] . Even though no clinical trial has been specifically designed to investigate the potential benefits of CsA in ARF, we reported, in a post hoc analysis of the CsA in cardiac arrest resuscitation (CYRUS) trial, that CsA may dramatically limit the severity of post-cardiac arrest ARF, corroborating the abovementioned pre-clinical findings [9, 10] . Encouragingly, we also observed, in a predefined ancillary study of the CYRUS trial, significantly higher total and CD4+ lymphocyte counts at 24 h after cardiac arrest in patients treated with CsA than in controls [11] . Importantly, no safety concerns, including an increase in nosocomial infections, were reported in trials (in which thousands of patients were included) that have tested short-term off-label CsA use, as it would be the case for COVID-19 [3, [9] [10] [11] [12] [13] ]. Yet, the toxicity of CsA cannot be excluded at concentrations that may be required to inhibit SARS-CoV-2 [3] [4] [5] [6] . This potential issue could be overcome using inhaled CsA, providing high lung tissue exposure (with minimal increase in plasma concentration), as it has been done safely and effectively after lung transplantation [14, 15] . Eventually, CsA is not expensive and might be used worldwide, including in countries where the COVID-19 health crisis is rapidly growing with little or no access to expensive therapies. Moreover, none of the antivirals against SARS-CoV-2 currently under investigation is contraindicated in combination with CsA. To summarize, CsA has the potential to prevent (1) uncontrolled inflammatory response, (2) SARS-CoV-2 replication, and (3) acute lung injury. We believe that there is a solid rationale for investigating whether CsA might bring clinical benefit in COVID-19 patients with ARF. blocks viral replication (middle box) and thus transcription of pro-inflammatory cytokines (e.g., interleukin-2). CsA, binding to cyclophilin D (Cyp-D), also prevents mitochondrial permeability transition pore (mPTP) opening-induced injury and thus cell death/dysfunction (right box). The red color is used to indicate the effects of CsA Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review Asian Critical Care Clinical Trials Group. 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All authors contributed equally to the manuscript. The authors read and approved the final manuscript.