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Establishing the equipoise between infection and rejection in any individual transplant recipient has always been the aim when prescribing immunosuppression. Today the world is facing a global pandemic which has never been seen in the era of transplantation and immunotherapy. As of April 7, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been confirmed in .1.25 million people worldwide with a mortality rate of 5.7%. The presence of comorbid conditions is associated with higher risk of death, which is concerning because significant comorbidity is common in recipients of transplants.1 The additional risk posed by immunosuppression in these patients cannot be estimated due to lack of data. Logically, transplant clinicians are needing to extrapolate from evidence obtained from treating other life-threatening infections in recipients of transplants, which involves reducing or stopping immunosuppression. At the time of writing, published data are available in 11 transplant patients infected with SARS-CoV-2 (eight adult and three pediatric patients).2–6 Calcineurin inhibitors (CNIs) are the cornerstone of transplant maintenance immunosuppressive regimens, and all patients were receiving CNIs at the time of diagnosis. In keeping with what is known in the general population, all pediatric outcomes were favorable. In the adult cases, seven of the eight case reports describe management that included withdrawal of both CNIs and antiproliferative agents; in these cases, outcomes were variable (three patients survived, three remain in critical care, and two deaths).2–4,6 Several guidelines have since been developed that recommend withdrawal of CNIs in transplant patients with severe SARS-CoV-2 infection.7,8 Two features of CNIs, one experimental and the other clinical, warrant attention because they may have important repercussions not only for patients who have received a transplant but also in the management of SARS-CoV-2 infection in general. Firstly, it is known that a number of viruses use active immunophilin pathways during their life cycle, and that CNIs may inhibit viral replication in vitro.9,10 Cyclosporine, for example, has been shown to inhibit the replication of several coronaviruses in vitro at noncytotoxic concentrations and independently of its immunosuppressive effect.10,11 In addition, the inhibitory effect of cyclosporine on hepatitis C virus replication in vitro is well documented.12However, the observed longer time to hepatitis C virus recurrence after liver transplantation in patients treatedwith cyclosporine comparedwith tacrolimus suggests a discordance in vivo between the different CNIs.12 Focusing explicitly on SARS-CoV infection, a genome-wide analysis of protein-protein interactionsbetweenSARS-CoVandhuman host proteins identified both cyclophilin family members and FK506 (tacrolimus)-binding proteins as interaction partners for SARS-CoV proteins.9 In addition, both FK506 treatment and knock down of FK506-binding proteins 1A and 1B inhibited SARS-CoV replication in vitro.13 This suggests that both commonly prescribed CNIs, cyclosporine and tacrolimus, have inhibitory potential in SARS-CoV. Althoughwe do not advocate the use of these drugs for their potential antiviral properties based solely on these experimental observations in related viruses, these findings may support their continued use as the preferred maintenance immunosuppressant in transplant recipients with SARS-CoV-2 infection. In addition, given that withdrawal of CNIs may result in increased corticosteroid usage in this population, it is also prudent to consider that there appears to be no therapeutic benefit from corticosteroid therapy in SARS-CoVand there maywell bedeleterious effects, acknowledging there are differences in the replacement dosage used in transplantation.14,15 Secondly, emerging evidence suggests acute respiratory distress syndrome is the leading cause of death after infection with SARS-CoV-2, and severe disease may be associated with a hyperinflammatory state

COVID-19 and Calcineurin Inhibitors: Should They Get Left Out in the Storm?