**5. Conclusions**

Calcineurin inhibitors have been proven to be effective in a number of coronaviral diseases and other related conditions. The most important CNIs used in the clinical context are cyclosporin and tacrolimus. They block the calcineurin pathway by forming complexes with immunophilins, being cyclophilin for cyclosporine A, and FKB12 for tacrolimus. These immunophilins prevent calcineurin from dephosphorylating the NF-AT transcription factor. This results in the inhibition of the transcription of genes encoding for cytokines, decreasing the risk of CSS.

Paradoxically, the CNIs that are crucial to solid organ transplantation and render SOT recipients more susceptible to opportunistic infections, appear to also have the ability to suppress the cytokine storm syndrome in COVID-19. In this regard it would not be rational to follow the guidelines of the Massachusetts General Hospital (Boston, MA, USA), which advises to consider decreasing tacrolimus/cyclosporin by 50% in solid organ transplant recipients with COVID-19, and in critical illness in liver and kidney transplant recipients to stop all immunosuppression except for prednisolone.

In the search of effective treatment options for the novel coronavirus SARS-CoV-2, CNIs should be evaluated as a first line treatment option because of the suggested direct antiviral effects as and its potential to suppress the severe systemic hyperinflammation state and thus reduce the disease severity of COVID-19 [64]. Based on the known CNI effects in various coronaviral diseases, they are likely to be effective in multiple coronaviral serotypes (including SARS-Cov-2) and, as multitarget agents, may more effectively reduce the likelihood of developing viral resistance as compared to other strategies. If CNIs can be proven to be effective also for previously immunocompetent patients with moderate to severe COVID-19, then they may be an easy and affordable option for the rapid management of the COVID-19 patients in many parts of the world, since these drugs are affordable and already quite widely available.
