Beneficial Effect of Tacrolimus… Cyclosporin A, Still up for Discussion!

To the Editors:

The management of immunosuppression in liver transplant recipients with coronavirus disease 2019 (COVID-19) is a matter of concern in scientific communities. Belli et al published the first multicenter study that demonstrate a beneficial effect of tacrolimus. They described in a large multicenter study that included 243 adult symptomatic cases from 36 centers and 9 countries that the use of tacrolimus was associated with a better survival in liver transplant recipients. Interestingly, they found no beneficial effect of the cyclosporin A (CsA), another calcineurin inhibitor.

An important point should be discussed; tacrolimus and CsA have similar intracellular mechanisms—an indirect immunomodulator activity and a direct antiviral activity, 2 related but independent mechanisms. Briefly, calcineurin is a calcium-calmodulin-activated serine/threonine-specific phosphatase that is a key player in T-cell activation. , Its phosphatase activity will allow the nuclear factor of activated T cells to be dephosphorylated, allowing nuclear translocation of its substrate, and consequently the expression of immune genes like IL-2, IL-4, and IL-6, the so-called immune response. CsA enters into the cells and forms a binary complex with its intracellular partners, the cyclophilins. In turn, these binaries sequester the calcineurin into a ternary complex and thus inhibit calcineurin activity. In this manner, CsA suppresses the immune response secondary to activation of cytotoxic and helper T cells.2, 3, 4 Tacrolimus is functionally but not structurally related to CsA. The immunosuppressive properties of tacrolimus depend on the formation of binary complex with FKBP proteins, that constitute the immunophilin superfamily together with cyclophilins. These binaries sequester the calcineurin into a ternary complex and thus inhibit calcineurin activity. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication relies on a variety of host factors, and expresses several structural proteins and many nonstructural proteins. Nonstructural protein 1 interacts with different cellular partners (CypA, CypB, CypH, CypG, FKBP1A, FKBP1B), which in turn increases signaling through the nuclear factor of activated T-cell pathway and enhances the induction of IL-2, IL-4, and IL-6. , CsA and tacrolimus have an antiviral effect by binding to the cyclophilins and FKBP proteins with subsequent inhibition of their peptidyl-prolyl isomerase activity, whose enzymatic activities are supposed to promote coronavirus replication. , The exact mechanism by which CsA and tacrolimus interact in coronavirus replication are unknown. Based on this information, both drugs should have similar mechanism and in theory they might have the same beneficial effect in SARS-CoV-2 infection.

At present, it is well-known that the risk factors of poor outcome in COVID-19 infection include older age, male sex, and the presence of comorbidities. The lack of beneficial effect could maybe be explained by the clinical characteristics of the CsA/other group. Indeed, Supplementary Table 3 of the article shows that the CsA/other group had:

A higher percentage of male (81.5 vs 64.8%; P = .0073).

A higher percentage of patients with ≥2 comorbidities (61.7% vs 35.2%; P = .0003).

A higher median time between liver transplantation and COVID-19 infection (12 years vs 7 years; P < .0001), which implies that they had a lower residual concentration of immunosuppressor directly related to the effect in the infection (which seems to be dose dependent).

A higher percentage of patients co-treated with mycophenolate mofetil (61.7% vs 42.6%; P = .0049). Few studies are available, but the use of mycophenolate mofetil in Middle East respiratory syndrome coronavirus had reported high viral loads with more severe or even fatal disease.

A lower percentage (but not significant) of patient with steroids (17.2% vs 25.9%; P = .1316). The beneficial effect of corticoids has been demonstrated mostly during the second inflammatory phase.

In conclusion, the main message remains that tacrolimus has a beneficial effect in SARS-CoV-2 infection. At this point, available data are not sufficient concerning the effect of CsA, but based on the intracellular mechanisms of both calcineurin inhibitors, a similar beneficial effect could be expected. Switching drugs or even dose adjustment of CsA need further controlled studies before a clinical recommendation could been done.