Cyclosporine has a potential role in the treatment of SARS.

Dear Sir,

We welcome Jasper Chan and colleagues' review of the isolation of a novel human betacoronavirus from two patients in 2012, and share their desire for further research on this group of emerging viral pathogens.

The absence of an evidence-base for treating coronavirus-associated severe acute respiratory syndrome (SARS) is worrying. The authors list several agents with in vitro activity against the SARS coronavirus but do not refer to the literature describing the anti-coronavirus activity of cyclophilin inhibitors. Pfefferle and co-workers adopted a systems biology approach to identify coronavirus–host interactions by using genome-wide yeast-two hybrid screening. They identified interactions between the coronavirus non-structural protein 1 (Nsp1) and several immunophilins; a group of molecules with a role in T-cell activation via the Calcineurin/NFAT pathway. In addition, Nsp1 was found to induce the expression of IL-2, thus implicating it in the cytokine dysregulation seen in SARS. High serum levels of IL-2 have previously been demonstrated to correlate with mortality (p < 0.05) and high APACHE II scores (p < 0.0001) in patients with acute respiratory distress syndrome. Importantly, Pfefferle et al. found that the cyclophilin inhibitor cyclosporine A inhibited SARS coronavirus replication in cell culture, as well as inhibiting NSP1-affected IL-2 induction. de Wilde and colleagues have also reported on the in vitro anti-coronavirus activity of cyclosporine A.

In addition, cyclosporine A has been found to suppress hepatitis C virus (HCV) replication in vitro, prompting an assessment of its role in HCV infection. In a study of 120 patients with chronic HCV infection, Inoue et al. compared treatment with IFN α2β and cyclosporine A versus IFN α2β alone. The two treatment groups did not differ significantly, and importantly displayed no significant difference in pre-treatment viral load nor virus genotype. They found that combination therapy was superior to monotherapy with IFN, resulting in significantly improved virological response (HCV RNA disappearance) during treatment and at follow up, and significantly improved biochemical response (ALT normalisation) at follow up. Encouragingly, there was no significant difference in the rate of adverse events during treatment between the two groups. A non-immunosuppressive cyclosporine, DEBIO-025, has been described that retains in vitro anti-HCV activity, making it an attractive candidate for further clinical trials.

In summary, there is tantalising in vitro evidence for cyclosporine as an anti-coronavirus agent, as well as having a potential disease-modifying role in SARS through the inhibition of virus-mediated IL-2 induction. This latter property is interesting, considering that early corticosteroid treatment (initiated to combat pulmonary inflammation) can result in an increased level of viraemia, which may be associated with reduced survival in SARS.8, 9 Furthermore, the in vitro anti-HCV activity of cyclosporine has translated into clinical benefit in humans and appears to be a safe therapy. Therefore, we advocate that trial of cyclosporine should be considered in the inevitable event of future cases of SARS.