(d) Direct Antifibrotic Effect of CsA

Pulmonary fibrosis is one of the major complications in COVID-19 patients [38], with acute respiratory distress syndrome (ARDS) being the main cause of post-COVID pulmonary fibrosis. Similar cytokine profiles in idiopathic pulmonary fibrosis (IPF) and COVID-19 suggest analogous pathomechanisms in both diseases. Interestingly, cytokine overexpression in IPF, COVID-19 and SARS/MERS all show elevated IL-1B, IL-6, MCP1, TNF-α and TGF-β [38]. Therefore, drugs useful in the treatment of IPF could also be beneficial for COVID-19 patients [38]. CsA might have a direct antifibrotic action, as has been demonstrated in patients with antisynthetase syndrome associated interstitial lung disease, who were refractory to corticosteroids, but improved on CsA [53,54]. In tacrolimus, the combination with methylprednisolone pulse therapy showed to mitigate acute exacerbations (AE) of IPF, prevented re-AE IPF, and contributed to a better prognosis compared to steroid monotherapy [55]. Studies have shown that CsA is superior to the corticosteroid monotherapy in terms of prognosis for IPF [56,57].

This feature of CsA may be an important aspect to consider when attempting to prevent post-COVID-19 pulmonary fibrosis, although further studies are still needed to elucidate the magnitude of the effect.
