Treating influenza A exacerbations: The case for pirfenidone over glucocorticoids.

Abstract

Introduction/Aim: Patients with respiratory diseases are more susceptible to viral infection and develop more severe symptoms, associated with immunosuppression by elevated transforming growth factor-beta (TGFbeta). Glucocorticosteroids (GCS) effectively reduce inflammation when inhaled prophylactically, or taken orally for exacerbations, but can also cause further immunosuppression. Oral pirfenidone (PFD), an anti-fibrotic used to treat patients with pulmonary fibrosis, has been shown to reduce TGFbeta-enhanced influenza A virus (IAV) infection in mice (Thomas et al., Respirology, 2021). The current aim was to determine if administration of inhaled PFD prior to infection, or with the addition of oral PFD post-infection, is as effective at reducing IAV-induced inflammation as GCS, without causing immunosuppression. Method(s): Mice were treated with i.n. vehicle (control), PFD (13.3 mg/kg) or GCS (1 mg/kg) daily, starting 2 days prior to infection with IAV (10 2 PFU, HKx31, n = 6-10). Separate mice were treated daily pre- and post-infection (i.n. then oral) with vehicle (i/o control), PFD (i/o PFD) or GCS (i/o GCS). Mice were culled 3 days post-infection to measure viral load, inflammation and immune responses in BALF and lung tissue. Result(s): Inhaled PFD, but not GCS, reduced viral load (p < 0.05). Both PFD and GCS reduced RANTES, while PFD, but not GCS, reduced IL-6, TNFalpha and KC. IAV-induced Inflammatory cells, notably macrophages and neutrophils, were further increased by GCS (p < 0.001) but not by PFD. Preliminary results suggest that i/o PFD reduced the severity of IAV infection, while i/o GCS increased severity. Conclusion : Treatment with either inhaled or i/o PFD afforded greater protection against TGFbeta-enhanced viral infection and inflammation than GCS. These positive findings support the repurposing of PFD beyond its current use in IPF to include other respiratory diseases, offering superior protection from worse disease outcomes associated with viral exacerbations.