1. The increased susceptibility to and severity of viral infections in patients with respiratory diseases may be due to the immunosuppressive actions of elevated lung transforming growth factor-beta (TGFb), prophylactic inhaled glucocorticosteroids (GCS) and oral GCS for exacerbations. The oral anti-fibrotic and anti-inflammatory drug pirfenidone (PFD) may offer a novel, non-immunosuppressive alternative (Thomas et al, Respirology, 2021).

2. Compare the efficacy of inhaled and oral PFD to standard GCS treatment in the context of viral-induced exacerbations.

3. Transgenic TGFb-overexpressing mice were treated daily for 2 days prior to infection with IAV (102 PFU, HKx31) then 3 days post-infection. Groups (n=4-6): intranasal prior to infection, then oral, vehicle (i/oVeh), i/oPFD (13.3mg/kg, 100mg/kg), o/oPFD (100mg/kg) or i/oGCS (1mg/kg). Lung viral loads and inflammation in bronchoalveolar lavage fluid were measured. Effects of treatments on IAV-induced impairment of dilator responses to salbutamol (SALB) were measured using precision cut lung slices (PCLS) from separate mice (Donovan et al, Clin Sci, 2016).

4. Treatment with o/oPFD, but not i/oPFD, reduced viral load, while both viral load and weight loss were increased with i/oGCS (p<0.01). KC was reduced by o/oPFD but not i/oGCS. In airways precontracted with methacholine, relaxation to SALB (1mM) was only 20% in PCLS from i/oVeh post-infection mice but 45-70% in PCLS from both PFD- and GCS-treated mice.

5. Treatment with PFD may offer greater protection against TGF?-enhanced viral infection severity and impaired dilator responses than GCS. Further investigation is warranted into the repurposing of PFD for viral-induced exacerbations of respiratory diseases.