Lung FDG-PET is an early pharmacodynamic biomarker of antiviral efficacy in preclinical influenza

Background. Influenza remains a major cause of global morbidity and mortality. Pharmacodynamic biomarkers that quantify treatment response within the lung could accelerate influenza therapeutic development. We evaluated [18F]-fluorodeoxyglucose positron emission tomography ([18F]-FDG-PET) as a non-invasive biomarker of antiviral efficacy. Methods. Serial [18F]-FDG-PET was evaluated in two murine H1N1 influenza models using mouse-adapted PR8 strain and CA-09 clinical isolate following treatment with favipiravir, baloxavir marboxil, or ribavirin. PET measures were compared with pulmonary viral burden, inflammatory cytokine expression, computed tomography (CT) imaging, and respiratory function measured by whole-body plethysmography (WBP). Results. Antiviral treatment in PR8 infection model reduced lung [18F]-FDG uptake by 27-49% and metabolic lung volume (MLV) by 40.5-74.6% (both p < 0.001). Antiviral response was detectable as early as 3 days post-infection, when uptake decreased by 28.7-53.2% and MLV by 33.8-75.0%. Lung uptake also strongly correlated with MLV (r = 0.93, p < 0.001) and with pulmonary viral burden and inflammatory mediators. These findings were reproduced in a model of pandemic H1N1/CA-09, where baloxavir reduced uptake by 37.4% (p = 0.02) and MLV by 67.5% (p < 0.001) at day 3. In both models, changes in [18F]-FDG-PET parameters preceded improvements in lung CT and respiratory function. Conclusions. Lung [18F]-FDG-PET provides an early, quantitative measure of antiviral response in experimental influenza, supporting its further evaluation as a translational pharmacodynamic endpoint.