In this prospective multicenter study, we used several approaches such as histopathological and immunohistochemical analyses on post-mortem tissues from subjects with fatal C-ARDS, and immune profiling of BALF and serum from patients across the COVID-19 severity spectrum to provide information on NLRP3-inflammasome activation and the involvement of IL-1 signaling in COVID-19 patients. The gene discussed is NLRP3; the disease is COVID-19.