CAMBON Audrey ^1,2,3* Christophe Guervilly ^1,4,5 DELTEIL Clémence ^1,6 POTERE Nicola ⁷ Richard Bachelier ^1,2,3,8 TELLIER Edwige ^1,2,3,8 ABDILI Evelyne ^1,2,9 LEPRINCE Marine ^1,10 GIANI Marco ¹¹ POLIDORO Ildo ^12,13 ALBANESE Valantina ¹³ FERRANTE Paolo ¹³ COFFIN Laurence ¹⁴ SCHIFFRIN Mickael ¹⁴ ARNAUD Laurent ^1,15 LACROIX Romaric ^1,15,2 ROQUE Sandrine ¹⁰ FOREL Jean-Marie ^1,5 Sami Hraiech ^1,5 Laurent Daniel ¹⁶ Laurent Papazian ¹⁷ DIGNAT-GEORGE Francoise ^1,18,2,3 Gilles Kaplanski ^1,10,2,3

• ¹ Aix-Marseille Université, Marseille, France
• ² Centre de recherche en CardioVasculaire et Nutrition, Faculté des Sciences Médicales et Paramédicales, Aix-Marseille Université, Marseille, Provence-Alpes-Côte d'Azur, France
• ³ INSERM U1263 Centre de Recherche en Cardiovasculaire et Nutrition, Marseille, Provence-Alpes-Côte d'Azur, France
• ⁴ Centre d’Etudes et de Recherches sur les Services de Santé et qualité de vie EA 3279, Aix-Marseille Université, 13005 Marseille,, Marseille, France
• ⁵ Service de Médecine Intensive Réanimation, Hôpital Nord, Assistance Publique- Hôpitaux de Marseille, Marseille, France, Marseille, France
• ⁶ Département de Médecine légale, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille University, Marseille, France., Marseille, France
• ⁷ School of Medicine and Health Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy, Chieti, Italy
• ⁸ INRAE 1260, Marseille, France
• ⁹ Laboratoire d'hématology, AP-HM, La Conception, Marseille, Provence-Alpes-Côte d'Azur, France
• ¹⁰ Service de Médecine interne et d’Immunologie clinique, Assistance Publique - Hôpitaux de Marseille, Hôpital La Conception, Marseille, France, Marseille, France
• ¹¹ School of Medicine and Health Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy, Chieti, France
• ¹² Santo Spirito Hospital, Pescara, Italy
• ¹³ Unit of Legal Medicine, “Santo Spirito” Hospital, Local Health Authority of Pescara, Pescara, Italy, Pescara, Italy
• ¹⁴ AB2 Bio EPFL Innovation Park Building B, Lausanne, Switzerland, Lausanne, Switzerland
• ¹⁵ Service d’Hématologie et de Biologie vasculaire, CHU La Timone, APHM, Marseille, France, Marseille, France
• ¹⁶ Service d’Anatomopathologie, APHM, Aix Marseille University, Marseille, France, Marseille, France
• ¹⁷ Service de Réanimation, Centre Hospitalier de Bastia, 604 Chemin de Falconaja, 20600 Bastia, France, Bastia, France
• ¹⁸ . Service d’Hématologie et de Biologie vasculaire, CHU La Timone, APHM, Marseille, France, Marseille, France

Rationale: COVID-19-associated acute-respiratory distress syndrome (C-ARDS) results from a direct viral injury associated with host excessive innate immune response mainly affecting the lungs. However, cytokine profile in the lung compartment of C-ARDS patients has not been widely studied, nor compared to non-COVID related ARDS (NC-ARDS). Objectives: To evaluate caspase-1 activation, IL-1 signature, and other inflammatory cytokine pathways associated with tissue damage using post-mortem lung tissues, bronchoalveolar lavage fluids (BALF), and serum across the spectrum of COVID-19 severity. Methods: Histological features were described and activated-caspase-1 labeling was performed in 40 post-mortem biopsies. Inflammatory cytokines were quantified in BALF and serum from 19 steroid-treated-C-ARDS and compared to 19 NC-ARDS. Cytokine concentrations were also measured in serum from 128 COVID-19 patients at different severity stages. Measurements and main results: Typical “diffuse alveolar damage” in lung biopsies were associated with activated caspase-1 expression and vascular lesions. Soluble Caspase-1p20, IL-1β, IL-1Ra, IL-6 and at lower level IFNγ and CXCL-10, were highly elevated in BALF from steroid-treated-C-ARDS as well as in NC-ARDS. IL-1β appeared concentrated in BALF, whereas circulating IL-6 and IL-1Ra concentrations were comparable to those in BALF and correlated with severity. TNFα, TNFR1 and CXCL8 however, were significantly higher in NC-ARDS compared to C-ARDS, treated by steroid. Conclusions: In the lungs of C-ARDS, both caspase-1 activation with a predominant IL-1β/IL-6 signature and IFNγ -associated chemokines are elevated despite steroid treatment. These pathways may be specifically targeted in ARDS to improve response to treatment and to limit alveolar and vascular lung damage.