In this study we report that elevated levels of anti-SARS-CoV-2 antibodies, IgA, IgM, and IgG, as well as specific cytokines, such as IL-6, IL-8, MIP-1β, during SARS-CoV-2 acute infection are associated with severe COVID-19, defined by the development of ARDS or the need for invasive mechanical ventilation or UCI admission. Here, CD40LG is linked to COVID-19.