An analysis of immune responses in 42 COVID-19 patients, both infected and recovered, identified immune signatures that distinguish severe COVID-19 cases. Notably, the analysis features insights not only into adaptive immune cell responses, but also those of innate immune cells responding to the virus. The findings will inform development of COVID-19 therapeutics. As the global COVID-19 pandemic continues, knowledge of the immunological signatures of severe COVID-19 is continually evolving. Whether there is a common profile of immune dysfunction in critically ill COVID-19 patients remains a question. To date, studies investigating this are limited, reporting on single patients or small cohorts. Seeking to expand upon them, Leticia Kuri-Cervantes and colleagues – a group overlapping in part with authors of the study by Mathew et al. published in Science today (15 July, 2020) – performed a high dimensional flow cytometry analysis on immune cells in blood from 42 COVID-19 patients with varying levels of disease state (moderate, severe, and recovered). Consistent with previous reports, they identified (and further defined) a characteristic immune phenotype in severe COVID-19 patients – distinct from the response in both healthy donors and also in COVID-19 patients with moderate or recovered disease. They also uncovered changes in the innate immune system – circulating neutrophils, monocytes and natural killer cells – in severe COVID-19 patients, though whether these are a “consequence or contributing factor towards COVID-19 severity remains to be defined,” they say. The authors suggest the immune dysregulation they observed in severe COVID-19 patients “may necessitate targeted strategies to effectively manage clinical care” for this group. Longitudinal studies will be needed, they say, to determine whether early detection of these immunological perturbations predict severe disease trajectory in patients who are asymptomatic or have mild disease.