3c). analysis identified four immune signatures, representing growth factors (A), type-2/3 cytokines (B), mixed type-1/2/3 cytokines (C), and chemokines (D) that correlated with three distinct disease trajectories. The immune profiles of patients who recovered from moderate COVID-19 were enriched in tissue reparative growth factor signature A, VEGFA whereas the profiles of those with who developed severe disease had elevated levels of D-Ribose all four signatures. Thus, we have identified a maladapted immune response profile associated with severe COVID-19 and poor clinical outcome, as well as early immune signatures that correlate with divergent disease trajectories. Introduction Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly infectious, zoonotic virus that exploits angiotensin-converting enzyme 2 (ACE2)5,6 as a cell entry receptor. Clinical presentation of COVID-19 involves a broad range of symptoms and disease trajectories. Understanding the nature of the immune response that leads to recovery over severe disease is key to developing effective treatment against COVID-19. Coronaviruses, including Severe Acute Respiratory Syndrome (SARS-CoV) and Middle Eastern Respiratory Syndrome (MERS), typically induce strong inflammatory responses and associated lymphopenia7,8. Studies of COVID-19 patients have reported increases in inflammatory monocytes and neutrophils and a sharp decrease in lymphocytes1C4, and an inflammatory milieu containing IL-1, IL-6, and TNF- in severe disease1,2,4,9,10. Despite these analyses, immune response dynamics during the course of SARS-CoV-2 infection and its possible correlation with clinical trajectory remain unknown. Immune responses against pathogens are divided roughly into three types11C13. Type-1 immunity, characterized by T-bet-dependent responses and IFN-, is generated against intracellular pathogens including viruses. In type-1 immunity, pathogen clearance is mediated through effector cells including ILC1, NK cells, cytotoxic T lymphocytes, and Th1 cells. Type-2 immunity, which relies on the GATA-3 transcription factor, mediates anti-helminths defense through effector molecules including IL-4, IL-5, IL-13, and IgE designed to expel these pathogens through the concerted action of epithelial cells, mast cells, eosinophils, and basophils. Type-3 immunity, orchestrated by the RORt-induced cytokines IL-17, IL-22 secreted by ILC3 and Th17 cells, is mounted against fungi and extracellular bacteria to elicit neutrophil-dependent clearance. In this study, we focused on the longitudinal analysis of these three types of immune responses to COVID-19 patients and identified correlations between distinct immune phenotype and disease. Results Overview of COVID-19 immunological features One hundred and thirteen patients with COVID-19 who were admitted to Yale New Haven Hospital (YNHH) between 18 March 2020 and 27 May 2020 were recruited to the Yale IMPACT (Implementing Medical and Public Health Action Against Coronavirus CT) study. We assessed viral RNA load (quantified by quantitative PCR with reverse tran- scription (RTCqPCR) using nasopharyngeal swabs); levels of plasma cytokines and chemokines; and leukocyte profiles (by flow cytometry using freshly isolated peripheral blood mononuclear cells; PBMCs). We performed 253 collections and follow-up measurements on the patient cohort with a range of one to seven longitudinal time-points that occurred 3C51 days after the onset of symptoms. In parallel, we enrolled 108 volunteer healthcare workers (HCWs), whose samples served as healthy controls (SARS-CoV-2-negative by RTCqPCR and D-Ribose serology). Basic demographic information stratified by disease severity is pro- vided in Extended Data Table 1 and detailed in Supplementary Table 1. Patients who had been admitted to YNHH were stratified into moder- ate and severe disease groups on the basis of supplemental oxygen requirements and admission to the intensive care unit (ICU) (Fig. 1a). Among our cohort, patients who developed moderate or severe dis- ease did not differ significantly with respect to age or sex. Body mass index (BMI) was generally higher among patients with severe disease, and extremes in BMI correlated with an increased relative risk (RR) of mortality (RR BMI 35: 1.62 (95% confidence interval (CI) 0.81C3.22)) (Extended Data Table 1, Extended Data Fig. 1a, ?,b).b). Exposure to select therapeutic regimens of interest was assessed in patients with moderate or severe disease (Extended Data Fig. 1c.) Initial presenting symptoms demonstrated a preponderance of headache (54.55%), fever (64.47%), cough (74.03%), and dyspnoea (67.09%) with no significant difference in symptom presentation between patients with moderate disease and those who developed severe disease. Finally, mortality was significantly higher in patients who were admitted to the ICU than D-Ribose in those.