A longitudinal study of 113 patients with moderate or severe COVID-19 revealed distinct immune profiles associated with disease severity. Immune profiling showed an increase in innate cell lineages and a decrease in T cell numbers, with early elevation in cytokines correlating with worse outcomes. Patients with moderate disease showed a progressive reduction in type 1 and type 3 immune responses, while those with severe disease maintained elevated responses. Severe cases also showed increased type 2 immune effectors, including IL-5, IL-13, and eosinophils. Unsupervised clustering identified four immune signatures linked to different disease trajectories. Patients who recovered had higher levels of tissue repair-related signatures, while those with severe disease had elevated levels of all four signatures. The study highlights a maladaptive immune response in severe cases, with early immune signatures predicting divergent outcomes. The immune response in severe cases involved broad inflammatory changes, including elevated type 1, type 2, and type 3 cytokines. Viral load correlated with interferon and cytokine levels, and early cytokine profiles were associated with severe outcomes. The study identified specific immune markers that appear early in the disease and correlate with poor outcomes. Retrospective analysis confirmed these findings, showing distinct immune profiles for different disease trajectories. The results suggest that early immunological interventions targeting inflammatory markers could be more beneficial than blocking late-appearing cytokines. The study provides insights into the immune dynamics of COVID-19 and the potential for targeted therapies based on early cytokine markers.A longitudinal study of 113 patients with moderate or severe COVID-19 revealed distinct immune profiles associated with disease severity. Immune profiling showed an increase in innate cell lineages and a decrease in T cell numbers, with early elevation in cytokines correlating with worse outcomes. Patients with moderate disease showed a progressive reduction in type 1 and type 3 immune responses, while those with severe disease maintained elevated responses. Severe cases also showed increased type 2 immune effectors, including IL-5, IL-13, and eosinophils. Unsupervised clustering identified four immune signatures linked to different disease trajectories. Patients who recovered had higher levels of tissue repair-related signatures, while those with severe disease had elevated levels of all four signatures. The study highlights a maladaptive immune response in severe cases, with early immune signatures predicting divergent outcomes. The immune response in severe cases involved broad inflammatory changes, including elevated type 1, type 2, and type 3 cytokines. Viral load correlated with interferon and cytokine levels, and early cytokine profiles were associated with severe outcomes. The study identified specific immune markers that appear early in the disease and correlate with poor outcomes. Retrospective analysis confirmed these findings, showing distinct immune profiles for different disease trajectories. The results suggest that early immunological interventions targeting inflammatory markers could be more beneficial than blocking late-appearing cytokines. The study provides insights into the immune dynamics of COVID-19 and the potential for targeted therapies based on early cytokine markers.