Taken together, our findings demonstrate that, compared to asymptomatic COVID-19 patients who presented with little to no disease, the severely ill patients and patients with fatal COVID-19 outcomes showed the following: (i) a broad and early lymphopenia (and leukocytosis), (ii) a decrease of bulk CD3+ T-cell lymphocytes number (equally affecting CD4+ and CD8+ T cells), and (iii) a reduction in CD4+ and CD8+ T cells specific to highly conserved CCCs/SARS-CoV-2 cross-reactive epitopes from structural, non-structural, and accessory protein antigens. This evidence concerns the gene CD4 and COVID-19.