Multi-omics analysis of hospitalized COVID-19 patients reveals three distinct interferon-stimulated gene expression patterns that operate independently of clinical severity. Patients with high interferon expression paradoxically showed impaired immune function despite elevated inflammatory markers. Their plasma contained depleted tricarboxylic acid cycle intermediates and reduced lipid classes essential for membrane integrity, creating metabolic dysfunction that correlated with weakened neutrophil and monocyte activation in laboratory tests. This discovery challenges the assumption that high interferon activity necessarily translates to better antiviral defense. The findings suggest an immune-metabolic axis where interferon-driven inflammation can become counterproductive, consuming metabolic resources needed for effective immune cell function. This metabolic depletion may explain why some patients with robust interferon responses still develop severe disease. For clinical practice, measuring both interferon expression and metabolic markers could better predict disease trajectory than inflammatory markers alone. However, this preprint awaits peer review, so these conclusions require validation. The research represents a significant conceptual advance in understanding COVID-19 pathophysiology, potentially informing targeted metabolic interventions to restore immune function in severe cases.