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While humoral responses to vaccination and infection have largely focused on IgG, there is an evolving literature on ways in which IgA may drive neutrophil activity in lung injury secondary to viral infections, including COVID-19. We evaluated 238 immune-naïve, critically ill patients in the first year of the COVID-19 pandemic. Employing a laboratory-developed, multiplexed antibody testing, clinical history, medical record, and machine learning, we pursued relationships between systemic IgA and disease severity. Individuals with elevated anti-N IgA had 4-fold odds of more severe disease. This work emphasizes the importance of continued work to understand how different elements of the immune system participate together in contributing to patient outcomes.