Genetic Architectures of Myeloid Dysregulation in Severe COVID-19

Background: Dysregulated myeloid responses are central to severe COVID-19, but the contribution of host genetics to this "emergency myelopoiesis" is poorly understood. Methods: We performed whole-exome sequencing in 77 hospitalized COVID-19 patients to analyze the impact of the cumulative burden of rare, high-impact variants (qualifying variants, QVs) in hemopoietic and inflammatory gene sets on longitudinal leukocyte counts. Predictive models were validated using repeated internal cross-validation (1000 resamples) and external population-scale exome data (Genebass, n > 380,000). Results: The QV burden was a significant predictor of peak neutrophil and monocyte counts, independent of age, sex, and clinical severity. This association remained robust in a microbiologically confirmed "pure viral" subcohort (n = 54) and was stable across internal cross-validation resamples. External validation revealed an 11.2-fold enrichment of myeloid-associated genes within our candidate gene sets (p ≈ 2.2 × 10^-63). Patients with a high QV burden exhibited significantly worse outcomes, including a four-fold increase in mortality (p = 0.00065), and a genetic profile linked to hyper-inflammation and thrombosis. Conclusion: These findings suggest that host genetic architecture may contribute to the magnitude of myeloid dysregulation in acute viral infection. Genetic stratification could identify patients predisposed to a hyperactive myeloid response, potentially guiding early, targeted immunomodulation to mitigate severe complications.