In a real-world cohort of 161 patients with COVID-19–associated PE, early critical outcomes were driven predominantly by the combination of extensive CT-quantified lung involvement and a clustered hyperinflammatory–thrombotic phenotype captured by CRP, ferritin, IL-6, fibrinogen, lactate, and D-dimer, rather than by traditional PE scores, thrombus location, or baseline comorbidities alone. The gene discussed is IL6; the disease is COVID-19.