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Background: Lung damage leading to gas-exchange deficit and sepsis leading to systemic hypoperfusion are well-known features of severe pneumonia. Although frequently described in COVID-19, their prognostic impact in COVID-19-related pneumonia versus COVID-19-unrelated pneumonia has never been compared. This study assesses fundamental gas-exchange and hemodynamic parameters and explores their prognostic impact in COVID-19 pneumonia and non-COVID-19 pneumonia., Methods: We prospectively evaluated arterial pO2/FiO2, alveolar to arterial O2 gradient, shock index, and serum lactate in 126 COVID-19 pneumonia patients, aged 18-65, presenting to the emergency department with acute, non-hypercapnic respiratory failure. As a control group we identified 1:1 age-, sex-, and pO2/FiO2-matched COVID-19-urelated pneumonia patients. Univariate and multivariable predictors of 30-day survival were identified in both groups., Results: COVID-19 patients showed lower arterial serum lactate concentration (P<0.001) and shock index (P<0.001) values as compared to non-COVID-19 patients. While we did not observe differences in lactate concentration or in shock index values in deceased vs. surviving COVID-19 patients (P=0.7 and P=0.6, respectively), non-COVID-19 deceased patients showed significantly higher lactate and shock index than non-COVID-19 survivors (P<0.001 and P=0.03). The pO2/FiO2 was the most powerful determinant of survival by Cox regression multivariate analysis in COVID-19 patients (P=0.006), while it was lactate in non-COVID-19 patients (P=0.001)., Conclusions: As compared to COVID19-unrelated pneumonia, COVID-19 pneumonia outcome seems more strictly correlated to the extent of lung damage, rather than to the systemic circulatory and metabolic derangements typical of sepsis.