Association of ulinastatin with 28-day mortality across different severities of viral pneumonia: a multicenter propensity score-matched study.

Introduction: Hyperinflammation drives mortality in severe or critical viral pneumonia. We evaluated the association of ulinastatin, an immunomodulatory agent, with 28 day mortality in patients with severe or critical pneumonia caused by COVID-19 or influenza. Methods: In this multicenter, retrospective cohort study, we included adult patients admitted to the intensive care unit (ICU) with confirmed SARS-CoV-2 or influenza infection. To control for confounding, 1:1 propensity score matching (PSM) was performed. Results: Of 330 eligible patients, 194 were included in the final matched cohort. In the overall matched cohort, ulinastatin treatment did not significantly reduce 28 day all-cause mortality compared with the control group (29.9% vs. 38.1%; HR 0.69, 95% CI 0.43 to 1.12, p = 0.128). However, exploratory subgroup analysis revealed that the survival benefit was driven predominantly by the critically ill subgroup (HR 0.51, 95% CI 0.30 to 0.87, p = 0.011), with no benefit observed in severe patients (HR 1.48, 95% CI 0.45 to 4.85, p = 0.513). This protective association in critical patients was consistent across COVID-19 and influenza etiologies (P for interaction = 0.313) and was not significantly modified by baseline metabolic comorbidities (all P for interaction > 0.05). Conclusion: Ulinastatin treatment did not significantly improve 28 day survival in the overall cohort of severe-to-critical viral pneumonia. However, exploratory subgroup analyses suggest a potential survival benefit specifically in critically ill patients, predominantly driven by the COVID-19 subset. Further studies are needed to confirm these findings across specific viral etiologies. These hypothesis-generating findings highlight the need for precision immunomodulation targeting the optimal therapeutic window.