Age–Comorbidity Interactions and Clinical Outcomes in Septic Shock: An Emergency Department-Based Multicenter Cohort Study

<b>Background</b>: Sepsis remains a leading cause of mortality worldwide. This study evaluated the independent and combined effects of age and chronic comorbidities on clinical outcomes in patients with septic shock. <b>Methods</b>: We conducted a multicenter retrospective observational study to evaluate the factors associated with 28-day mortality in the Korean Shock Society registry between 2015 and 2023. Adults with suspected infection and refractory hypotension or hypoperfusion within 6 h of emergency department (ED) arrival were included. Patients were grouped by age (<50, 50-74, and ≥75 years) and comorbidity status. Comorbidities encompass major chronic conditions including hypertension, diabetes mellitus, malignancy, history of organ transplant, dementia, nursing home residence, chronic disease of cardiac, lung, liver, and kidney. The primary outcome was 28-day mortality. Multivariable logistic regression analysis was used. <b>Results</b>: Among 8787 patients (median age 70.2 years), the 28-day mortality rate was 22.9% (n = 2018). Elderly patients with comorbidities had the highest mortality (27.5%). Additionally, patients aged over 50 with at least one comorbidity accounted for 18% of the total cohort (n = 1605) but accounted for nearly 80% of all 28-day deaths. Although younger patients without comorbidities represented a small subgroup, their mortality was not negligible (7.3%) and was substantially higher with comorbidities (22.2%). Compared with patients <50 years, adjusted odds ratios (aORs) of 28-day mortality were 1.81 (95% CI, 1.08-3.03) for 50-74 years and 3.21 (95% CI, 1.92-5.37) for ≥75. The presence of any comorbidities was independently associated with higher odds of 28-day mortality compared with no comorbidity (aOR 2.67; 95% CI, 1.57-4.54). A significant interaction between age and comorbidity status (<i>p</i> for interaction = 0.008) suggested that the age-related gradient in mortality differed depending on comorbidity burden. <b>Conclusions</b>: Age and comorbidities were both significantly associated with septic shock mortality, and their significant interaction demonstrates effect modification, indicating that the prognostic impact of comorbidities differs by age group and that age-related mortality gradients are influenced by comorbidity burden.