BACKGROUND: As a heterogeneous syndrome, acute respiratory distress syndrome (ARDS) patients with comorbidities are significantly more severely ill. We aim to investigate the clinical characteristics and analyze the risk factors for mortality in children with moderate-to-severe acute respiratory distress syndrome (ARDS) who also have concurrent hematological or immune-related diseases. METHODS: A retrospective observational study was conducted from September 2020 to May 2022 in the pediatric intensive care unit (PICU) at Children's Hospital of Chongqing Medical University (Chongqing, China). All children with moderate-to-severe ARDS were included and divided into two groups based on the presence or absence of hematological or immune-related diseases. Clinical characteristics, treatment, and outcome data were collected. Univariate logistic regression and multivariate Firth regression analysis were used to identify risk factors for mortality in children with moderate-to-severe ARDS with concurrent hematological or immune-related diseases. RESULTS: A total of 215 children with moderate-to-severe ARDS were included in the study, of whom 65 had hematological or immune-related diseases (30.2%). These children were older (p <
0.002), had higher Pediatric Index of Mortality 3 scores (p = 0.002), higher lactate levels (p = 0.042), higher rates of positive pathogen detection (p <
0.002), shorter PICU stay (p = 0.023), higher incidence of multiple organ dysfunction syndrome (p = 0.012), and higher 28-day mortality rates (p <
0.002). Firth regression analysis showed that invasive fungal infection (OR = 4.954, 95% CI 0.245-3.158, p <
0.05), use of vasoactive drugs (OR = 7.638, 95% CI 0.524-3.811, p <
0.05), and high-frequency oscillatory ventilation (OR = 6.551, 95% CI 0.134-3.908, p <
0.05) were associated with increased mortality rates in children with moderate-to-severe ARDS with concurrent hematological or immune-related diseases. CONCLUSION: The incidence of moderate-to-severe ARDS is higher in children with concurrent hematological or immune-related diseases, and their prognosis is worse. In this group, children with invasive fungal infections, greater use of vasoactive drugs, or high-frequency oscillatory ventilation had a higher 28-day mortality rate.