Impact of genetic variants on outcomes in ICU patients with acute respiratory failure syndromes

Abstract

Acute respiratory failure (ARF) and acute respiratory distress syndrome (ARDS) represent major causes of morbidity and mortality in the intensive care unit (ICU). Although clinical triggers such as pneumonia, sepsis, trauma, and viral infections are well characterized, substantial inter-individual variability in disease susceptibility, severity, and treatment response suggests an important contribution of genetic factors. Emerging evidence from genome-wide association studies, polygenic analyses, and sequencing of rare variants highlights key pathways including endothelial barrier regulation, innate immunity, and inflammatory signaling that shape host responses during critical illness. Pharmacogenomic studies further indicate that genetic variation influences responses to sedatives, corticosteroids, and other ICU therapies, although clinical translation remains limited. Environmental exposures and critical care interventions interact with inherited variation, emphasizing the multidimensional nature of ARF. This review synthesizes current knowledge on genetic determinants of ARF and ARDS, examines their relationship with clinical outcomes in the ICU, and outlines how gene-environment interactions and pharmacogenomics contribute to treatment heterogeneity. Despite promising discoveries, major gaps persist, including limited ancestry diversity, modest effect sizes, and scarce genotype-informed interventional trials. A deeper integration of genomics with multi-omics profiling and clinical phenotyping is essential to advance precision medicine approaches for critically ill patients.