Toll-like receptor 1 polymorphisms and associated outcomes in sepsis after traumatic injury: a candidate gene association study.

OBJECTIVE: To determine whether single nucleotide polymorphisms (SNPs) in TLR1 are associated with mortality, specifically sepsis-associated mortality, in a traumatically injured population. BACKGROUND: Innate immune responses mediated by toll-like receptors (TLRs) induce early inflammatory responses to pathogen and damage-associated molecular patterns. Genetic variation in TLRs has been associated with susceptibility and outcomes in a number of infectious and noninfectious disease states. METHODS: Patients admitted to the trauma intensive care unit at a level 1 trauma center serving 4 states were enrolled and followed for development of infection, sepsis, and death. Genomic DNA was genotyped and logistic regression analysis was performed to determine associations between TLR1 SNPs and mortality. We further examined for associations between TLR1 SNPs and mortality in subgroups on the basis of the presence of sepsis and the type of sepsis-associated organism. RESULTS: We enrolled 1961 patients. TLR1-7202G (rs5743551) was associated with increased mortality after traumatic injury and this association was primarily observed in the subset of patients who developed sepsis [adjusted odds ratio (OR): 3.16; 95% confidence interval (CI): 1.43-6.97, P=0.004]. This association persisted after further restriction to gram-positive sepsis. TLR1(742A/G(Asn248Ser)) (rs4833095), a coding SNP in LD with TLR1-7202G, was also associated with mortality in gram-positive sepsis (adjusted OR: 4.16; 95% CI: 1.22-14.19, P=0.023). CONCLUSIONS: Genetic variation in TLR1 is associated with increased mortality in patients with sepsis after traumatic injury and may represent a novel marker of risk for death in critically injured patients.

Association between age and acute respiratory distress syndrome development and mortality following trauma.

BACKGROUND: Improved understanding of the relationship between patient age and acute respiratory distress syndrome (ARDS) development and mortality following traumatic injury may help facilitate generation of new hypotheses about ARDS pathophysiology and the role of novel treatments to improve outcomes across the age spectrum. METHODS: We conducted a retrospective cohort study of trauma patients included in the National Trauma Data Bank who were admitted to an intensive care unit from 2007 to 2016. We determined ARDS incidence and mortality across eight age groups for the entire 10-year study period and by year. We used generalized linear Poisson regression models adjusted for underlying mortality risk (injury mechanism, Injury Severity Score, admission Glasgow Coma Scale score, admission heart rate, and admission hypotension). RESULTS: Acute respiratory distress syndrome occurred in 3.1% of 1,297,190 trauma encounters. Acute respiratory distress syndrome incidence was lowest among pediatric patients and highest among adults aged 35 to 64 years. Acute respiratory distress syndrome mortality was highest among patients 80 years or older (43.9%), followed by 65 to 79 years (30.6%) and 4 years or younger (25.3%). The relative risk of mortality associated with ARDS was highest among the pediatric age groups, with an adjusted relative risk (aRR) of 2.06 (95% confidence interval [CI], 1.72-2.70) among patients 4 years or younger compared with an aRR of 1.51 (95% CI, 1.42-1.62) for the entire cohort. Acute respiratory distress syndrome mortality increased over the 10-year study period (aRR, 1.03 per year; 95% CI, 1.02-1.05 per year), whereas all-cause mortality decreased (aRR, 0.98 per year; 95% CI, 0.98-0.99 per year). CONCLUSIONS: While ARDS development following traumatic injury was most common in middle-aged adults, patients 4 years or younger and 65 years or older with ARDS experienced the highest burden of mortality. Children 4 years or younger were disproportionately affected by ARDS relative to their low underlying mortality following trauma that was not complicated by ARDS. Acute respiratory distress syndrome-associated mortality following trauma has worsened over the past decade, emphasizing the need for new prevention and treatment strategies. LEVEL OF EVIDENCE: Prognostic/epidemiological study, level III.