HLA-A Locus is Associated With Sepsis and Septic Shock After Traumatic Injury.

OBJECTIVE: Determine whether variation in the HLA region is associated with the development of post-traumatic sepsis and septic shock. BACKGROUND: Sepsis-related deaths remain a major source of mortality after traumatic injury. Genetic characteristics may contribute to susceptibility to adverse outcomes including sepsis and septic shock. Recent advances in next-generation sequencing technology now allow comprehensive genotyping of the HLA region. METHODS: White adult trauma patients requiring more than 2 days of mechanical ventilation underwent HLA genotyping, and were followed for the development of sepsis and septic shock. Odds ratios (OR) for the associations between our outcomes and HLA variants were estimated, a correction for multiple comparisons was applied, and significant variants were included in regression models adjusting for potential confounders. RESULTS: A total of 1184 patients were included. Patients were severely injured (median injury severity score 33); 33% developed sepsis, 6% septic shock, and in-hospital mortality was 14%. An amino acid variant (156Q) within the HLA-A peptide-binding groove was associated with greater odds of sepsis [OR 1.50, (1.18-1.89)]. HLA-A∗02:01 was associated with lower odds of septic shock [OR 0.52, (0.32-0.82)]. These associations remained significant after adjusting for potential confounders. CONCLUSIONS: This is the first study to apply next-generation sequencing techniques to evaluate associations between immunogenetic factors and post-traumatic sepsis and septic shock. Associations with class I HLA variants are novel as they implicate adaptive immunity in post-traumatic sepsis. These findings are a step towards developing a panel of genetic markers assessing risk of infection-related complications as we move towards more personalized medicine.

Persistent metabolomic alterations characterize chronic critical illness after severe trauma.

BACKGROUND: Following trauma, persistent inflammation, immunosuppression, and catabolism may characterize delayed recovery or failure to recover. Understanding the metabolic response associated with these adverse outcomes may facilitate earlier identification and intervention. We characterized the metabolic profiles of trauma victims who died or developed chronic critical illness (CCI) and hypothesized that differences would be evident within 1-week postinjury. METHODS: Venous blood samples from trauma victims with shock who survived at least 7 days were analyzed using mass spectrometry. Subjects who died or developed CCI (intensive care unit length of stay of ≥14 days with persistent organ dysfunction) were compared with subjects who recovered rapidly (intensive care unit length of stay, ≤7 days) and uninjured controls. We used partial least squares discriminant analysis, t tests, linear mixed effects regression, and pathway enrichment analyses to make broad comparisons and identify differences in metabolite concentrations and pathways. RESULTS: We identified 27 patients who died or developed CCI and 33 who recovered rapidly. Subjects were predominantly male (65%) with a median age of 53 years and Injury Severity Score of 36. Healthy controls (n = 48) had similar age and sex distributions. Overall, from the 163 metabolites detected in the samples, 56 metabolites and 21 pathways differed between injury outcome groups, and partial least squares discriminant analysis models distinguished injury outcome groups as early as 1-day postinjury. Differences were observed in tryptophan, phenylalanine, and tyrosine metabolism; metabolites associated with oxidative stress via methionine metabolism; inflammatory mediators including kynurenine, arachidonate, and glucuronic acid; and products of the gut microbiome including indole-3-propionate. CONCLUSIONS: The metabolic profiles in subjects who ultimately die or develop CCI differ from those who have recovered. In particular, we have identified differences in markers of inflammation, oxidative stress, amino acid metabolism, and alterations in the gut microbiome. Targeted metabolomics has the potential to identify important metabolic changes postinjury to improve early diagnosis and targeted intervention. LEVEL OF EVIDENCE: Prognostic/epidemiologic, level III.

Predictors of mortality, limb loss, and discharge disposition at admission among patients with necrotizing skin and soft tissue infections.

BACKGROUND: Necrotizing soft tissue infections (NSTI) represent a heterogeneous group of rapidly progressive skin and soft tissue infections associated with significant morbidity and mortality. Efforts to identify factors associated with death have produced mixed results, and little or no data is available for other adverse outcomes. We sought to determine whether admission variables were associated with mortality, limb loss, and discharge disposition in patients with NSTI. METHODS: We analyzed prospectively collected data of adult patients with surgically confirmed NSTI from an NSTI registry maintained at a quaternary referral center. Factors independently associated with mortality, amputation, and skilled nursing facility discharge were identified using logistic regression. RESULTS: Between 2015 and 2018, 446 patients were identified. The median age was 55 years (interquartile range, 43-62). The majority of patients were male (65%), white (77%), and transferred from another facility (90%). The perineum was most commonly involved (37%), followed by the lower extremity (34%). The median number of operative debridements was 3 (interquartile range, 2-4). Overall mortality was 15%, and 21% of extremity NSTI patients required amputation. Age greater than 60 years; creatinine greater than 2 mg/dL; white blood cell count greater than 30 x 10^ /µl, platelets less than 150 × 10/µL, and clostridial involvement were independently associated with greater odds of death; perineal involvement was associated with lower odds of death. Age greater than 60 years; sex, male; nonwhite race; diabetes; chronic wound as etiology; leg involvement; transfer status; and sodium, less than 130 mEq/L were independently associated with amputation. Age greater than 60 years; sex, female; nonwhite race; perineal involvement; and amputation were associated with skilled care facility discharge. CONCLUSION: Necrotizing soft tissue infections are a heterogeneous group of infections involving significantly different patient populations with different outcomes; efforts to differentiate and predict adverse outcomes in NSTI should include laboratory data, comorbidities, infection site, and/or etiology to improve predictions and better account for this heterogeneity. LEVEL OF EVIDENCE: Prognostic, Level III.