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1.
Shock ; 2024 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-39178207

RESUMEN

BACKGROUND: Critical illness stemming from severe traumatic injury is a leading cause of morbidity and mortality worldwide, and involves the dysfunction of multiple organ systems, driven, at least in part, by dysregulated inflammation. We and others have shown a key role for genetic predisposition to dysregulated inflammation and downstream adverse critical illness outcomes. Recently, we demonstrated an association among genotypes at the single-nucleotide polymorphism (SNP) rs10404939 in LYPD4, dysregulated systemic inflammation, and adverse clinical outcomes in a broad sample of ~1000 critically ill patients. METHODS: We sought to gain mechanistic insights into the role of LYPD4 in critical illness by bioinformatically analyzing potential interactions among rs10404939 and other SNPs. We analyzed a dataset of common (i.e., not rare) SNPs previously defined to be associated with genotype-specific, significantly dysregulated systemic inflammation trajectories in trauma patients, in comparison to a control dataset of common SNPs determined to exhibit an absence of genotype-specific inflammatory responses. RESULTS: In the control dataset, this analysis implicated SNPs associated with phosphatidylinositol and various membrane transport proteins, but not LYPD4. In the patient subset with genotypically dysregulated inflammation, our analysis suggested the co-localization to lipid rafts of LYPD4 and the complement receptor CD55, as well as the neurally related CNTNAP2 and RIMS4. Segregation of trauma patients based on genotype of the CD55 SNP rs11117564 showed distinct trajectories of organ dysfunction and systemic inflammation despite similar demographics and injury characteristics. CONCLUSION: These analyses define novel interactions among SNPs that could enhance our understanding of the response to traumatic injury and critical illness.

2.
iScience ; 26(12): 108333, 2023 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-38034362

RESUMEN

Acute inflammation is heterogeneous in critical illness and predictive of outcome. We hypothesized that genetic variability in novel, yet common, gene variants contributes to this heterogeneity and could stratify patient outcomes. We searched algorithmically for significant differences in systemic inflammatory mediators associated with any of 551,839 SNPs in one derivation (n = 380 patients with blunt trauma) and two validation (n = 75 trauma and n = 537 non-trauma patients) cohorts. This analysis identified rs10404939 in the LYPD4 gene. Trauma patients homozygous for the A allele (rs10404939AA; 27%) had different trajectories of systemic inflammation along with persistently elevated multiple organ dysfunction (MOD) indices vs. patients homozygous for the G allele (rs10404939GG; 26%). rs10404939AA homozygotes in the trauma validation cohort had elevated MOD indices, and non-trauma patients displayed more complex inflammatory networks and worse 90-day survival compared to rs10404939GG homozygotes. Thus, rs10404939 emerged as a common, broadly prognostic SNP in critical illness.

3.
Nat Commun ; 13(1): 6789, 2022 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-36357394

RESUMEN

Alterations in lipid metabolism have the potential to be markers as well as drivers of pathobiology of acute critical illness. Here, we took advantage of the temporal precision offered by trauma as a common cause of critical illness to identify the dynamic patterns in the circulating lipidome in critically ill humans. The major findings include an early loss of all classes of circulating lipids followed by a delayed and selective lipogenesis in patients destined to remain critically ill. The previously reported survival benefit of early thawed plasma administration was associated with preserved lipid levels that related to favorable changes in coagulation and inflammation biomarkers in causal modelling. Phosphatidylethanolamines (PE) were elevated in patients with persistent critical illness and PE levels were prognostic for worse outcomes not only in trauma but also severe COVID-19 patients. Here we show selective rise in systemic PE as a common prognostic feature of critical illness.


Asunto(s)
COVID-19 , Enfermedad Crítica , Humanos , Lipidómica , Biomarcadores , Inflamación
4.
EBioMedicine ; 76: 103860, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35124428

RESUMEN

BACKGROUND: While bulk and single cell transcriptomic patterns in circulating leukocytes from trauma patients have been reported, how these relate to changes in open chromatin patterns remain unstudied. Here, we investigated whether single-cell ATAC-seq would provide further resolution of transcriptomic patterns that align with patient outcomes. METHODS: We performed scATAC-seq on peripheral blood mononuclear cells from four trauma patients at <4 h, 24 h, 72 h post-injury and four matched healthy controls, and extracted the features associated with the global epigenetic alterations. Three large-scale bulk transcriptomic datasets from trauma, burn and sepsis patients were used to validate the scATAC-seq derived signature, explore patient epigenetic heterogeneity (Epigenetic Groups: EG_hi vs. EG_lo), and associate patterns with clinical outcomes in critical illness. FINDINGS: Patient subsets with gene expression patterns in blood leukocytes representative of a high global epigenetic signature (EG_hi) had worse outcomes across three etiologies of critical illness. EG_hi designation contributed independent of the known immune leukocyte transcriptomic responses to patient prognosis (Trauma: HR=0.62 [95% CI: 0.43-0.89, event set as recovery], p=0.01, n=167; Burns: HR=4.35 [95% CI: 0.816-23.2, event set as death], p=0.085, n=121; Sepsis: HR=1.60 [95% CI: 1.10-2.33, event set as death], p=0.013, n=479; Cox proportional hazards regression). INTERPRETATION: The inclusion of gene expression patterns that associate with global epigenetic changes in circulating leukocytes improves the resolution of transcriptome-based patient classification in acute critical illnesses. Early detection of both the global epigenetic signature and the known immune transcriptomic patterns associates with the worse prognosis in trauma, burns and sepsis. FUNDING: This project was supported by an R35 grant from National Institutes of Health: 1R35GM127027-01 (T.B.).


Asunto(s)
Enfermedad Crítica , Transcriptoma , Secuenciación de Inmunoprecipitación de Cromatina , Epigénesis Genética , Humanos , Leucocitos , Leucocitos Mononucleares , Pronóstico
5.
Sci Rep ; 11(1): 9703, 2021 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-33958628

RESUMEN

Systemic inflammation is complex and likely drives clinical outcomes in critical illness such as that which ensues following severe injury. We obtained time course data on multiple inflammatory mediators in the blood of blunt trauma patients. Using dynamic network analyses, we inferred a novel control architecture for systemic inflammation: a three-way switch comprising the chemokines MCP-1/CCL2, MIG/CXCL9, and IP-10/CXCL10. To test this hypothesis, we created a logical model comprising this putative architecture. This model predicted key qualitative features of systemic inflammation in patient sub-groups, as well as the different patterns of hospital discharge of moderately vs. severely injured patients. Thus, a rational transition from data to data-driven models to mechanistic models suggests a novel, chemokine-based mechanism for control of acute inflammation in humans and points to the potential utility of this workflow in defining novel features in other complex diseases.


Asunto(s)
Quimiocinas/metabolismo , Inflamación/metabolismo , Heridas y Lesiones/metabolismo , Adulto , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad
6.
Trauma Surg Acute Care Open ; 6(1): e000619, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33748428

RESUMEN

BACKGROUND: Trauma elicits a complex inflammatory response that, among multiple presenting factors, is greatly impacted by the magnitude of injury severity. Herein, we compared the changes in circulating levels of mediators with known proinflammatory roles to those with known protective/reparative actions as a function of injury severity in injured humans. METHODS: Clinical and biobank data were obtained from 472 (trauma database-1 (TD-1), University of Pittsburgh) and 89 (trauma database-2 (TD-2), Indiana University) trauma patients admitted to the intensive care unit (ICU) and who survived to discharge. Injury severity was estimated based on the Injury Severity Score (ISS), and this was used as both a continuous variable and for the purpose of grouping patients into severity-based cohorts. Samples within the first 24 hours were obtained from all patients and then daily up to day 7 postinjury in TD-1. Sixteen cytokines were assayed using Luminex and were analyzed using two-way analysis of variance (p<0.05). RESULTS: Patients with higher ISSs had longer ICU and hospital stays, days on mechanical ventilation and higher rates of nosocomial infection when compared with the mild and moderate groups. Time course analysis and correlations with ISS showed that 11 inflammatory mediators correlated positively with injury severity, consistent with previous reports. However, five mediators (interleukin (IL)-9, IL-21, IL-22, IL-23 and IL-17E/25) were suppressed in patients with high ISS and inversely correlated with ISS. DISCUSSION: These findings suggest that severe injury is associated with a suppression of a subset of cytokines known to be involved in tissue protection and regeneration (IL-9, IL-22 and IL-17E/25) and lymphocyte differentiation (IL-21 and IL-23), which in turn correlates with adverse clinical outcomes. Thus, patterns of proinflammatory versus protective/reparative mediators diverge with increasing ISS.

7.
J Am Coll Surg ; 232(3): 276-287.e1, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33453380

RESUMEN

BACKGROUND: Trauma is the leading cause of death and disability for individuals under age 55. Many severely injured trauma patients experience complicated clinical courses despite appropriate initial therapy. We sought to identify novel circulating metabolomic signatures associated with clinical outcomes following trauma. STUDY DESIGN: Untargeted metabolomics and circulating plasma immune mediator analysis was performed on plasma collected during 3 post-injury time periods (<6 hours [h], 6 h-24h, day 2-day 5) in critically ill trauma patients enrolled between April 2004 and May 2013 at UPMC Presbyterian Hospital in Pittsburgh, PA. Inclusion criteria were age ≥ 18 years, blunt mechanism, ICU admission, and expected survival ≥ 24 h. Exclusion criteria were isolated head injury, spinal cord injury, and pregnancy. Exploratory endpoints included length of stay (overall and ICU), ventilator requirements, nosocomial infection, and Marshall organ dysfunction (MOD) score. The top 50 metabolites were isolated using repeated measures ANOVA and multivariate empirical Bayesian analysis for further study. RESULTS: Eighty-six patients were included for analysis. Sphingolipids were enriched significantly (chi-square, p < 10-6) among the top 50 metabolites. Clustering of sphingolipid patterns identified 3 patient subclasses: nonresponders (no time-dependent change in sphingolipids, n = 41), sphingosine/sphinganine-enhanced (n = 24), and glycosphingolipid-enhanced (n = 21). Compared with the sphingolipid-enhanced subclasses, nonresponders had longer mean length of stay, more ventilator days, higher MOD scores, and higher circulating levels of proinflammatory immune mediators IL-6, IL-8, IL-10, MCP1/CCL2, IP10/CXCL10, and MIG/CXCL9 (all p < 0.05), despite similar Injury Severity Scores (p = 0.12). CONCLUSIONS: Metabolomic analysis identified broad alterations in circulating plasma sphingolipids after blunt trauma. Circulating sphingolipid signatures and their association with both clinical outcomes and circulating inflammatory mediators suggest a possible link between sphingolipid metabolism and the immune response to trauma.


Asunto(s)
Metaboloma , Esfingolípidos/sangre , Heridas no Penetrantes/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Cuidados Críticos/métodos , Cuidados Críticos/estadística & datos numéricos , Enfermedad Crítica , Femenino , Humanos , Puntaje de Gravedad del Traumatismo , Tiempo de Internación/estadística & datos numéricos , Estudios Longitudinales , Masculino , Metabolómica , Persona de Mediana Edad , Puntuaciones en la Disfunción de Órganos , Pronóstico , Estudios Prospectivos , Heridas no Penetrantes/diagnóstico , Heridas no Penetrantes/inmunología , Heridas no Penetrantes/terapia , Adulto Joven
8.
Res Sq ; 2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33442677

RESUMEN

Alterations in lipid metabolism have the potential to be markers as well as drivers of the pathobiology of acute critical illness. Here, we took advantage of the temporal precision offered by trauma as a common cause of critical illness to identify the dynamic patterns in the circulating lipidome in critically ill humans. The major findings include an early loss of all classes of circulating lipids followed by a delayed and selective lipogenesis in patients destined to remain critically ill. Early in the clinical course, Fresh Frozen Plasma administration led to improved survival in association with preserved lipid levels that related to favorable changes in coagulation and inflammation biomarkers. Late over-representation of phosphatidylethanolamines with critical illness led to the validation of a Lipid Reprogramming Score that was prognostic not only in trauma but also severe COVID-19 patients. Our lipidomic findings provide a new paradigm for the lipid response underlying critical illness.

9.
Cell Rep Med ; 2(12): 100478, 2021 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-35028617

RESUMEN

Trauma is a leading cause of death and morbidity worldwide. Here, we present the analysis of a longitudinal multi-omic dataset comprising clinical, cytokine, endotheliopathy biomarker, lipidome, metabolome, and proteome data from severely injured humans. A "systemic storm" pattern with release of 1,061 markers, together with a pattern suggestive of the "massive consumption" of 892 constitutive circulating markers, is identified in the acute phase post-trauma. Data integration reveals two human injury response endotypes, which align with clinical trajectory. Prehospital thawed plasma rescues only endotype 2 patients with traumatic brain injury (30-day mortality: 30.3 versus 75.0%; p = 0.0015). Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) was identified as the most predictive circulating biomarker to identify endotype 2-traumatic brain injury (TBI) patients. These response patterns refine the paradigm for human injury, while the datasets provide a resource for the study of critical illness, trauma, and human stress responses.


Asunto(s)
Lesiones Traumáticas del Encéfalo/genética , Lesiones Traumáticas del Encéfalo/terapia , Genómica , Análisis por Conglomerados , Estudios de Cohortes , Humanos , Metaboloma , Plasma , Proteoma/metabolismo , Factores de Tiempo , Resultado del Tratamiento
10.
JCI Insight ; 6(2)2021 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-33320841

RESUMEN

Immune dysfunction is an important factor driving mortality and adverse outcomes after trauma but remains poorly understood, especially at the cellular level. To deconvolute the trauma-induced immune response, we applied single-cell RNA sequencing to circulating and bone marrow mononuclear cells in injured mice and circulating mononuclear cells in trauma patients. In mice, the greatest changes in gene expression were seen in monocytes across both compartments. After systemic injury, the gene expression pattern of monocytes markedly deviated from steady state with corresponding changes in critical transcription factors, which can be traced back to myeloid progenitors. These changes were largely recapitulated in the human single-cell analysis. We generalized the major changes in human CD14+ monocytes into 6 signatures, which further defined 2 trauma patient subtypes (SG1 vs. SG2) identified in the whole-blood leukocyte transcriptome in the initial 12 hours after injury. Compared with SG2, SG1 patients exhibited delayed recovery, more severe organ dysfunction, and a higher incidence of infection and noninfectious complications. The 2 patient subtypes were also recapitulated in burn and sepsis patients, revealing a shared pattern of immune response across critical illness. Our data will be broadly useful to further explore the immune response to inflammatory diseases and critical illness.


Asunto(s)
Heridas y Lesiones/genética , Heridas y Lesiones/inmunología , Adulto , Animales , Células de la Médula Ósea/inmunología , Quemaduras/sangre , Quemaduras/genética , Quemaduras/inmunología , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Femenino , Humanos , Leucocitos Mononucleares/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , RNA-Seq , Sepsis/sangre , Sepsis/genética , Sepsis/inmunología , Choque Hemorrágico/sangre , Choque Hemorrágico/genética , Choque Hemorrágico/inmunología , Análisis de la Célula Individual , Factores de Tiempo , Transcriptoma , Heridas y Lesiones/clasificación , Adulto Joven
11.
J Trauma Acute Care Surg ; 90(3): 441-450, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33093290

RESUMEN

BACKGROUND: Multiply injured patients (MIPs) are at risk of complications including infections, and acute and prolonged organ dysfunction. The immunologic response to injury has been shown to affect outcomes. Recent advances in computational capabilities have shown that early dynamic coordination of the immunologic response is associated with improved outcomes after trauma. We hypothesized that patients who were sensitive or tolerant of hemorrhage would demonstrate differences in dynamic immunologic orchestration within hours of injury. METHODS: We identified two groups of MIPs who demonstrated distinct clinical tolerance to hemorrhage (n = 10) or distinct clinical sensitivity to hemorrhage (n = 9) from a consecutive cohort of 100 MIPs. Hemorrhage was quantified by integrating elevated shock index values for 24 hours after injury (shock volume). Clinical outcomes were quantified by average Marshall Organ Dysfunction Scores from days 2 to 5 after injury. Shock-sensitive patients had high cumulative organ dysfunction after lower magnitude hemorrhage. Shock-tolerant (ST) patients had low cumulative organ dysfunction after higher magnitude hemorrhage. Computational methods were used to analyze a panel of 20 immunologic mediators collected serially over the initial 72 hours after injury. RESULTS: Dynamic network analysis demonstrated the ST patients had increased orchestration of cytokines that are reparative and protective including interleukins 9, 17E/25, 21, 22, 23, and 33 during the initial 0- to 8-hour and 8- to 24-hour intervals after injury. Shock-sensitive patients had delayed immunologic orchestration of a network of largely proinflammatory and anti-inflammatory mediators. Elastic net linear regression demonstrated that a group of five mediators could discriminate between shock-sensitive and ST patients. CONCLUSIONS: Preliminary evidence from this study suggests that early immunologic orchestration discriminates between patients who are notably tolerant or sensitive to hemorrhage. Early orchestration of a group of reparative/protective mediators was amplified in shock-tolerant patients. LEVEL OF EVIDENCE: Prospective clinical outcomes study, level III.


Asunto(s)
Traumatismo Múltiple/inmunología , Traumatismo Múltiple/metabolismo , Choque Hemorrágico/diagnóstico , Choque Hemorrágico/metabolismo , Adulto , Estudios de Cohortes , Cuidados Críticos , Citocinas/sangre , Femenino , Escala de Coma de Glasgow , Humanos , Puntaje de Gravedad del Traumatismo , Tiempo de Internación , Masculino , Persona de Mediana Edad , Traumatismo Múltiple/complicaciones , Respiración Artificial , Choque Hemorrágico/etiología
12.
Front Med (Lausanne) ; 7: 46, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32161760

RESUMEN

Purpose: We sought to identify a MODS score parameter that highly correlates with adverse outcomes and then use this parameter to test the hypothesis that multiple severity-based MODS clusters could be identified after blunt trauma. Methods: MOD score across days (D) 2-5 was subjected to Fuzzy C-means Clustering Analysis (FCM) followed by eight Clustering Validity Indices (CVI) to derive organ dysfunction patterns among 376 blunt trauma patients admitted to the intensive care unit (ICU) who survived to discharge. Thirty-one inflammation biomarkers were assayed (Luminex™) in serial blood samples (3 samples within the first 24 h and then daily up to D 5) and were analyzed using Two-Way ANOVA and Dynamic Network analysis (DyNA). Results: The FCM followed by CVI suggested four distinct clusters based on MOD score magnitude between D2 and D5. Distinct patterns of organ dysfunction emerged in each of the four clusters and exhibited statistically significant differences with regards to in-hospital outcomes. Interleukin (IL)-6, MCP-1, IL-10, IL-8, IP-10, sST2, and MIG were elevated differentially over time across the four clusters. DyNA identified remarkable differences in inflammatory network interconnectivity. Conclusion: These results suggest the existence of four distinct organ failure patterns based on MOD score magnitude in blunt trauma patients admitted to the ICU who survive to discharge.

13.
Shock ; 53(2): 146-155, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31318836

RESUMEN

The contribution of individual genetic determinants of aging to the adverse clinical outcomes and altered inflammation mediator networks characteristic of aged trauma patients is unknown. The AA genotype of the aging-related single-nucleotide polymorphism (SNP) rs2075650 in TOMM40 has been associated with longevity, while the AG and GG genotypes are associated with an increased risk of Alzheimer disease. Here, we studied the effect of rs2075650 on clinical outcomes and dynamic biomarker patterns after traumatic injury. Genomic DNA was obtained from blunt trauma patients admitted to the ICU and examined for 551,839 SNPs using an Illumina microarray kit. Plasma was sampled from each patient three times within the first 24 h and daily from day 1 to 7 then assayed for 31 biomarkers using Luminex. Aged patients (65-90 years) were segregated into AA (n = 77) and AG/GG (n = 17) genotypes. Additional comparisons were made with matched groups of young patients (18-30 years), controlling for injury severity score (ISS) and sex ratio, and also segregated into AA (n = 56) and AG/GG (n = 19) genotypes. Aged patients with the AA genotype had a significantly lower requirement for ventilation and fewer days on mechanical ventilation, as well as significantly higher levels of one mediator and lower levels of two mediators. Dynamic Bayesian Network inference revealed IL-23 as a central node in each network regardless of age or genotype, with MIG and IP-10 also as key mediators in the networks of the aged patients. These findings suggest that an aging-related SNP, rs2075650, may influence clinical outcomes and inflammation networks in aged patients following blunt trauma, and thus may serve as a predictive outcome biomarker in the setting of polytrauma.


Asunto(s)
Polimorfismo de Nucleótido Simple/genética , Heridas y Lesiones/sangre , Heridas y Lesiones/genética , Heridas no Penetrantes/genética , Heridas no Penetrantes/inmunología , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Envejecimiento/fisiología , Teorema de Bayes , Biomarcadores/sangre , Femenino , Genotipo , Humanos , Puntaje de Gravedad del Traumatismo , Masculino , Reacción en Cadena en Tiempo Real de la Polimerasa , Respiración Artificial , Estudios Retrospectivos
14.
Shock ; 53(3): 256-268, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31365490

RESUMEN

Acute illness is a complex constellation of responses involving dysregulated inflammatory and immune responses, which are ultimately associated with multiple organ dysfunction. Gene association studies have associated single-nucleotide polymorphisms (SNPs) with clinical and pharmacological outcomes in a variety of disease states, including acute illness. With approximately 4 to 5 million SNPs in the human genome and recent studies suggesting that a large portion of SNP studies are not reproducible, we suggest that the ultimate clinical utility of SNPs in acute illness depends on validation and quality control measures. To investigate this issue, in December 2018 and January 2019 we searched the literature for peer-reviewed studies reporting data on associations between SNPs and clinical outcomes and between SNPs and pharmaceuticals (i.e., pharmacogenomics) published between January 2011 to February 2019. We review key methodologies and results from a variety of clinical and pharmacological gene association studies, including trauma and sepsis studies, as illustrative examples on current SNP association studies. In this review article, we have found three key points which strengthen the potential accuracy of SNP association studies in acute illness and other diseases: providing evidence of following a protocol quality control method such as the one in Nature Protocols or the OncoArray QC Guidelines; enrolling enough patients to have large cohort groups; and validating the SNPs using an independent technique such as a second study using the same SNPs with new patient cohorts. Our survey suggests the need to standardize validation methods and SNP quality control measures in medicine in general, and specifically in the context of complex disease states such as acute illness.


Asunto(s)
Enfermedad Aguda , Estudios de Asociación Genética , Control de Calidad , Humanos , Polimorfismo de Nucleótido Simple , Reproducibilidad de los Resultados
15.
Ann Transl Med ; 8(23): 1576, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33437775

RESUMEN

BACKGROUND: Severe injury initiates a complex physiologic response encompassing multiple systems and varies phenotypically between patients. Trauma-induced coagulopathy may be an early warning of a poorly coordinated response at the molecular level, including a deleterious immunologic response and worsening of shock states. The onset of trauma-induced coagulopathy (TIC) may be subtle however. In previous work, we identified an early warning sign of coagulopathy from the admission thromboelastogram, called the MAR ratio. We hypothesized that a low MAR ratio would be associated with specific derangements in the inflammatory response. METHODS: In this prospective, observational study, 88 blunt trauma patients admitted to the intensive care unit (ICU) were identified. Concentrations of inflammatory mediators were recorded serially over the course of a week and the MAR ratio was calculated from the admission thromboelastogram. Correlation analysis was used to assess the relationship between MAR and inflammatory mediators. Dynamic network analysis was used to assess coordination of immunologic response. RESULTS: Seventy-nine percent of patients were male and mean age was 37 years (SD 12). The mean ISS was 30.2 (SD 12) and mortality was 7.2%. CRITICAL patients (MAR ratio ≤14.2) had statistically higher shock volumes at three time points in the first day compared to NORMAL patients (MAR ratio >14.2). CRITICAL patients had significant differences in IL-6 (P=0.0065), IL-8 (P=0.0115), IL-10 (P=0.0316) and MCP-1 (P=0.0039) concentrations compared to NORMAL. Differences in degree of expression and discoordination of immune response continued in CRITICAL patients throughout the first day. CONCLUSIONS: The admission MAR ratio may be the earliest warning signal of a pathologic inflammatory response associated with hypoperfusion and TIC. A low MAR ratio is an early indication of complicated dysfunction of multiple molecular processes following trauma.

16.
Front Immunol ; 11: 589304, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33537029

RESUMEN

Systemic inflammation ensues following traumatic injury, driving immune dysregulation and multiple organ dysfunction (MOD). While a balanced immune/inflammatory response is ideal for promoting tissue regeneration, most trauma patients exhibit variable and either overly exuberant or overly damped responses that likely drive adverse clinical outcomes. We hypothesized that these inflammatory phenotypes occur in the context of severe injury, and therefore sought to define clinically distinct endotypes of trauma patients based on their systemic inflammatory responses. Using Patient-Specific Principal Component Analysis followed by unsupervised hierarchical clustering of circulating inflammatory mediators obtained in the first 24 h after injury, we segregated a cohort of 227 blunt trauma survivors into three core endotypes exhibiting significant differences in requirement for mechanical ventilation, duration of ventilation, and MOD over 7 days. Nine non-survivors co-segregated with survivors. Dynamic network inference, Fisher Score analysis, and correlations of IL-17A with GM-CSF, IL-10, and IL-22 in the three survivor sub-groups suggested a role for type 3 immunity, in part regulated by Th17 and γδ 17 cells, and related tissue-protective cytokines as a key feature of systemic inflammation following injury. These endotypes may represent archetypal adaptive, over-exuberant, and overly damped inflammatory responses.


Asunto(s)
Inflamación/inmunología , Heridas y Lesiones/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Citocinas/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Análisis de Componente Principal , Linfocitos T/inmunología , Adulto Joven
17.
Front Immunol ; 10: 2699, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31824494

RESUMEN

Animal studies suggest that the time of day is a determinant of the immunological response to both injury and infection. We hypothesized that due to this diurnal variation, time of injury could affect the systemic inflammatory response and outcomes post-trauma and tested this hypothesis by examining the dynamics of circulating inflammatory mediators in blunt trauma patients injured during daytime vs. nighttime. From a cohort of 472 blunt trauma survivors, two stringently matched sub-cohorts of moderately/severely injured patients [injury severity score (ISS) >20] were identified. Fifteen propensity-matched, daytime-inured ("mDay") patients (age 43.6 ± 5.2, M/F 11/4, ISS 22.9 ± 0.7) presented during the shortest local annual period (8:00 am-5:00 pm), and 15 propensity-matched "mNight" patients (age 43 ± 4.3, M/F 11/4, ISS 24.5 ± 2.5) presented during the shortest night period (10:00 pm-5:00 am). Serial blood samples were obtained (3 samples within the first 24 h and daily from days 1-7) from all patients. Thirty-two plasma inflammatory mediators were assayed. Two-way Analysis of Variance (ANOVA) was used to compare groups. Dynamic Network Analysis (DyNA) and Dynamic Bayesian Network (DyBN) inference were utilized to infer dynamic interrelationships among inflammatory mediators. Both total hospital and intensive care unit length of stay were significantly prolonged in the mNight group. Circulating IL-17A was elevated significantly in the mNight group from 24 h to 7 days post-injury. Circulating MIP-1α, IL-7, IL-15, GM-CSF, and sST2 were elevated in the mDay group. DyNA demonstrated elevated network complexity in the mNight vs. the mDay group. DyBN suggested that cortisol and sST2 were central nodes upstream of TGF-ß1, chemokines, and Th17/protective mediators in both groups, with IL-6 being an additional downstream node in the mNight group only. Our results suggest that time of injury affects clinical outcomes in severely injured patients in a manner associated with an altered systemic inflammation program, possibly implying a role for diurnal or circadian variation in the response to traumatic injury.


Asunto(s)
Quimiocinas/inmunología , Ritmo Circadiano/inmunología , Inflamación/inmunología , Heridas no Penetrantes/inmunología , Adulto , Teorema de Bayes , Quimiocinas/sangre , Femenino , Humanos , Inflamación/sangre , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Heridas no Penetrantes/sangre
18.
Front Genet ; 10: 1115, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31781170

RESUMEN

Trauma is a leading cause of morbidity and mortality. It is unclear why some trauma victims follow a complicated clinical course and die, while others, with apparently similar injury characteristics, do not. Interpatient genomic differences, in the form of single nucleotide polymorphisms (SNPs), have been associated previously with adverse outcomes after trauma. Recently, we identified seven novel SNPs associated with mortality following trauma. The aim of the present study was to determine if one or more of these SNPs was also associated with worse clinical outcomes and altered inflammatory trajectories in trauma survivors. Accordingly, of 413 trauma survivors, DNA samples, full blood samples, and clinical data were collected at multiple time points in the first 24 h and then daily over 7 days following hospital admission. Subsequently, single-SNP groups were created and outcomes, such as hospital length of stay (LOS), ICU LOS, and requirement for mechanical ventilation, were compared. Across a broad range of Injury Severity Scores (ISS), patients carrying the rs2065418 TT SNP in the metallophosphoesterase domain-containing 2 (MPPED2) gene exhibited higher Marshall MODScores vs. the control group of rs2065418 TG/GG patients. In patients with high-severity trauma (ISS ≥ 25, n = 94), those carrying the rs2065418 TT SNP in MPPED2 exhibited higher Marshall MODScores, longer hospital LOS (21.8 ± 2 days), a greater requirement for mechanical ventilation (9.2 ± 1.4 days on ventilator, DOV), and higher creatinine plasma levels over 7 days vs. the control group of rs2065418 TG/GG high-severity trauma patients (LOS: 15.9 ± 1.2 days, p = 0.03; DOV: 5.7 ± 1 days, p = 0.04; plasma creatinine; p < 0.0001 MODScore: p = 0.0003). Furthermore, rs2065418 TT patients with ISS ≥ 25 had significantly different plasma levels of nine circulating inflammatory mediators and elevated dynamic network complexity. These studies suggest that the rs2065418 TT genotype in the MPPED2 gene is associated with altered systemic inflammation, increased organ dysfunction, and greater hospital resource utilization. A screening for this specific SNP at admission might stratify severely injured patients regarding their lung and kidney function and clinical complications.

19.
J Surg Res ; 244: 23-33, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31279260

RESUMEN

BACKGROUND: Soluble suppression of tumorigenicity 2 (sST2), a decoy receptor for interleukin (IL)-33, has emerged as a novel biomarker in various disease processes. Recent studies have elucidated the role of the sST2/IL-33 complex in modulating the balance of Th1/Th2 immune responses after tissue stress. However, the role of sST2 as a biomarker after traumatic injury remains unclear. To address this, we evaluated serum sST2 correlations with mortality and in-hospital adverse outcomes as endpoints in blunt trauma patients. METHODS: We retrospectively analyzed clinical and biobank data of 493 blunt trauma victims 472 survivors (mean age: 48.4 ± 0.87; injury severity score [ISS]: 19.6 ± 0.48) and 19 nonsurvivors (mean age: 58.8 ± 4.5; ISS: 23.3 ± 2.1) admitted to the intensive care unit. Given the confounding impact of age on the inflammatory response, we derived a propensity-matched survivor subgroup (n = 19; mean age: 59 ± 3; ISS: 23.4 ± 2) using an IBM SPSS case-control matching algorithm. Serial blood samples were obtained from all patients (3 samples within the first 24 h and then once daily from day [D] 1 to D5 after injury). sST2 and twenty-nine inflammatory biomarkers were assayed using enzyme-linked immunosorbent assay and Luminex, respectively. Two-way analysis of variance on ranks was used to compare groups (P < 0.05). Spearman rank correlation was performed to determine the association of circulating sST2 levels with biomarker levels and in-hospital clinical outcomes. RESULTS: Circulating sST2 levels of the nonsurvivor cohort were statistically significantly elevated at 12 h after injury and remained elevated up to D5 when compared either to the overall 472 survivor cohort or a matched 19 survivor subcohort. Admission sST2 levels obtained from the first blood draw after injury in the survivor cohort correlated positively with admission base deficit (correlation coefficient [CC] = 0.1; P = 0.02), international normalized ratio (CC = 0.1, P = 0.03), ISS (CC = 0.1, P = 0.008), and the average Marshall multiple organ dysfunction score between D2 and D5 (CC = 0.1, P = 0.04). Correlations with ISS revealed a positive correlation of ISS with plasma sST2 levels across the mild ISS (CC = 0.47, P < 0.001), moderate ISS (CC = 0.58, P < 0.001), and severe ISS groups (CC = 0.63, P < 0.001). Analysis of biomarker correlations in the matched survivor group over the initial 24 h after injury showed that sST2 correlates strongly and positively with IL-4 (CC = 0.65, P = 0.002), IL-5 (CC = 0.57, P = 0.01), IL-21 (CC = 0.52, P = 0.02), IL-2 (CC = 0.51, P = 0.02), soluble IL-2 receptor-α (CC = 0.5, P = 0.02), IL-13 (CC = 0.49, P = 0.02), and IL-17A (CC = 0.48, P = 0.03). This was not seen in the matched nonsurvivor group. sST2/IL-33 ratios were significantly elevated in nonsurvivors and patients with severe injury based on ISS ≥ 25. CONCLUSIONS: Elevations in serum sST2 levels are associated with poor clinical trajectories and mortality after blunt trauma. High sST2 coupled with low IL-33 associates with severe injury, mortality, and worse clinical outcomes. These findings suggest that sST2 could serve as an early prognostic biomarker in trauma patients and that sustained elevations of sST2 could contribute to a detrimental suppression of IL-33 bioavailability in patients with high injury severity.


Asunto(s)
Proteína 1 Similar al Receptor de Interleucina-1/sangre , Heridas no Penetrantes/mortalidad , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Mortalidad Hospitalaria , Humanos , Puntaje de Gravedad del Traumatismo , Unidades de Cuidados Intensivos/estadística & datos numéricos , Interleucina-33/sangre , Masculino , Persona de Mediana Edad , Puntuaciones en la Disfunción de Órganos , Pronóstico , Estudios Retrospectivos , Heridas no Penetrantes/sangre , Heridas no Penetrantes/diagnóstico
20.
PLoS One ; 14(6): e0217577, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31163056

RESUMEN

Extremity and soft tissue injuries contribute significantly to inflammation and adverse in-hospital outcomes for trauma survivors; accordingly, we examined the complex association between clinical outcomes inflammatory responses in this setting using in silico tools. Two stringently propensity-matched, moderately/severely injured (Injury Severity Score > 16) patient sub-cohorts of ~30 patients each were derived retrospectively from a cohort of 472 blunt trauma survivors and segregated based on their degree of extremity injury severity (above or below 3 on the Abbreviated Injury Scale). Serial blood samples were analyzed for 31 plasma inflammatory mediators. In addition to standard statistical analyses, Dynamic Network Analysis (DyNA) and Principal Component Analysis (PCA) were used to model systemic inflammation following trauma. Patients in the severe extremity injury sub-cohort experienced longer intensive care unit length of stay (LOS), total LOS, and days on a mechanical ventilator, with higher Marshall Multiple Organ Dysfunction (MOD) Scores over the first 7 days post-injury as compared to the mild/moderate extremity injury sub-cohort. The higher severity cohort had statistically significant elevated lactate, base deficit, and creatine phosphokinase on first blood draw, along with significant changes in multiple circulating inflammatory mediators. DyNA pointed to a sustained role for type 17 immunity in both sub-cohorts, along with IFN-γ in the severe extremity injury group. DyNA network complexity increased over 7 days post-injury in the severe injury group, while generally decreasing over this same time period in the mild/moderate injury group. PCA suggested a more robust activation of multiple pathways in the severe extremity injury group as compared to the mild/moderate injury group. These studies thus point to the possibility of self-sustaining inflammation following severe extremity injury vs. resolving inflammation following less severe extremity injury.


Asunto(s)
Simulación por Computador , Extremidades/lesiones , Inflamación/complicaciones , Puntaje de Gravedad del Traumatismo , Traumatismo Múltiple/complicaciones , Adulto , Área Bajo la Curva , Biomarcadores/metabolismo , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Componente Principal , Factores de Tiempo , Resultado del Tratamiento
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