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BACKGROUND: Acute kidney injury (AKI) is common in hospitalized patients and results in significant morbidity and mortality. The objective of the study was to explore the systemic immune response of intensive care unit patients presenting with AKI, especially the association between immune profiles and persistent AKI during the first week after admission following various types of injuries (sepsis, trauma, surgery, and burns). METHODS: REALAKI is an ancillary analysis of the REAnimation Low Immune Status Marker (REALISM) cohort study, in which 359 critically ill patients were enrolled in three different intensive care units. Patients with end-stage renal disease were excluded from the REALAKI study. Clinical samples and data were collected three times after admission: at day 1 or 2 (D1-2), day 3 or 4 (D3-4) and day 5, 6 or 7 (D5-7). Immune profiles were compared between patients presenting with or without AKI. Patients with AKI at both D1-2 and D5-7 were defined as persistent AKI. A multivariable logistic regression model was performed to determine the independent association between AKI and patients' immunological parameters. RESULTS: Three hundred and fifty-nine patients were included in this analysis. Among them, 137 (38%) were trauma patients, 103 (29%) post-surgery patients, 95 (26%) sepsis patients, and 24 (7%) were burn patients. One hundred and thirty-nine (39%) patients presented with AKI at D1-2 and 61 (20%) at D5-7. Overall, 94% presented with persistent AKI at D5-7. Patients with AKI presented with increased pro and anti-inflammatory cytokines and altered innate and adaptive immune responses. The modifications observed in the immune profiles tended to be more pronounced with increasing KDIGO stages. In the logistic regression model, a statistically significant association was observed at D1-2 between AKI and CD10lowCD16low immature neutrophils (OR 3.03 [1.7-5.5]-p < 0.001). At D5-7, increased interleukin-10 (IL-10) levels and reduced ex vivo TNF-α production after LPS stimulation were significantly associated with the presence of AKI (OR 1.38 [1.12-1.71]-p = 0.001 and 0.51 [0.27-0.91]-p = 0.03, respectively). Patients who recovered from AKI between D1-2 and D5-7 compared to patients with persistent AKI at D5-7, tended to correct these alterations. CONCLUSION: Following various types of severe injuries, early AKI is associated with the initial inflammatory response. Presence of AKI at the end of the first week after injury is associated with injury-induced immunosuppression.
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Injúria Renal Aguda , Estado Terminal , Humanos , Masculino , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/etiologia , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Estudos de Coortes , Unidades de Terapia Intensiva/estatística & dados numéricos , Unidades de Terapia Intensiva/organização & administração , Ferimentos e Lesões/complicações , Ferimentos e Lesões/imunologia , Estudos Prospectivos , Fatores de Tempo , Biomarcadores/sangue , Biomarcadores/análise , Sepse/complicações , Sepse/imunologiaRESUMO
OBJECTIVE: To assess the compliance with French guidelines for the prevention of central venous catheter (CVC)-related infections in two university hospitals. METHODS: An observational audit was conducted in 7 wards using a digital tool. RESULTS: The prerequisite of hand hygiene (HH) were respected by 90% of health-care worker; 86% performed HH prior to equipment preparation and 59% repeated it prior to infusion. Wearing gloves when necessary and rinsing were respected in 46.7% and 75.6% of the observations. CONCLUSION: Findings showed an acceptable level of adherence to recommended practices for CVC management. However, barriers of unrespect evidence-based recommendations need to be investigated in depth.
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Pseudomonas aeruginosa is one of the main causes of healthcare-associated infection in Europe that increases patient morbidity and mortality. Multi-resistant pathogens are a major public health issue in burn centers. Mortality increases when the initial antibiotic treatment is inappropriate, especially if the patient is infected with P. aeruginosa strains that are resistant to many antibiotics. Phage therapy is an emerging option to treat severe P. aeruginosa infections. It involves using natural viruses called bacteriophages, which have the ability to infect, replicate, and, theoretically, destroy the P. aeruginosa population in an infected patient. We report here the case of a severely burned patient who experienced relapsing ventilator-associated pneumonia associated with skin graft infection and bacteremia due to extensively drug-resistant P. aeruginosa. The patient was successfully treated with personalized nebulized and intravenous phage therapy in combination with immunostimulation (interferon-γ) and last-resort antimicrobial therapy (imipenem-relebactam).
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Bacteriemia , Queimaduras , Farmacorresistência Bacteriana Múltipla , Terapia por Fagos , Pneumonia Associada à Ventilação Mecânica , Infecções por Pseudomonas , Pseudomonas aeruginosa , Humanos , Pseudomonas aeruginosa/virologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pneumonia Associada à Ventilação Mecânica/terapia , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Pneumonia Associada à Ventilação Mecânica/microbiologia , Terapia por Fagos/métodos , Infecções por Pseudomonas/terapia , Infecções por Pseudomonas/tratamento farmacológico , Queimaduras/complicações , Queimaduras/terapia , Bacteriemia/terapia , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Antibacterianos/uso terapêutico , Masculino , Recidiva , Bacteriófagos/fisiologiaRESUMO
The recent SarsCov2 pandemic has disrupted healthcare system notably impacting intensive care units (ICU). In severe cases, the immune system is dysregulated, associating signs of hyperinflammation and immunosuppression. In the present work, we investigated, using a joint modeling approach, whether the trajectories of cellular immunological parameters were associated with survival of COVID-19 ICU patients. This study is based on the REA-IMMUNO-COVID cohort including 538 COVID-19 patients admitted to ICU between March 2020 and May 2022. Measurements of monocyte HLA-DR expression (mHLA-DR), counts of neutrophils, of total lymphocytes, and of CD4+ and CD8+ subsets were performed five times during the first month after ICU admission. Univariate joint models combining survival at day 28 (D28), hospital discharge and longitudinal analysis of those biomarkers' kinetics with mixed-effects models were performed prior to the building of a multivariate joint model. We showed that a higher mHLA-DR value was associated with a lower risk of death. Predicted mHLA-DR nadir cutoff value that maximized the Youden index was 5414 Ab/C and led to an AUC = 0.70 confidence interval (95%CI) = [0.65; 0.75] regarding association with D28 mortality while dynamic predictions using mHLA-DR kinetics until D7, D12 and D20 showed AUCs of 0.82 [0.77; 0.87], 0.81 [0.75; 0.87] and 0.84 [0.75; 0.93]. Therefore, the final joint model provided adequate discrimination performances at D28 after collection of biomarker samples until D7, which improved as more samples were collected. After severe COVID-19, decreased mHLA-DR expression is associated with a greater risk of death at D28 independently of usual clinical confounders.
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COVID-19 , Antígenos HLA-DR , Monócitos , Humanos , COVID-19/mortalidade , COVID-19/imunologia , Masculino , Feminino , Monócitos/metabolismo , Monócitos/imunologia , Pessoa de Meia-Idade , Idoso , Unidades de Terapia Intensiva , SARS-CoV-2 , Biomarcadores/sangue , Índice de Gravidade de DoençaRESUMO
BACKGROUND: The efficacy and safety of cefiderocol in ICU patients with difficult-to-treat resistance (DTR) non-fermenting Gram-negative bacteria (Nf-GNB) are not as well-established. Consequently, we conducted a cohort study to compare Cefiderocol with the Best Available Therapy (BAT) in ICU patients. METHODS: We included adult patients from 9 different ICUs, including a burn ICU unit, from 2019 to 2023 treated with Cefiderocol for DTR Nf-GNB isolated from the blood or lungs. We matched each patient at a 1:2 ratio based on the same DTR Nf-GBN isolated pathogen, and when possible, within the same type of ICU (burn unit or not). The primary endpoint of the study was the clinical cure at 15 days, with secondary endpoints including clinical cure at 30 days, relapse, and in-ICU mortality. For each outcome, adjusted odds ratios were estimated using bidirectional stepwise regression in a final model, which included 13 preselected confounders. RESULTS: We included 27 patients with cefiderocol, matched with 54 patients receiving the BAT. Four patients were not exactly matched on the type of ICU unit. Characteristics were comparable between groups, mostly male with a Charlson Comorbidity Index of 3 [1-5], and 28% had immunosuppression. Cefiderocol patients were most likely to have higher number of antibiotic lines. The main DTR Nf-GNB identified was Pseudomonas aeruginosa (81.5%), followed by Acinetobater baumanii (14.8%) and Stenotrophomonas maltophilia (3.7%). Pneumonia was the identified infection in 21 (78.8%) patients in the Cefiderocol group and in 51 (94.4%) patients in the BAT group (p = 0.054). Clinical cure at 15 and 30-day and the in-ICU mortality was comparable between groups, however relapse was higher in the cefiderocol group (8-29.6% vs. 4-7.4%;aOR 10.06[1.96;51.53]) CONCLUSION: Cefiderocol did not show an improvement in clinical cure or mortality rates compared to BAT in the treatment of DTR Nf-GNB, but it was associated with a higher relapse rate.
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Sepsis induces intense, dynamic and heterogeneous host response modulations. Despite improvement of patient management, the risk of mortality and healthcare-associated infections remains high. Treatments to counterbalance immune response are under evaluation, but effective biomarkers are still lacking to perform patient stratification. The design of the present study was defined to alleviate the limitations of existing literature: we selected patients who survived the initial hyperinflammatory response and are still hospitalized at day 5-7 after ICU admission. Using the Immune Profiling Panel (IPP), a fully automated RT-qPCR multiplex prototype, we optimized a machine learning model combining the IPP gene expression levels for the identification of patients at high risk of worsening, a composite endpoint defined as death or secondary infection, within one week after sampling. This was done on 332 sepsis patients selected from two retrospective studies. The IPP model identified a high-risk group comprising 30% of patients, with a significant increased proportion of worsening events at day 28 compared to the low-risk group (49% vs. 28%, respectively). These preliminary results underline the potential clinical application of IPP for sepsis patient stratification in a personalized medicine perspective, that will be confirmed in a larger prospective multicenter study.
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Biomarcadores , Sepse , Humanos , Sepse/imunologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Aprendizado de Máquina , Estudos Retrospectivos , PrognósticoRESUMO
BACKGROUND: A 10-day dexamethasone regimen has emerged as the internationally adopted standard-of-care for severe COVID-19 patients. However, the immune response triggered by SARS-CoV-2 infection remains a complex and dynamic phenomenon, leading to various immune profiles and trajectories. The immune status of severe COVID-19 patients following complete dexamethasone treatment has yet to be thoroughly documented. RESULTS: To analyze monocyte HLA-DR expression (mHLA-DR) and CD4 + T lymphocyte count (CD4) in critically ill COVID-19 patients after a dexamethasone course and evaluate their association with 28-day ICU mortality, adult COVID-19 patients (n = 176) with an ICU length of stay of at least 10 days and under dexamethasone treatment were included. Associations between each biomarker value (or in combination) measured at day 10 after ICU admission and 28-day mortality in ICU were evaluated. At day 10, the majority of patients presented decreased values of both parameters. A significant association between low mHLA-DR and 28-day mortality was observed. This association remained significant in a multivariate analysis including age, comorbidities or pre-existing immunosuppression (adjusted Hazard ratio (aHR) = 2.86 [1.30-6.32], p = 0.009). Similar results were obtained with decreased CD4 + T cell count (aHR = 2.10 [1.09-4.04], p = 0.027). When combining these biomarkers, patients with both decreased mHLA-DR and low CD4 presented with an independent and significant elevated risk of 28-day mortality (i.e., 60%, aHR = 4.83 (1.72-13.57), p = 0.001). CONCLUSIONS: By using standardized immunomonitoring tools available in clinical practice, it is possible to identify a subgroup of patients at high risk of mortality at the end of a 10-day dexamethasone treatment. This emphasizes the significance of integrating immune monitoring into the surveillance of intensive care patients in order to guide further immumodulation approaches.
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This retrospective study aimed to compare the mortality and burden of respiratory syncytial virus (RSV group), SARS-CoV-2 (COVID-19 group), non-H1N1 (Seasonal influenza group) and H1N1 influenza (H1N1 group) in adult patients admitted to intensive care unit (ICU) with respiratory failure. A total of 807 patients were included. Mortality was compared between the four following groups: RSV, COVID-19, seasonal influenza, and H1N1 groups. Patients in the RSV group had significantly more comorbidities than the other patients. At admission, patients in the COVID-19 group were significantly less severe than the others according to the simplified acute physiology score-2 (SAPS-II) and sepsis-related organ failure assessment (SOFA) scores. Using competing risk regression, COVID-19 (sHR = 1.61; 95% CI 1.10; 2.36) and H1N1 (sHR = 1.87; 95% CI 1.20; 2.93) were associated with a statistically significant higher mortality while seasonal influenza was not (sHR = 0.93; 95% CI 0.65; 1.31), when compared to RSV. Despite occurring in more severe patients, RSV and seasonal influenza group appear to be associated with a more favorable outcome than COVID-19 and H1N1 groups.
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COVID-19 , Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Infecções por Vírus Respiratório Sincicial , Adulto , Humanos , Estudos Retrospectivos , Unidades de Terapia Intensiva , Vírus Sinciciais RespiratóriosRESUMO
Guided biomarker-personalized immunotherapy is advancing rapidly as a means to rejuvenate immune function in injured patients who are the most immunosuppressed. A recent study introduced a fully automated interferon-γ release assay (IGRA) for monitoring the functionality of T lymphocytes in patients with septic shock. While a significant decrease in IFN-γ release capacity was observed, a significant correlation with CD8 lymphocyte absolute count was also reported, raising the question of whether ex-vivo IFN-γ production would be only a surrogate marker for lymphocyte count or if these two parameters conveyed distinct and complementary information. In a large cohort of more than 353 critically ill patients following various injuries (sepsis, trauma, major surgery), the primary objective of the present study was to simultaneously evaluate the association between ex vivo IFN-γ release and CD8 cell count with regard to adverse outcome. Our findings provide a clear-cut result, as they distinctly demonstrate that IGRA offers higher-quality information than CD8 count in terms of an independent association with the occurrence of an adverse outcome. These results strengthen the case for incorporating IGRA into the array of biomarkers of interest for defining endotypes in sepsis. This holds especially true given that fully automated tests are now readily available and could be used in routine clinical practice.
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Testes de Liberação de Interferon-gama , Sepse , Humanos , Testes de Liberação de Interferon-gama/métodos , Interferon gama , Estado Terminal , Terapia de Imunossupressão , Contagem de Linfócitos , Linfócitos T CD8-Positivos , BiomarcadoresRESUMO
Sepsis triggers a complex response marked by the simultaneous presence of proinflammatory and immunosuppressive elements, disrupting the mechanisms intended to maintain homeostasis. While the NLRP3 inflammasome has been demonstrated to contribute to the inflammatory side, its connection with delayed sepsis-induced immunosuppression remains unexplored. The present objective was to concomitantly and prospectively assess NLRP3 activation (IL-1ß, IL-18, and soluble receptors) and features of immune failure (IL-10, mHLA-DR, myeloid-derived suppressor cells) in septic patients. To validate our findings, we conducted a transcriptomic analysis of mRNA of NLRP3-related genes (IL-18R1, IL-1R2) on an additional cohort of 107 patients. Two distinct endotypes were identified. One cluster displayed moderate inflammation rapidly returning to normal values, while the other exhibited a higher inflammatory response persisting until day 28, which was associated with persistent marked immunosuppression and higher 28-d mortality. Identifying endotypes with different pro/anti-inflammatory trajectories could hold important clinical implications for the management of sepsis.
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Inflamassomos , Sepse , Humanos , Terapia de Imunossupressão , Inflamassomos/genética , Interleucina-1beta/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Sepse/genéticaRESUMO
Sepsis is a life-threatening organ dysfunction caused by a dysregulated response to infection. In this context, the aberrant activation of the NLRP3 inflammasome has been documented mostly through the measurement of increased plasmatic concentrations of IL-1ß and IL-18. At the cellular level, contradictory results have been published. However, no study has comprehensively monitored NLRP3 inflammasome activation at the basal level and after ex vivo reactivation of whole blood monocytes and neutrophils focusing on ICU patients with bacterial and viral sepsis, including a longitudinal analysis. Thus, we conducted a prospective longitudinal study, examining NLRP3 inflammasome functionality in COVID-19 ICU patients (n = 15) and bacterial septic shock patients (n = 17) during the first week of ICU hospitalization, compared with healthy donors. Using two whole-blood flow cytometry assays, we detected ASC speck-positive monocytes (i.e., monocytes presenting the polymerization of ASC proteins) and activated caspase-1 in polymorphonuclear cells as read-outs, both at baseline and following nigericin stimulation, a drug that forms pores and activates the NLRP3 inflammasome. Our findings showed that, at baseline and regardless of the type of infection, patients exhibited reduced ASC speck-positive monocytes and decreased activated caspase-1 in PMN compared to healthy volunteers. This decrease was prominent at day 0. Following nigericin stimulation, this reduction was also observed and persisted throughout the first week of hospitalization, irrespective of the cellular population or parameter being considered. Notably, at day 0, this diminished activation and response to stimulation of NLRP3 was associated with a higher 28-day mortality rate. Consequently, our observations highlighted a concurrent decline in both basal expression and ex vivo activation of the NLRP3 inflammasome in circulating myeloid cells from patients with bacterial and viral sepsis in association with increased mortality.
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Inflamassomos , Sepse , Humanos , Caspase 1/metabolismo , Inflamassomos/metabolismo , Estudos Longitudinais , Nigericina , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estudos Prospectivos , Sepse/mortalidadeRESUMO
BACKGROUND: Understanding the mechanisms underlying immune dysregulation in sepsis is a major challenge in developing more individualized therapy, as early and persistent inflammation, as well as immunosuppression, play a significant role in pathophysiology. As part of the antimicrobial response, neutrophils can release extracellular traps (NETs) which neutralize and kill microorganisms. However, excessive NETs formation may also contribute to pathogenesis, tissue damage and organ dysfunction. Recently, a novel automated assay has been proposed for the routine measurement of nucleosomes H3.1 (fundamental units of chromatin) that are released during NETs formation. The aim of the present study was to measure nucleosome levels in 151 septic shock patients (according to sepsis-3 definition) and to determine association with mortality. RESULTS: The nucleosome H3.1 levels (as determined by a chemiluminescence immunoassay performed on an automated immunoanalyzer system) were markedly and significantly elevated at all-time points in septic shock patients compared to the control group. Immunological parameters indicated tremendous early inflammation (IL-6 = 1335 pg/mL at day 1-2) along with marked immunosuppression (e.g., mHLA-DR = 3853 AB/C and CD4 = 338 cell /µL at day 3-4). We found significantly positive correlation between nucleosome levels and organ failure and severity scores, IL-6 concentrations and neutrophil count. Significantly higher values (day 1-2 and 3-4) were measured in non-survivor patients (28-day mortality). This association was still significant after multivariate analysis and was more pronounced with highest concentration. Early (day 1-2) increased nucleosome levels were also independently associated with 5-day mortality. At day 6-8, persistent elevated nucleosome levels were negatively correlated to mHLA-DR values. CONCLUSIONS: This study reports a significant elevation of nucleosome in patients during a one-week follow-up. The nucleosome levels showed correlation with neutrophil count, IL-6 and were found to be independently associated with mortality assessed at day 5 or 28. Therefore, nucleosome concentration seems to be a promising biomarker for detecting hyper-inflammatory phenotype upon a patient's admission. Additional investigations are required to evaluate the potential association between sustained elevation of nucleosome and sepsis-induced immunosuppression.
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PURPOSE: This study aimed to assess the outcome and factors associated with mortality in patients who received urgent chemotherapy (CT) in the intensive care unit (ICU) in Lyon, France. MATERIAL AND METHODS: A total of 147 adult patients diagnosed with cancer and requiring urgent CT during ICU stay between October 2014 and December 2019 were included in this retrospective study. RESULTS: Hematological cancer was found in 77% of patients, and acute respiratory failure was the leading cause of ICU admission (46.3%). The 6-month mortality rate was 69.4%; patients with solid cancer had a higher risk of mortality. Patients who died within 6 months had a poor performance score and a higher SOFA score at admission. The multivariate analysis showed that solid tumors, sepsis on the day of CT, and SOFA score on the day of CT were associated with 6-month mortality. Additionally, 95% of patients who survived the ICU resumed conventional CT, with a higher likelihood of resuming CT among those with hematological cancer. CONCLUSION: Urgent CT in the ICU is feasible in a specific subset of patients, mainly those with hematological cancer, with resumption of the curative treatment regimen after ICU discharge.
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Neoplasias Hematológicas , Leucemia Mieloide Aguda , Adulto , Humanos , Estudos Retrospectivos , Prognóstico , Unidades de Terapia Intensiva , Mortalidade HospitalarRESUMO
In sepsis, personalized immunotherapy is being evaluated as a means of restoring immune function in the most severely affected patients. Biomarkers play a crucial role in this process, as there are no clear clinical indicators of immune dysfunction. Functional testing is considered a gold standard for assessing immune function, but this approach faces analytical challenges in terms of clinical implementation. The use of technician-dependent, time-consuming, home-made protocols often leads to poor standardization. This study represents the first beta testing of a fully automated interferon-γ release assay (IGRA) for monitoring the functionality of antigen-independent T lymphocytes. We observed a significant decrease in IFN-γ release capacity, which was associated with typical alterations in immunological cellular parameters (such as low mHLA-DR expression and decreased CD8 T lymphocyte count), in 22 patients with septic shock. Since the test is performed using whole blood and requires no technician intervention, with results available within 4 h, it may offer new possibilities for monitoring patients with immune alterations in routine clinical conditions. Further investigations in larger cohorts of patients are now needed to validate its clinical potential.
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Sepse , Choque Séptico , Humanos , Testes de Liberação de Interferon-gama , Estudo de Prova de Conceito , Sepse/metabolismo , Linfócitos T CD8-Positivos/metabolismoAssuntos
Monócitos , Sepse , Humanos , Monócitos/metabolismo , Citometria de Fluxo , Antígenos HLA-DR , Sepse/diagnóstico , Biomarcadores/metabolismoRESUMO
Importance: General anesthesia and procedural sedation are common practice for mechanical thrombectomy in acute ischemic stroke. However, risks and benefits of each strategy are unclear. Objective: To determine whether general anesthesia or procedural sedation for anterior circulation large-vessel occlusion acute ischemic stroke thrombectomy are associated with a difference in periprocedural complications and 3-month functional outcome. Design, Setting, and Participants: This open-label, blinded end point randomized clinical trial was conducted between August 2017 and February 2020, with final follow-up in May 2020, at 10 centers in France. Adults with occlusion of the intracranial internal carotid artery and/or the proximal middle cerebral artery treated with thrombectomy were enrolled. Interventions: Patients were assigned to receive general anesthesia with tracheal intubation (n = 135) or procedural sedation (n = 138). Main Outcomes and Measures: The prespecified primary composite outcome was functional independence (a score of 0 to 2 on the modified Rankin Scale, which ranges from 0 [no neurologic disability] to 6 [death]) at 90 days and absence of major periprocedural complications (procedure-related serious adverse events, pneumonia, myocardial infarction, cardiogenic acute pulmonary edema, or malignant stroke) at 7 days. Results: Among 273 patients evaluable for the primary outcome in the modified intention-to-treat population, 142 (52.0%) were women, and the mean (SD) age was 71.6 (13.8) years. The primary outcome occurred in 38 of 135 patients (28.2%) assigned to general anesthesia and in 50 of 138 patients (36.2%) assigned to procedural sedation (absolute difference, 8.1 percentage points; 95% CI, -2.3 to 19.1; P = .15). At 90 days, the rate of patients achieving functional independence was 33.3% (45 of 135) with general anesthesia and 39.1% (54 of 138) with procedural sedation (relative risk, 1.18; 95% CI, 0.86-1.61; P = .32). The rate of patients without major periprocedural complications at 7 days was 65.9% (89 of 135) with general anesthesia and 67.4% (93 of 138) with procedural sedation (relative risk, 1.02; 95% CI, 0.86-1.21; P = .80). Conclusions and Relevance: In patients treated with mechanical thrombectomy for anterior circulation acute ischemic stroke, general anesthesia and procedural sedation were associated with similar rates of functional independence and major periprocedural complications. Trial Registration: ClinicalTrials.gov Identifier: NCT03229148.
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Isquemia Encefálica , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Adulto , Humanos , Feminino , Idoso , Masculino , AVC Isquêmico/etiologia , Isquemia Encefálica/complicações , Sedação Consciente , Acidente Vascular Cerebral/tratamento farmacológico , Anestesia Geral , Trombectomia/efeitos adversos , Procedimentos Endovasculares/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: The development of stratification tools based on the assessment of circulating mRNA of genes involved in the immune response is constrained by the heterogeneity of septic patients. The aim of this study is to develop a transcriptomic score based on a pragmatic combination of immune-related genes detected with a prototype multiplex PCR tool. METHODS: As training cohort, we used the gene expression dataset obtained from 176 critically ill patients enrolled in the REALISM study (NCT02638779) with various etiologies and still hospitalized in intensive care unit (ICU) at day 5-7. Based on the performances of each gene taken independently to identify patients developing ICU-acquired infections (ICU-AI) after day 5-7, we built an unweighted score assuming the independence of each gene. We then determined the performances of this score to identify a subgroup of patients at high risk to develop ICU-AI, and both longer ICU length of stay and mortality of this high-risk group were assessed. Finally, we validated the effectiveness of this score in a retrospective cohort of 257 septic patients. RESULTS: This transcriptomic score (TScore) enabled the identification of a high-risk group of patients (49%) with an increased rate of ICU-AI when compared to the low-risk group (49% vs. 4%, respectively), with longer ICU length of stay (13 days [95% CI 8-30] vs. 7 days [95% CI 6-9], p < 0.001) and higher ICU mortality (15% vs. 2%). High-risk patients exhibited biological features of immune suppression with low monocytic HLA-DR levels, higher immature neutrophils rates and higher IL10 concentrations. Using the TScore, we identified 160 high-risk patients (62%) in the validation cohort, with 30% of ICU-AI (vs. 18% in the low-risk group, p = 0.06), and significantly higher mortality and longer ICU length of stay. CONCLUSIONS: The transcriptomic score provides a useful and reliable companion diagnostic tool to further develop immune modulating drugs in sepsis in the context of personalized medicine.
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Sepse , Transcriptoma , Humanos , Estudos Retrospectivos , Estado Terminal , Sepse/diagnóstico , Sepse/genética , Unidades de Terapia Intensiva , Progressão da DoençaRESUMO
OBJECTIVES: There is a crucial unmet need for biomarker-guided diagnostic and prognostic enrichment in clinical trials evaluating immune modulating therapies in critically ill patients. Low monocyte expression of human leukocyte antigen-DR (mHLA-DR), considered as a reference surrogate to identify immunosuppressed patients, has been proposed for patient stratification in immunostimulation approaches. However, its widespread use in clinic has been somewhat hampered by technical constraints inherent to flow cytometry technology. The objective of the present study was to evaluate the ability of a prototype multiplex polymerase chain reaction tool (immune profiling panel [IPP]) to identify immunosuppressed ICU patients characterized by a low mHLA-DR expression. DESIGN: Retrospective observational cohort study. SETTING: Adult ICU in a University Hospital, Lyon, France. PATIENTS: Critically ill patients with various etiologies enrolled in the REAnimation Low Immune Status Marker study (NCT02638779). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: mHLA-DR and IPP data were obtained from 1,731 blood samples collected from critically ill patients with various etiologies and healthy volunteers. A partial least square regression model combining the expression levels of IPP markers was trained and used for the identification of samples from patients presenting with evidence of immunosuppression, defined here as mHLADR less than 8,000 antibodies bound per cell (AB/C). The IPP gene set had an area under the receiver operating characteristic curve (AUC) of 0.86 (95% CI 0.83-0.89) for the identification of immunosuppressed patients. In addition, when applied to the 123 patients still in the ICU at days 5-7 after admission, IPP similarly enriched the number of patients with ICU-acquired infections in the immunosuppressed group (26%), in comparison with low mHLA-DR (22%). CONCLUSIONS: This study reports on the potential of the IPP gene set to identify ICU patients presenting with mHLA-DR less than 8,000 AB/C. Upon further optimization and validation, this molecular tool may help in the stratification of patients that could benefit from immunostimulation in the context of personalized medicine.