A Whole Blood Enzyme-Linked Immunospot Assay for Functional Immune Endotyping of Septic Patients.

Sepsis initiates simultaneous pro- and anti-inflammatory processes, the pattern and intensity of which vary over time. The inability to evaluate the immune status of patients with sepsis in a rapid and quantifiable manner has undoubtedly been a major reason for the failure of many therapeutic trials. Although there has been considerable effort to immunophenotype septic patients, these methods have often not accurately assessed the functional state of host immunity, lack dynamic range, and are more reflective of molecular processes rather than host immunity. In contrast, ELISpot assay measures the number and intensity of cytokine-secreting cells and has excellent dynamic range with rapid turnaround. We investigated the ability of a (to our knowledge) novel whole blood ELISpot assay and compared it with a more traditional ELISpot assay using PBMCs in sepsis. IFN-γ and TNF-α ELISpot assays on whole blood and PBMCs were undertaken in control, critically ill nonseptic, and septic patients. Whole blood ELISpot was easy to perform, and results were generally comparable to PBMC-based ELISpot. However, the whole blood ELISpot assay revealed that nonmonocyte, myeloid populations are a significant source of ex vivo TNF-α production. Septic patients who died had early, profound, and sustained suppression of innate and adaptive immunity. A cohort of septic patients had increased cytokine production compared with controls consistent with either an appropriate or excessive immune response. IL-7 restored ex vivo IFN-γ production in septic patients. The whole blood ELISpot assay offers a significant advance in the ability to immunophenotype patients with sepsis and to guide potential new immunotherapies.

Temperature Management in the ICU.

OBJECTIVE: Temperature abnormalities are recognized as a marker of human disease, and the therapeutic value of temperature is an attractive treatment target. The objective of this synthetic review is to summarize and critically appraise evidence for active temperature management in critically ill patients. DATA SOURCES: We searched MEDLINE for publications relevant to body temperature management (including targeted temperature management and antipyretic therapy) in cardiac arrest, acute ischemic and hemorrhagic stroke, traumatic brain injury, and sepsis. Bibliographies of included articles were also searched to identify additional relevant studies. STUDY SELECTION: English-language systematic reviews, meta-analyses, randomized trials, observational studies, and nonhuman data were reviewed, with a focus on the most recent randomized control trial evidence. DATA EXTRACTION: Data regarding study methodology, patient population, temperature management strategy, and clinical outcomes were qualitatively assessed. DATA SYNTHESIS: Temperature management is common in critically ill patients, and multiple large trials have been conducted to elucidate temperature targets, management strategies, and timing. The strongest data concerning the use of therapeutic hypothermia exist in comatose survivors of cardiac arrest, and recent trials suggest that appropriate postarrest temperature targets between 33°C and 37.5°C are reasonable. Targeted temperature management in other critical illnesses, including acute stroke, traumatic brain injury, and sepsis, has not shown benefit in large clinical trials. Likewise, trials of pharmacologic antipyretic therapy have not demonstrated improved outcomes, although national guidelines do recommend treatment of fever in patients with stroke and traumatic brain injury based on observational evidence associating fever with worse outcomes. CONCLUSIONS: Body temperature management in critically ill patients remains an appealing therapy for several illnesses, and additional studies are needed to clarify management strategies and therapeutic pathways.

Therapeutic Hyperthermia Is Associated With Improved Survival in Afebrile Critically Ill Patients With Sepsis: A Pilot Randomized Trial.

OBJECTIVES: To test the hypothesis that forced-air warming of critically ill afebrile sepsis patients improves immune function compared to standard temperature management. DESIGN: Single-center, prospective, open-label, randomized controlled trial. SETTING: One thousand two hundred-bed academic medical center. PATIENTS: Eligible patients were mechanically ventilated septic adults with: 1) a diagnosis of sepsis within 48 hours of enrollment; 2) anticipated need for mechanical ventilation of greater than 48 hours; and 3) a maximum temperature less than 38.3°C within the 24 hours prior to enrollment. Primary exclusion criteria included: immunologic diseases, immune-suppressing medications, and any existing condition sensitive to therapeutic hyperthermia (e.g., brain injury). The primary outcome was monocyte human leukocyte antigen (HLA)-DR expression, with secondary outcomes of CD3/CD28-induced interferon gamma (IFN-γ) production, mortality, and 28-day hospital-free days. INTERVENTIONS: External warming using a forced-air warming blanket for 48 hours, with a goal temperature 1.5°C above the lowest temperature documented in the previous 24 hours. MEASUREMENTS AND MAIN RESULTS: We enrolled 56 participants in the study. No differences were observed between the groups in HLA-DR expression (692 vs 2,002; p = 0.396) or IFN-γ production (31 vs 69; p = 0.678). Participants allocated to external warming had lower 28-day mortality (18% vs 43%; absolute risk reduction, 25%; 95% CI, 2-48%) and more 28-day hospital-free days (difference, 2.6 d; 95% CI, 0-11.6). CONCLUSIONS: Participants randomized to external forced-air warming did not have a difference in HLA-DR expression or IFN-γ production. In this pilot study, however, 28-day mortality was lower in the intervention group. Future research should seek to better elucidate the impact of temperature modulation on immune and nonimmune organ failure pathways in sepsis.

Awareness With Paralysis Among Critically Ill Emergency Department Patients: A Prospective Cohort Study.

OBJECTIVES: In mechanically ventilated patients, awareness with paralysis (AWP) can have devastating consequences, including post-traumatic stress disorder (PTSD), depression, and thoughts of suicide. Single-center data from the emergency department (ED) demonstrate an event rate for AWP factors higher than that reported from the operating room. However, there remains a lack of data on AWP among critically ill, mechanically ventilated patients. The objective was to assess the proportion of ED patients experiencing AWP and investigate modifiable variables associated with its occurrence. DESIGN: An a priori planned secondary analysis of a multicenter, prospective, before-and-after clinical trial. SETTING: The ED of three academic medical centers. PATIENTS: Mechanically ventilated adult patients that received neuromuscular blockers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All data related to sedation and analgesia were collected. AWP was the primary outcome, assessed with the modified Brice questionnaire, and was independently adjudicated by three expert reviewers. Perceived threat, in the causal pathway for PTSD, was the secondary outcome. A total of 388 patients were studied. The proportion of patients experiencing AWP was 3.4% ( n = 13), the majority of whom received rocuronium ( n = 12/13; 92.3%). Among patients who received rocuronium, 5.5% ( n = 12/230) experienced AWP, compared with 0.6% ( n = 1/158) among patients who did not receive rocuronium in the ED (odds ratio, 8.64; 95% CI, 1.11-67.15). Patients experiencing AWP had a higher mean ( sd ) threat perception scale score, compared with patients without AWP (15.6 [5.8] vs 7.7 [6.0]; p < 0.01). CONCLUSIONS: AWP was present in a concerning proportion of mechanically ventilated ED patients, was associated with rocuronium exposure in the ED, and led to increased levels of perceived threat, placing patients at greater risk for PTSD. Studies that aim to further quantify AWP in this vulnerable population and eliminate its occurrence are urgently needed.

The Feasibility of Implementing Targeted SEDation in Mechanically Ventilated Emergency Department Patients: The ED-SED Pilot Trial.

OBJECTIVES: Deep sedation in the emergency department (ED) is common, increases deep sedation in the ICU, and is negatively associated with outcome. Limiting ED deep sedation may, therefore, be a high-yield intervention to improve outcome. However, the feasibility of conducting an adequately powered ED-based clinical sedation trial is unknown. Our objectives were to assess trial feasibility in terms of: 1) recruitment, 2) protocol implementation and practice change, and 3) safety. Patient-centered clinical outcomes were assessed to better plan for a future large-scale clinical trial. DESIGN: Pragmatic, multicenter ( n = 3), prospective before-after pilot and feasibility trial. SETTING: The ED and ICUs at three medical centers. PATIENTS: Consecutive, adult mechanically ventilation ED patients. INTERVENTIONS: An educational initiative aimed at reliable ED sedation depth documentation and reducing the proportion of deeply sedated patients (primary outcome). MEASUREMENTS AND MAIN RESULTS: Sedation-related data in the ED and the first 48 ICU hours were recorded. Deep sedation was defined as a Richmond Agitation-Sedation Scale of -3 to -5 or a Sedation-Agitation Scale of 1-3. One thousand three hundred fifty-six patients were screened; 415 comprised the final population. Lighter ED sedation was achieved in the intervention group, and the proportion of deeply sedated patients was reduced from 60.2% to 38.8% ( p < 0.01). There were no concerning trends in adverse events (i.e., inadvertent extubation, device removal, and awareness with paralysis). Mortality was 10.0% in the intervention group and 20.4% in the preintervention group ( p < 0.01). Compared with preintervention, the intervention group experienced more ventilator-free days [22.0 (9.0) vs 19.9 (10.6)] and ICU-free days [20.8 (8.7) vs 18.1 (10.4)], p < 0.05 for both. CONCLUSIONS: This pilot trial confirmed the feasibility of targeting the ED in order to improve sedation practices and reduce deep sedation. These findings justify an appropriately powered clinical trial regarding ED-based sedation to improve clinical outcomes.

The ED-AWARENESS Study: A Prospective, Observational Cohort Study of Awareness With Paralysis in Mechanically Ventilated Patients Admitted From the Emergency Department.

STUDY OBJECTIVE: Awareness with paralysis is a devastating complication for patients receiving mechanical ventilation and risks long-term psychological morbidity. Data from the emergency department (ED) demonstrate a high rate of longer-acting neuromuscular blocking agent use, delayed analgosedation, and a lack of sedation depth monitoring. These practices are discordant with recommendations for preventing awareness with paralysis. Despite this, awareness with paralysis has not been rigorously studied in the ED population. Our objective is to assess the prevalence of awareness with paralysis in ED patients receiving mechanical ventilation. METHODS: This was a single-center, prospective, observational cohort study on 383 mechanically ventilated ED patients. After extubation, we assessed patients for awareness with paralysis by using the modified Brice questionnaire. Three expert reviewers independently adjudicated awareness with paralysis. We report the prevalence of awareness with paralysis (primary outcome); the secondary outcome was perceived threat, a mediator for development of posttraumatic stress disorder. RESULTS: The prevalence of awareness with paralysis was 2.6% (10/383). Exposure to rocuronium at any point in the ED was significantly different between patients who experienced awareness with paralysis (70%) versus the rest of the cohort (31.4%) (unadjusted odds ratio 5.1; 95% confidence interval 1.30 to 20.1). Patients experiencing awareness with paralysis had higher mean values on the threat perception scale, denoting a higher degree of perceived threat, compared with patients who did not experience awareness with paralysis (13.4 [SD 7.7] versus 8.5 [SD 6.2]; mean difference 4.9; 95% confidence interval 0.94 to 8.8). CONCLUSION: Awareness with paralysis occurs in a significant minority of ED patients who receive mechanical ventilation. Potential associations of awareness with paralysis with ED care and increased perceived threat warrant further evaluation.

IL-10 Has Differential Effects on the Innate and Adaptive Immune Systems of Septic Patients.

Sepsis, a disease of divergent pro- and anti-inflammatory-mediated pathways, has a high prevalence of morbidity and mortality, yet an understanding of potential unifying mediators between these pathways that may improve clinical outcomes is largely unclear. IL-10 has classically been designated an immunosuppressive cytokine, although recent data suggest that under certain conditions IL-10 can be immune stimulatory. We sought to further investigate the effect of IL-10 on innate and adaptive immunity in an in vitro human observational cohort study in patients with sepsis via modulation of IL-10 on IFN-γ production by T cells and TNF-α production and HLA-DR expression by monocytes. These results were compared with critically ill nonseptic patients and healthy volunteers. ELISpot analysis was performed using PBMC fraction from patient whole-blood samples. Finally, to provide additional potential clinical relevance, we examined the effect of IL-10 on T cell IFN-γ production in an in vivo cecal ligation and puncture model of sepsis using C57 black/J6 female mice. We found that inhibition of IL-10 significantly increased both production of T cell IFN-γ and monocyte TNF-α, whereas addition of IL-10 increased T cell IFN-γ production but decreased monocyte production of TNF-α and HLA-DR expression. There was no significant effect of IL-10 on control cohorts. IL-10-treated septic mice demonstrated increased IFN-γ production in splenocytes. Thus, IL-10 demonstrates both pro- and anti-inflammatory effects in the septic microenvironment, which is likely cell and context dependent. Further elucidation of relevant signaling pathways may direct future therapeutic targets.

Association Between Partial Pressure of Arterial Carbon Dioxide and Survival to Hospital Discharge Among Patients Diagnosed With Sepsis in the Emergency Department.

OBJECTIVE: The objective of this study was to test the association between the partial pressure of arterial carbon dioxide and survival to hospital discharge among mechanically ventilated patients diagnosed with sepsis in the emergency department. DESIGN: Retrospective cohort study of a single center trial registry. SETTING: Academic medical center. PATIENTS: Mechanically ventilated emergency department patients. INCLUSION CRITERIA: age 18 years and older, diagnosed with sepsis in the emergency department, and mechanical ventilation initiated in the emergency department. INTERVENTIONS: Arterial blood gases obtained after initiation of mechanical ventilation were analyzed. The primary outcome was survival to hospital discharge. We tested the association between partial pressure of arterial carbon dioxide and survival using multivariable logistic regression adjusting for potential confounders. Sensitivity analyses, including propensity score matching were also performed. MEASUREMENTS AND MAIN RESULTS: Six hundred subjects were included, and 429 (72%) survived to hospital discharge. The median (interquartile range) partial pressure of arterial carbon dioxide was 42 (34-53) mm Hg for the entire cohort and 44 (35-57) and 39 (31-45) mm Hg among survivors and nonsurvivors, respectively (p < 0.0001 Wilcox rank-sum test). On multivariable analysis, a 1 mm Hg rise in partial pressure of arterial carbon dioxide was associated with a 3% increase in odds of survival (adjusted odds ratio, 1.03; 95% CI, 1.01-1.04) after adjusting for tidal volume and other potential confounders. These results remained significant on all sensitivity analyses. CONCLUSION: In this sample of mechanically ventilated sepsis patients, we found an association between increasing levels of partial pressure of arterial carbon dioxide and survival to hospital discharge. These findings justify future studies to determine the optimal target partial pressure of arterial carbon dioxide range for mechanically ventilated sepsis patients.

Thirty-day hospital readmissions among mechanically ventilated emergency department patients.

BACKGROUND: Unplanned 30-day readmissions have a negative impact on patients and healthcare systems. Mechanically ventilated ED patients are at high risk for complications, but factors associated with readmission are unknown. OBJECTIVE: (1) Determine the rate of 30-day hospital readmission for ED patients receiving mechanical ventilation. (2) Identify associations between ED-based risk factors and readmission. DESIGN: Retrospective cohort study. SETTING: Tertiary-care, academic medical centre. PATIENTS: Adult ED patients receiving mechanical ventilation. MEASUREMENTS: Baseline demographics, comorbid conditions, illness severity and treatment variables were collected, as were clinical outcomes occurring during the index hospitalisation. The primary outcome was 30-day hospital readmission rate. Multivariable logistic regression was used to evaluate factors associated with the primary outcome. RESULTS: A total of 1262 patients were studied. The primary outcome occurred in 287 (22.7%) patients. There was no association between care in the ED and readmission. During the index hospitalisation, readmitted patients had shorter ventilator, hospital and intensive care unit duration (P<0.05 for all). The primary outcome was associated with African-American race (adjusted OR 1.34 (95% CI 1.02 to 1.78)), chronic obstructive pulmonary disease (adjusted OR 1.52 (95% CI 1.12 to 2.06)), diabetes mellitus (adjusted OR 1.34 (95% CI 1.02 to 1.78)) and higher illness severity (adjusted OR 1.03 (95% CI 1.01 to 1.05)). CONCLUSIONS: Almost one in four mechanically ventilated ED patients are readmitted within 30 days, and readmission is associated with patient-level and institutional-level factors. Strategies must be developed to identify, treat and coordinate care for the most at-risk patients.

Diagnostic Accuracy of Central Venous Catheter Confirmation by Bedside Ultrasound Versus Chest Radiography in Critically Ill Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: We performed a systematic review and meta-analysis to examine the accuracy of bedside ultrasound for confirmation of central venous catheter position and exclusion of pneumothorax compared with chest radiography. DATA SOURCES: PubMed, Embase, Cochrane Central Register of Controlled Trials, reference lists, conference proceedings and ClinicalTrials.gov. STUDY SELECTION: Articles and abstracts describing the diagnostic accuracy of bedside ultrasound compared with chest radiography for confirmation of central venous catheters in sufficient detail to reconstruct 2 × 2 contingency tables were reviewed. Primary outcomes included the accuracy of confirming catheter positioning and detecting a pneumothorax. Secondary outcomes included feasibility, interrater reliability, and efficiency to complete bedside ultrasound confirmation of central venous catheter position. DATA EXTRACTION: Investigators abstracted study details including research design and sonographic imaging technique to detect catheter malposition and procedure-related pneumothorax. Diagnostic accuracy measures included pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio. DATA SYNTHESIS: Fifteen studies with 1,553 central venous catheter placements were identified with a pooled sensitivity and specificity of catheter malposition by ultrasound of 0.82 (0.77-0.86) and 0.98 (0.97-0.99), respectively. The pooled positive and negative likelihood ratios of catheter malposition by ultrasound were 31.12 (14.72-65.78) and 0.25 (0.13-0.47). The sensitivity and specificity of ultrasound for pneumothorax detection was nearly 100% in the participating studies. Bedside ultrasound reduced mean central venous catheter confirmation time by 58.3 minutes. Risk of bias and clinical heterogeneity in the studies were high. CONCLUSIONS: Bedside ultrasound is faster than radiography at identifying pneumothorax after central venous catheter insertion. When a central venous catheter malposition exists, bedside ultrasound will identify four out of every five earlier than chest radiography.

Antipyretic Therapy in Critically Ill Septic Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: This meta-analysis aimed to examine the impact of antipyretic therapy on mortality in critically ill septic adults. DATA SOURCES: Literature searches were implemented in Ovid Medline, Embase, Scopus, Cumulative Index of Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, and ClinicalTrials.gov through February 2016. STUDY SELECTION: Inclusion criteria were observational or randomized studies of septic patients, evaluation of antipyretic treatment, mortality reported, and English-language version available. Studies were excluded if they enrolled pediatric patients, patients with neurologic injury, or healthy volunteers. Criteria were applied by two independent reviewers. DATA EXTRACTION: Two reviewers independently extracted data and evaluated methodologic quality. Outcomes included mortality, frequency of shock reversal, acquisition of nosocomial infections, and changes in body temperature, heart rate, and minute ventilation. Randomized and observational studies were analyzed separately. DATA SYNTHESIS: Eight randomized studies (1,507 patients) and eight observational studies (17,432 patients) were analyzed. Antipyretic therapy did not reduce 28-day/hospital mortality in the randomized studies (relative risk, 0.93; 95% CI, 0.77-1.13; I = 0.0%) or observational studies (odds ratio, 0.90; 95% CI, 0.54-1.51; I = 76.1%). Shock reversal (relative risk, 1.13; 95% CI, 0.68-1.90; I = 51.6%) and acquisition of nosocomial infections (relative risk, 1.13; 95% CI, 0.61-2.09; I = 61.0%) were also unchanged. Antipyretic therapy decreased body temperature (mean difference, -0.38°C; 95% CI, -0.63 to -0.13; I = 84.0%), but not heart rate or minute ventilation. CONCLUSIONS: Antipyretic treatment does not significantly improve 28-day/hospital mortality in adult patients with sepsis.

A Quasi-Experimental, Before-After Trial Examining the Impact of an Emergency Department Mechanical Ventilator Protocol on Clinical Outcomes and Lung-Protective Ventilation in Acute Respiratory Distress Syndrome.

OBJECTIVES: To evaluate the impact of an emergency department mechanical ventilation protocol on clinical outcomes and adherence to lung-protective ventilation in patients with acute respiratory distress syndrome. DESIGN: Quasi-experimental, before-after trial. SETTING: Emergency department and ICUs of an academic center. PATIENTS: Mechanically ventilated emergency department patients experiencing acute respiratory distress syndrome while in the emergency department or after admission to the ICU. INTERVENTIONS: An emergency department ventilator protocol which targeted variables in need of quality improvement, as identified by prior work: 1) lung-protective tidal volume, 2) appropriate setting of positive end-expiratory pressure, 3) oxygen weaning, and 4) head-of-bed elevation. MEASUREMENTS AND MAIN RESULTS: A total of 229 patients (186 preintervention group, 43 intervention group) were studied. In the emergency department, the intervention was associated with significant changes (p < 0.01 for all) in tidal volume, positive end-expiratory pressure, respiratory rate, oxygen administration, and head-of-bed elevation. There was a reduction in emergency department tidal volume from 8.1 mL/kg predicted body weight (7.0-9.1) to 6.4 mL/kg predicted body weight (6.1-6.7) and an increase in lung-protective ventilation from 11.1% to 61.5%, p value of less than 0.01. The intervention was associated with a reduction in mortality from 54.8% to 39.5% (odds ratio, 0.38; 95% CI, 0.17-0.83; p = 0.02) and a 3.9 day increase in ventilator-free days, p value equals to 0.01. CONCLUSIONS: This before-after study of mechanically ventilated patients with acute respiratory distress syndrome demonstrates that implementing a mechanical ventilator protocol in the emergency department is feasible and associated with improved clinical outcomes.

Lung-Protective Ventilation Initiated in the Emergency Department (LOV-ED): A Quasi-Experimental, Before-After Trial.

STUDY OBJECTIVE: We evaluated the efficacy of an emergency department (ED)-based lung-protective mechanical ventilation protocol for the prevention of pulmonary complications. METHODS: This was a quasi-experimental, before-after study that consisted of a preintervention period, a run-in period of approximately 6 months, and a prospective intervention period. The intervention was a multifaceted ED-based mechanical ventilator protocol targeting lung-protective tidal volume, appropriate setting of positive end-expiratory pressure, rapid oxygen weaning, and head-of-bed elevation. A propensity score-matched analysis was used to evaluate the primary outcome, which was the composite incidence of acute respiratory distress syndrome and ventilator-associated conditions. RESULTS: A total of 1,192 patients in the preintervention group and 513 patients in the intervention group were included. Lung-protective ventilation increased by 48.4% in the intervention group. In the propensity score-matched analysis (n=490 in each group), the primary outcome occurred in 71 patients (14.5%) in the preintervention group compared with 36 patients (7.4%) in the intervention group (adjusted odds ratio 0.47; 95% confidence interval [CI] 0.31 to 0.71). There was an increase in ventilator-free days (mean difference 3.7; 95% CI 2.3 to 5.1), ICU-free days (mean difference 2.4; 95% CI 1.0 to 3.7), and hospital-free days (mean difference 2.4; 95% CI 1.2 to 3.6) associated with the intervention. The mortality rate was 34.1% in the preintervention group and 19.6% in the intervention group (adjusted odds ratio 0.47; 95% CI 0.35 to 0.63). CONCLUSION: Implementing a mechanical ventilator protocol in the ED is feasible and is associated with significant improvements in the delivery of safe mechanical ventilation and clinical outcome.

T cells from patients with Candida sepsis display a suppressive immunophenotype.

BACKGROUND: Despite appropriate therapy, Candida bloodstream infections are associated with a mortality rate of approximately 40%. In animal models, impaired immunity due to T cell exhaustion has been implicated in fungal sepsis mortality. The purpose of this study was to determine potential mechanisms of fungal-induced immunosuppression via immunophenotyping of circulating T lymphocytes from patients with microbiologically documented Candida bloodstream infections. METHODS: Patients with blood cultures positive for any Candida species were studied. Non-septic critically ill patients with no evidence of bacterial or fungal infection were controls. T cells were analyzed via flow cytometry for cellular activation and for expression of positive and negative co-stimulatory molecules. Both the percentages of cells expressing particular immunophenotypic markers as well as the geometric mean fluorescence intensity (GMFI), a measure of expression of the number of receptors or ligands per cell, were quantitated. RESULTS: Twenty-seven patients with Candida bloodstream infections and 16 control patients were studied. Compared to control patients, CD8 T cells from patients with Candidemia had evidence of cellular activation as indicated by increased CD69 expression while CD4 T cells had decreased expression of the major positive co-stimulatory molecule CD28. CD4 and CD8 T cells from patients with Candidemia expressed markers typical of T cell exhaustion as indicated by either increased percentages of or increased MFI for programmed cell death 1 (PD-1) or its ligand (PD-L1). CONCLUSIONS: Circulating immune effector cells from patients with Candidemia display an immunophenotype consistent with immunosuppression as evidenced by T cell exhaustion and concomitant downregulation of positive co-stimulatory molecules. These findings may help explain why patients with fungal sepsis have a high mortality despite appropriate antifungal therapy. Development of immunoadjuvants that reverse T cell exhaustion and boost host immunity may offer one way to improve outcome in this highly lethal disorder.

Comparison of monocyte human leukocyte antigen-DR expression and stimulated tumor necrosis factor alpha production as outcome predictors in severe sepsis: a prospective observational study.

BACKGROUND: Identifying patients in the immunosuppressive phase of sepsis is essential for development of immunomodulatory therapies. Little data exists comparing the ability of the two most well-studied markers of sepsis-induced immunosuppression, human leukocyte antigen (HLA)-DR expression and lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-ɑ) production, to predict mortality and morbidity. The purpose of this study was to compare HLA-DR expression and LPS-induced TNF-ɑ production as predictors of 28-day mortality and acquisition of secondary infections in adult septic patients. METHODS: A single-center, prospective observational study of 83 adult septic patients admitted to a medical or surgical intensive care unit. Blood samples were collected at three time points during the septic course (days 1-2, days 3-4, and days 6-8 after sepsis diagnosis) and assayed for HLA-DR expression and LPS-induced TNF-ɑ production. A repeated measures mixed model analysis was used to compare values of these immunological markers among survivors and non-survivors and among those who did and did not develop a secondary infection. RESULTS: Twenty-five patients (30.1 %) died within 28 days of sepsis diagnosis. HLA-DR expression was significantly lower in non-survivors as compared to survivors on days 3-4 (p = 0.04) and days 6-8 (p = 0.002). The change in HLA-DR from days 1-2 to days 6-8 was also lower in non-survivors (p = 0.04). Median HLA-DR expression decreased from days 1-2 to days 3-4 in patients who developed secondary infections while it increased in those without secondary infections (p = 0.054). TNF-ɑ production did not differ between survivors and non-survivors or between patients who did and did not develop a secondary infection. CONCLUSIONS: Monocyte HLA-DR expression may be a more accurate predictor of mortality and acquisition of secondary infections than LPS-stimulated TNF-ɑ production in adult medical and surgical critically ill patients.

The presence of hypothermia within 24 hours of sepsis diagnosis predicts persistent lymphopenia.

OBJECTIVE: To determine whether hypothermia within 24 hours of sepsis diagnosis is associated with development of persistent lymphopenia, a feature of sepsis-induced immunosuppression. DESIGN: Retrospective cohort study. SETTING: A 1,200-bed university-affiliated tertiary care hospital. PATIENTS: Adult patients diagnosed with bacteremia and sepsis within 5 days of hospital admission between January 1, 2010, and July 31, 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Leukocyte counts were recorded during the first 4 days following sepsis diagnosis. Persistent lymphopenia was defined as an absolute lymphocyte count less than 1.2 cells/µL×10(3) present on the fourth day after diagnosis. Of the 445 patients with sepsis included, hypothermia developed in 64 patients (14.4%) (defined as a body temperature<36.0°C) within 24 hours of sepsis diagnosis. Hypothermia was a significant independent predictor of persistent lymphopenia (adjusted odds ratio, 2.70 [95% CI, 1.10, 6.60]; p=0.03) after accounting for age, disease severity, comorbidities, source of bacteremia, and type of organism. Compared with the nonhypothermic patients, hypothermic patients had higher 28-day (50.0% vs 24.9%, p<0.001) and 1-year mortality (60.9% vs 47.0%, p=0.001). CONCLUSIONS: Hypothermia is associated with higher mortality and an increased risk of persistent lymphopenia in patients with sepsis, and it may be an early clinical predictor of sepsis-induced immunosuppression.