Future Sepsis Research Articles

Metabolic resuscitation in pediatric sepsis: a narrative review.

Sepsis, defined as infection with associated organ dysfunction, accounts for most childhood deaths due to infection globally. Evidence for the optimal support of children with septic shock refractory to the initial sepsis management bundle remains minimal. There is an urgent need for more effective interventions. Administration of hydrocortisone in children with septic shock might fasten shock resolution, and has been shown to dampen the systemic host immune response, augment adrenergic effects, and support the stress response. Ascorbic acid (vitamin C) is one of the most powerful naturally occurring antioxidants and has beneficial effects on multiple pathways which are severely deranged during septic shock. A regimen combining hydrocortisone, ascorbic acid, and thiamine termed “metabolic resuscitation” or “HAT therapy” has been tested in large trials in critically ill adults with sepsis with conflicting results. Available information on intravenous ascorbic acid indicates an excellent safety profile even at very high doses both in adults and children. Given the pharmacological properties and beneficial effects shown both in vitro and in animal studies, and its safety profile, ascorbic acid either as a single therapy or as part of HAT treatment represents a promising candidate for future pediatric sepsis treatments. While pediatric age groups may be more susceptible to ascorbic acid deficiency during sepsis, there is a lack of high-quality trial data on HAT therapy in this age group. A single centre retrospective study identified potential for mortality benefit in children with septic shock, and the results from a randomized controlled pilot trial are being awaited. It is imperative for pediatric research on ascorbic acid and HAT in children with sepsis to critically investigate key questions related to pharmacology, dosing, timing, feasibility, safety, effects on short- and long-term outcomes, and generalisability in view of the global burden of sepsis.

Children with appendectomy have increased risk of future sepsis: Real-world data in Taiwan.

Appendectomy is one of the most commonly performed surgeries worldwide. Sepsis is a major aetiology of morbidity and mortality in children. Our preliminary research revealed a positive correlation amongst appendectomy and future risk of sepsis in adults. However, to date, the relationship between appendectomy and future risk of sepsis in children remains unknown. The aim of this research was to investigate the relationship between appendectomy and the hazard of future sepsis in children. We applied a nationwide population-based cohort to assess whether children who received appendectomy were at increased risk of subsequent sepsis. Overall, 57261 subjects aged below 18 undergoing appendectomy as appendectomy group and 57261 matched controls were identified as a non-appendectomy group from the National Health Insurance Research Database in Taiwan. We use propensity score analysis to match the age, sex, urbanisation level and parental occupation at the ratio to 1:1. Multiple Cox regression and stratified analyses were used to appraise the adjusted hazard ratio (aHR) for developing sepsis in children. Children who received appendectomy had a 2.38 times higher risk (aHR: 2.38; 95% confidence interval [CI]=1.98, 2.87) of developing sepsis than those who did not, and the risk was higher in all age groups (aHR: 2.98, 95% CI=1.84, 4.83; aHR: 2.45, 95% CI=1.08, 2.05; aHR: 2.18, 95% CI=1.70, 2.80 in children aged <6, 7-12 and 13-18years, respectively). Patients with <1-year follow-up showed a 4.53-fold risk of sepsis in the appendectomy cohort (aHR: 4.53, 95% CI=2.80, 7.35). Patients with 1-4 and ≥5years' follow-up showed a 2.19- and 1.94-times risk of sepsis (aHR: 2.19, 95% CI=1.61, 2.97; aHR: 1.94, 95% CI=1.48, 2.56 in 1-4 and >5years, respectively). Appendectomy was correlative to a 2.38-fold increased future sepsis risk in children, and the risk in all age groups was higher. More studies to interpret the possible biological mechanisms of the associations amongst sepsis and appendectomy are warranted.

Are we overlooking the rural patient journey when it comes to sepsis diagnosis and management?

Surviving Sepsis Campaign guidelines have progressively moved towards faster time-based treatment targets over recent years despite international data consistently showing low protocol adherence. A key stakeholder in Australian healthcare remains overlooked in sepsis research: the under-resourced rural ED. The journey of the rural patient markedly differs to that of the metropolitan patient, involving greater reliance upon patient transfers, reduced staffing and resource inaccessibility, directly impacting on sepsis protocol adherence and patient outcomes. Greater representation of rural patients and EDs in Australian sepsis research is paramount in guiding future sepsis treatment protocols. This perspective piece explores current international sepsis literature, recognising significant barriers to sepsis protocol adherence specific to rural Australian EDs.

TLR4 and TNFR1 blockade dampen M1 macrophage activation and shifts them towards an M2 phenotype.

The Gram-negative bacterial lipopolysaccharide (LPS)-induced sepsis has emerged as major concern worldwide due to the pressing need to develop its effective treatment strategies which is not available yet. LPS is the major causative agent in the pathogenesis of septic shock. In macrophages, LPS interacts with cell surface TLR4 leading to reactive oxygen species (ROS), TNF-α, IL-1β production, oxidative stress and markedly activated the MAPKs and NF-kB pathway. Post cell isolation, the macrophages were subjected to administration with neutralizing antibodies to TLR4 and TNFR1 either alone or in combination prior to LPS challenge. Subsequently, we performed flow cytometric analysis along with Western blots, reactive oxygen species production, and TNF-α, IL-1β release. Outcomes suggested that the dual blockade of TLR4 and TNFR1 was indeed beneficial in shifting the LPS-induced M1 polarization towards M2. Both TLR4 and TNFR1 exhibited dependency during LPS stimulation. Furthermore, the switch towards the M2 phenotype might be responsible for the decreased levels of TNF-α, IL-1β, NO, and superoxide anion and the simultaneous elevation in the activity level of anti-oxidant enzymes like SOD, CAT (catalase), and GSH content in the isolated peritoneal macrophages. Simultaneous blocking of both TLR4 and TNFR1 also showed reduced expression of NF-kB, JNK, and COX-2 by promoting TNFR2-mediated TNF-α signaling. The increased arginase activity further confirmed the polarization towards M2. Thus it may be inferred that dual blockade of TLR4 and TNFR1 might be an alternative therapeutic approach for regulating of sepsis in future.

Therapeutic Potential of Extracellular Vesicles for Sepsis Treatment.

Sepsis is a deadly condition lacking a specific treatment despite decades of research. This has prompted the exploration of new approaches, with extracellular vesicles (EVs) emerging as a focal area. EVs are nanosized, cell-derived particles that transport bioactive components (i.e., proteins, DNA, and RNA) between cells, enabling both normal physiological functions and disease progression depending on context. In particular, EVs have been identified as critical mediators of sepsis pathophysiology. However, EVs are also thought to constitute the biologically active component of cell-based therapies and have demonstrated anti-inflammatory, anti-apoptotic, and immunomodulatory effects in sepsis models. The dual nature of EVs in sepsis is explored here, discussing their endogenous roles and highlighting their therapeutic properties and potential. Related to the latter component, prior studies involving EVs from mesenchymal stem/stromal cells (MSCs) and other sources are discussed and emerging producer cells that could play important roles in future EV-based sepsis therapies are identified. Further, how methodologies could impact therapeutic development toward sepsis treatment to enhance and control EV potency is described.

Targeting Toll-Like Receptors in Sepsis: From Bench to Clinical Trials.

Significance: Sepsis is a critical clinical syndrome with life-threatening organ dysfunction induced by a dysregulated host response to infection. Despite decades of intensive research, sepsis remains a leading cause of in-hospital mortality with few specific treatments. Recent Advances: Toll-like receptors (TLRs) are a part of the innate immune system and play an important role in host defense against invading pathogens such as bacteria, virus, and fungi. Using a combination of genetically modified animal models and pharmacological agents, numerous preclinical studies during the past two decades have demonstrated that dysregulated TLR signaling may contribute to sepsis pathogenesis. However, many clinical trials targeting inflammation and innate immunity such as TLR4 have yielded mixed results. Critical Issues: Here we review various TLRs and the specific molecules these TLRs sense-both the pathogen-associated and host-derived stress molecules, and their converging signaling pathways. We critically analyze preclinical investigations into the role of TLRs in animal sepsis, the complexity of targeting TLRs for sepsis intervention, and the disappointing clinical trials of the TLR4 antagonist eritoran. Future Directions: Future sepsis treatments will depend on better understanding the complex biological mechanisms of sepsis pathogenesis, the high heterogeneity of septic humans as defined by clinical presentations and unique immunological biomarkers, and improved stratifications for targeted interventions.

T cell cytokines in the diagnostic of early-onset sepsis.

Early-onset sepsis (EOS) remains a substantial cause of morbidity and mortality among neonates. Yet, currently available biological parameters have not proven to be accurate enough to predict EOS reliably. This study aimed to determine serum concentrations of 13 cytokines in umbilical cord blood and evaluate their diagnostic value for EOS. A prospective single-center study that included analysis of umbilical cord blood of term and preterm neonates who were born from March 2017 to November 2017. Using ELISA analysis, 13 cytokines were simultaneously quantified and correlated with the development of EOS. Four hundred and seventy-four neonates were included, of which seven met the criteria for culture-positive EOS. Interleukin (IL)-6 (p < 0.001), IL-9 (p = 0.003), and IL-21 (p < 0.001) were significantly increased in neonates with EOS compared to controls. Sensitivity and specificity for IL-6, IL-9, and IL-21 at the defined cut-off points were 85.7 and 77.3%, 71.4 and 62.5%, and 71.4 and 52.0%, respectively. In neonates with EOS, IL-9 and IL-21 are significantly elevated and may be employed in the diagnostic of EOS. However, diagnostic accuracy remains lower than with IL-6. Values of 13 T cell cytokines may be used as reference values for future studies in neonates. Interleukin-9 (IL-9) and interleukin-21 (IL-21) are significantly elevated in neonates with early-onset sepsis. IL-9 and IL-21 have been shown to play a specific role in neonatal sepsis. Neonatal reference values were generated for several cytokines. IL-9 and IL-21 might be attractive biomarkers for neonatal sepsis in future. This study is likely to promote further research in this area. Values of several T cell cytokines may be used as reference values for future studies in neonates.

Effect of obesity and body mass index on coronavirus disease 2019 severity: A systematic review and meta-analysis.

We conducted a systematic review of observational studies to examine the effects of body mass index (BMI) and obesity (BMI ≥ 30 kg/m2 ) on coronavirus disease 2019 (COVID-19). Medline, Embase, and the Cochrane Library were searched. Sixteen articles were finally included in the meta-analysis, and a random effects model was used. BMI was found to be higher in patients with severe disease than in those with mild or moderate disease (MD 1.6, 95% CI, 0.8-2.4; p = .0002) in China; however, the heterogeneity was high (I2 = 75%). Elevated BMI was associated with invasive mechanical ventilation (IMV) use (MD 4.1, 95% CI, 2.1-6.1; p < .0001) in Western countries, and this result was consistent across studies (I2 = 0%). Additionally, there were increased odds ratios of IMV use (OR 2.0, 95% CI, 1.4-2.9; p < .0001) and hospitalization (OR 1.4, 95% CI, 1.3-1.60; p < .00001) in patients with obesity. There was no substantial heterogeneity (I2 = 0%). In conclusion, obesity or high BMI increased the risk of hospitalization, severe disease and invasive mechanical ventilation in COVID-19. Physicians must be alert to these early indicators to identify critical patients.

Levels of mannose-binding lectin (MBL) associates with sepsis-related in-hospital mortality in women

BackgroundMannose-binding lectin (MBL) mediates the innate immune response either through direct opsonisation of microorganisms or through activation of the complement system. There are conflicting data whether MBL deficiency leads to increased susceptibility to infections or not. The aim of this study was to determine if low levels of mannose-binding lectin (MBL) predict sepsis development, sepsis severity and outcome from severe sepsis or septic shock.MethodPatients aged 18 years or more with documented sepsis within 24 h after admission to the intensive care unit were included if they had participated in a health survey and donated blood samples prior to the sepsis event. A subset of these patients had stored plasma also from the acute phase. Two matched referents free of known sepsis were selected for each case. Plasma levels MBL were determined in stored samples from health surveys (baseline) and from ICU admission (acute phase). The association between MBL and sepsis, sepsis severity and in-hospital mortality were determined with 1300 ng/mL as cut-off for low levels.ResultsWe identified 148 patients (61.5% women) with a first-time sepsis event 6.5 years (median with IQR 7.7) after participation in a health survey, of which 122 also had samples from the acute septic phase. Both high MBL levels in the acute phase (odds ratio [95% confidence interval]) (2.84 [1.20–6.26]), and an increase in MBL levels from baseline to the acute phase (3.76 [1.21–11.72]) were associated with increased risk for in-hospital death in women, but not in men (0.47 [0.11–2.06]). Baseline MBL levels did not predict future sepsis, sepsis severity or in-hospital mortality.ConclusionsAn increase from baseline to the acute phase as well as high levels in the acute phase associated with an unfavourable outcome in women.

Temporal trend and survival impact of infection source among patients with sepsis: a nationwide study

To determine the temporal trends of incidence and outcome based on different sources of sepsis using a nationwide administrative database. From 2002 to 2012, the entire Taiwan's health insurance claims data of emergency-treated and hospital-treated sepsis were analysed for incidence and mortality trends. The information about patients with sepsis and sources of sepsis was identified using a set of validated International Classification of Diseases, ninth revision, clinical modification (ICD-9-CM) codes. The 30-day all-cause mortality was verified by linked death certificate database. A total of 1 259 578 episodes of sepsis were identified during the 11-year study period. Lower respiratory tract infection is the most common source of sepsis in patients, with the highest mortality rate. The incidence of genitourinary tract infection has the fastest growing rate. The sepsis mortality was declining at different rates for each source of sepsis. Co-infections in patients with sepsis are associated with higher mortality rate. The temporal trends of sepsis incidence and mortality varied among different sources of sepsis, with lower respiratory tract being the highest burden among patients with sepsis. Furthermore, sources of sepsis and the presence of co-infection are independent predictors of mortality. Our results support source-specific preventive and treatment strategies for future sepsis management.

The early change of SOFA score as a prognostic marker of 28-day sepsis mortality: analysis through a derivation and a validation cohort

BackgroundSince the Sepsis-3 criteria, change in Sequential Organ Failure Assessment (SOFA) score has become a key component of sepsis identification. Thus, it could be argued that reversal of this change (ΔSOFA) may reflect sepsis response and could be used as measure of efficacy in interventional trials. We aimed to assess the predictive performance of ΔSOFA for 28-day mortality.MethodsData from two previously published randomized controlled trials were studied: the first reporting on patients with severe Gram-negative infections as a derivation cohort and the second reporting on patients with ventilator-associated pneumonia as a validation cohort. Only patients with sepsis according to the Sepsis-3 definition were included in this analysis. SOFA scores were calculated on days 1, 2, 3, 5, 7, 14, and 28.ResultsWe included 448 patients within the derivation cohort and 199 within the validation cohort. Mean SOFA scores on day 1 were 6.06 ± 4.07 and 7.84 ± 3.39, and 28 day mortality 22.8% and 29.6%, respectively. In the derivation cohort, the earliest time point where ΔSOFA score predicted mortality was day 7 (AUROC (95% CI) 0.84 (0.80–0.89); p < 0.001). The best tradeoff for prediction was found with 25% changes (78% sensitivity, 80% specificity); less than 25% decrease of admission SOFA was associated with increased mortality (odds ratio for death 14.87). This finding was confirmed in the validation cohort.ConclusionsΔSOFA on day 7 is a useful early prognostic marker of 28-day mortality and could serve as an endpoint in future sepsis trials alongside mortality.Trial registrationClinicalTrials.gov numbers NCT01223690 and NCT00297674

Population enrichment for critical care trials: phenotypes and differential outcomes.

Sepsis and acute respiratory distress syndrome (ARDS) are two heterogenous acute illnesses where numerous RCTs have indeterminate results. We present a narrative review on the recent developments in enriching patient populations for future sepsis and ARDS trials. Many researchers are actively pursuing enrichment strategies to reduce heterogeneity to increase the sensitivity of future trials. Enrichment refers to the use of measurable patient characteristics, known before randomisation, to refine trial populations. Biomarkers could increase the diagnostic certainty of sepsis, whereas chest radiology training to enhance reliability of interpretation and stabilisation period of mechanical ventilation have been considered to increase the diagnostic certainty of ARDS. Clinical and biomarker data analyses identifies four to six sepsis clinical phenotypes and two ARDS clinical phenotypes. Similarly, leukocyte gene expression data identifies two to four sepsis molecular phenotypes. Use of a test-dose identifies ARDS subpopulations who are likely to benefit from higher PEEP. Early-phase trials report how a biomarker that is altered by the intervention, such as lymphocyte count for recombinant interleukin-7 therapy and higher check point inhibitor expression for anti-check point treatments in sepsis, could identify a higher treatment effect population for future trials. Enrichment reduces heterogeneity and will enhance the sensitivity of future trials. However, enrichment, even when it identifies more homogenous populations, may not be efficient to deploy in trials or clinical practice.

Robustness of sepsis-3 criteria in critically ill patients

BackgroundEarly recognition of sepsis is challenging, and diagnostic criteria have changed repeatedly. We assessed the robustness of sepsis-3 criteria in intensive care unit (ICU) patients.MethodsWe studied the apparent incidence and associated mortality of sepsis-3 among patients who were prospectively enrolled in the Molecular Diagnosis and Risk Stratification of Sepsis (MARS) cohort in the Netherlands, and explored the effects of minor variations in the precise definition and timing of diagnostic criteria for organ failure.ResultsAmong 1081 patients with suspected infection upon ICU admission, 648 (60%) were considered to have sepsis according to prospective adjudication in the MARS study, whereas 976 (90%) met sepsis-3 criteria, yielding only 64% agreement at the individual patient level. Among 501 subjects developing ICU-acquired infection, these rates were 270 (54%) and 260 (52%), respectively (yielding 58% agreement). Hospital mortality was 234 (36%) vs 277 (28%) for those meeting MARS-sepsis or sepsis-3 criteria upon presentation (p < 0.001), and 121 (45%) vs 103 (40%) for those having sepsis onset in the ICU (p < 0.001). Minor variations in timing and interpretation of organ failure criteria had a considerable effect on the apparent prevalence of sepsis-3, which ranged from 68 to 96% among those with infection at admission, and from 22 to 99% among ICU-acquired cases.ConclusionThe sepsis-3 definition lacks robustness as well as discriminatory ability, since nearly all patients presenting to ICU with suspected infection fulfill its criteria. These should therefore be specified in greater detail, and applied more consistently, during future sepsis studies.Trial registrationThe MARS study is registered at ClinicalTrials.gov (identifier NCT 01905033).

Pathophysiologic Characterization of a Novel Rabbit Model of Biliary Tract Infection-Derived Sepsis

Biliary tract infection (BTI)-derived sepsis remains a serious problem with significant morbidity and mortality in the modern era of critical care management. Current animal models of BTI have relied mostly on injecting purified bacteria or their toxins into the biliary tract. These models do not fully reflect pathophysiology or disease processes of clinical cholangitis or cholecystitis. In the current study, we developed a novel model of BTI by performing cholecystocolonic anastomosis (CCA) in rabbits and characterized pathophysiologic changes in this model. This model is intended to mimic the clinical process of cholecystocolonic fistula with reflux cholangitis, a severe form of BTI. Adult male rabbits were subjected to BTI-derived sepsis through an anastomosis of the gall bladder to the colon (i.e., CCA). The animals were monitored for 7 days to record survival. In additional groups of animals, various bacterial, hemodynamic, histological and biochemical parameters were measured at 12, 24, 48 and 72 h after CCA. The anastomosis between the gallbladder and the colon required about 5–8 min to finish. The median survival time for rabbits after CCA was 96 h. The positive rates of bacterial culture at 72 h after CCA were 83.3% and 100% in the blood and liver, respectively. The most common microorganism was Escherichia coli followed by Enterococcus. Plasma Tumor Necrosis Factor-α (TNF-α), Lnterleukin-10 (IL-10), Lnterleukin-6 (IL-6), and High-mobility group box 1 protein (HMGB-1) levels were greatly elevated after CCA. The cardiac index and heart rate increased slightly at 12 h after CCA and then continued to decrease. Systemic hypotension developed 48 h after CCA. Histological studies showed reflux cholangitis with acute lung and kidney injury. Cholecystocolonic anastomosis produces polymicrobial sepsis in rabbits, which mimics many aspects of human BTI-derived sepsis. It is reproducible and easy to perform and may serve as an excellent model for future sepsis research.

Necrostatin-1 accelerates time to death in a rat model of cecal ligation and puncture and massively increases hepatocyte caspase-3 cleavage.

Necroptosis, a form of regulated necrosis, has been reported to be involved in numerous pathologies, including sepsis. However, a protective effect of the selective inhibitor of necroptosis, necrostatin-1 (Nec-1), against sepsis remains to be confirmed. Animals (rats and mice) were subjected to cecal ligation and puncture (CLP) to mimic clinical sepsis. Nec-1 or its vehicle (control) was administered 20 min before CLP. Survival time was observed up to 72 h after CLP. Specimens of liver tissue and serum were obtained at 6 h, 12 h, and 18 h. Expression of necroptosis-related proteins [receptor-interacting protein kinase (RIP)1, RIP3, and mixed lineage kinase domain-like (MLKL)] was determined by Western blot analysis. The RIP1/RIP3 interaction and the recruitment of MLKL to RIP3 were also analyzed. Liver function, histopathological changes, serum inflammation cytokines, TUNEL staining, and the expression of apoptosis-related protein, including caspase-3, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X (Bax), was determined. As expected, Nec-1 administration reduced the expression of necroptosis-related proteins and the RIP1/RIP3 interaction, indicating inhibited necroptosis. Surprisingly, Nec-1 treatment exacerbated the liver injury and shortened survival time of septic rats with increased TUNEL-positive cells, cleaved caspase-3 protein content, and Bax/Bcl-2 ratio. Collectively, these findings show that Nec-1 administration inhibited the hepatocyte necroptosis pathway but accelerated apoptosis via the apoptotic pathway in CLP-induced sepsis rat. NEW & NOTEWORTHY The present study demonstrated that a chemical inhibitor necrostatin-1 (Nec-1) or receptor-interacting protein kinase(RIP1) knock down targeted at necroptosis inhibition accelerated liver injury of following sepsis. For fundamental research, these results warrant further investigation of the potential link between Nec-1 administration and the cellular apoptosis following sepsis induced liver injury. For applied research, these results suggest the potential harmful effect of Nec-1 on future sepsis treatment.

Enhanced Screening and Research Data Collection via Automated EHR Data Capture and Early Identification of Sepsis.

Clinical research in sepsis patients often requires gathering large amounts of longitudinal information. The electronic health record can be used to identify patients with sepsis, improve participant study recruitment, and extract data. The process of extracting data in a reliable and usable format is challenging, despite standard programming language. The aims of this project were to explore infrastructures for capturing electronic health record data and to apply criteria for identifying patients with sepsis. We conducted a prospective feasibility study to locate and capture/abstract electronic health record data for future sepsis studies. We located parameters as displayed to providers within the system and then captured data transmitted in Health Level Seven® interfaces between electronic health record systems into a prototype database. We evaluated our ability to successfully identify patients admitted with sepsis in the target intensive care unit (ICU) at two cross-sectional time points and then over a 2-month period. A majority of the selected parameters were accessible using an iterative process to locate and abstract them to the prototype database. We successfully identified patients admitted to a 20-bed ICU with sepsis using four data interfaces. Retrospectively applying similar criteria to data captured for 319 patients admitted to ICU over a 2-month period was less sensitive in identifying patients admitted directly to the ICU with sepsis. Classification into three admission categories (sepsis, no-sepsis, and other) was fair (Kappa .39) when compared with manual chart review. This project confirms reported barriers in data extraction. Data can be abstracted for future research, although more work is needed to refine and create customizable reports. We recommend that researchers engage their information technology department to electronically apply research criteria for improved research screening at the point of ICU admission. Using clinical electronic health records data to classify patients with sepsis over time is complex and challenging.

Advances in sepsis induced immunosuppression and immunomodulation therapy

Immunosuppression plays a vital role in the pathophysiological mechanism of sepsis, and it is the main cause of death in patients with sepsis during the later phase. Sepsis induced immunosuppression is gradually recognized. Its underlying mechanisms involve immune cell apoptosis, autophagy, cell metabolism reprogramming, endotoxin tolerance, central nervous system regulation, and epigenetic regulation. New approaches that target the host immune response and reconstruct the immune balance are the keys to improve the prognosis of patients with sepsis. With the help of immune status monitor, novel immunomodulatory agents, such as thymosin α1, γ- interferon (IFN-γ), interleukin-7 (IL-7), granulocyte-macrophage colony stimulating factor (GM-CSF) and anti-programmed death receptor 1 (PD-1) antibody, are expected to become a new strategy for the treatment of sepsis in future.

Association mapping in biomedical time series via statistically significant shapelet mining.

MotivationMost modern intensive care units record the physiological and vital signs of patients. These data can be used to extract signatures, commonly known as biomarkers, that help physicians understand the biological complexity of many syndromes. However, most biological biomarkers suffer from either poor predictive performance or weak explanatory power. Recent developments in time series classification focus on discovering shapelets, i.e. subsequences that are most predictive in terms of class membership. Shapelets have the advantage of combining a high predictive performance with an interpretable component—their shape. Currently, most shapelet discovery methods do not rely on statistical tests to verify the significance of individual shapelets. Therefore, identifying associations between the shapelets of physiological biomarkers and patients that exhibit certain phenotypes of interest enables the discovery and subsequent ranking of physiological signatures that are interpretable, statistically validated and accurate predictors of clinical endpoints.ResultsWe present a novel and scalable method for scanning time series and identifying discriminative patterns that are statistically significant. The significance of a shapelet is evaluated while considering the problem of multiple hypothesis testing and mitigating it by efficiently pruning untestable shapelet candidates with Tarone’s method. We demonstrate the utility of our method by discovering patterns in three of a patient’s vital signs: heart rate, respiratory rate and systolic blood pressure that are indicators of the severity of a future sepsis event, i.e. an inflammatory response to an infective agent that can lead to organ failure and death, if not treated in time.Availability and implementationWe make our method and the scripts that are required to reproduce the experiments publicly available at https://github.com/BorgwardtLab/S3M.Supplementary information Supplementary data are available at Bioinformatics online.

Lymphocyte subset expression and serum concentrations of PD-1/PD-L1 in sepsis - pilot study

BackgroundSepsis remains a major cause of mortality in critical care, for which specific treatments are lacking. The dysregulated response to infection seen in sepsis includes features of lymphocyte dysfunction and exhaustion, suggesting that immune-stimulatory therapy may improve outcomes in certain patient groups. Monoclonal antibodies targeting checkpoint molecules, such as programmed-death 1 protein (PD-1) and its ligand PD-L1, have shown success in stimulating the immune response in patients with cancer, and are being considered for future sepsis trials. The aims of this pilot study were to compare lymphocyte subset expression of PD-1 and its ligands between patients with sepsis and controls; to characterize serum levels of PD-1 and PD-L1 in patients with sepsis and controls, and determine if serum concentrations correlated with cell surface expression.MethodsExpression levels of PD-1, PD-L1 and PD-L2 on four lymphocyte subsets (CD27 + CD19+ B cells, CD27-CD19+ B cells, CD27 + CD4+ T cells and CD27-CD4+ T cells) were compared between 22 patients with sepsis (including 11 survivors and 11 non-survivors) and 11 healthy controls using flow cytometry. Levels of soluble PD-1 and PD-L1 were also compared using commercially available ELISA kits.ResultsExpression of PD-1 and PD-L1 was higher on all lymphocyte subsets in patients with sepsis compared to controls (p < 0.05). PD-L2 expression on CD27+ B cells was also higher in patients with sepsis (p = 0.0317). There was differential expression of PD-1 by CD27 status, with expression being higher in the B and T cell subsets associated with memory status (CD27+ and CD27-, respectively; p < 0.001). Higher PD-1 and PD-L1 expression was not associated with mortality or with a higher risk of nosocomial infection. There were no differences in levels of soluble PD-1 or PD-L1 between patients with sepsis and controls.ConclusionsHigher expression of PD-1 by memory subpopulations of B cells and CD4+ T cells, with normal soluble PD-1 and PD-L1 in patients with sepsis, are novel findings. This information may be useful to enrich sepsis populations for trials of PD-1/PD-L1 blockade.

The effect of community socioeconomic status on sepsis-attributable mortality

PurposeCommunity factors may play a role in determining individual risk for sepsis, as well as sepsis-related morbidity and mortality. We sought to define the relationship between community socioeconomic status and mortality due to sepsis in an urban locale. MethodsUsing community statistical areas of Baltimore City, we dichotomized neighborhoods at median household income, and compared distribution of outcomes of interest within the two income categories. We performed multivariable regression analyses to determine the relationship between socioeconomic variables and sepsis-attributable mortality. ResultsThe collective median household income was $38,660 (IQR $32,530, 54,480), family poverty rate was 28.4% (IQR 13.5, 38.8%), and rate of death from sepsis was 3.1 per 10,000 persons (IQR 2.60, 4.10). Lower household income communities demonstrated higher rates of death from sepsis (3.65 (IQR 2.78, 4.40)) than higher household income communities (2.80 (IQR 2.05, 3.55)) (p = .02). In regression models, household income (β = −8.42, p = .006) and percentage of poverty in communities (β = 2.71, p = .01) demonstrated associations with sepsis-attributable mortality. DiscussionOur findings suggest that socioeconomic variables play significant role in sepsis-attributable mortality. Such confirmation of regional disparities in mortality due to sepsis warrants further consideration, as well as integration, for future national sepsis policies.