The pediatric sepsis biomarker risk model: potential implications for sepsis therapy and biology

Sepsis remains a major cause of morbidity and mortality in adult and pediatric intensive care units. Heterogeneity of demographics, comorbidities, biological mechanisms, and severity of illness leads to difficulty in determining which patients are at highest risk of mortality. Determining mortality risk is important for weighing the potential benefits of more aggressive interventions and for deciding whom to enroll in clinical trials. Biomarkers can be used to parse patients into different risk categories and can outperform current methods of patient risk stratification based on physiologic parameters. Here we review the Pediatric Sepsis Biomarker Risk Model that has also been modified and applied to estimate mortality risk in adult patients. We compare the two models and speculate on the biological implications of the biomarkers in patients with sepsis.     

前肾上腺髓质素作为脓毒症危险分层新标志物的探讨

目的 探讨前肾上腺髓质素(pro-ADM)在脓毒症预测和危险分层中的价值.方法 采用前瞻性分析方法将51例入住重症加强治疗病房的危重病患者按国际脓毒症标准分为全身炎症反应综合征(SIRS)组(25例)、脓毒症组(12例)、严重脓毒症组(9例)、脓毒性休克组(5例)4组.取静脉血,采用新型夹心免疫荧光测量法检测pro-ADM浓度,并与急性生理学与慢性健康状况评分系统I(APACHE I)评分及降钙素原(PCT)、C-反应蛋白(CRP)和白细胞介素-6(IL-6)水平相比较.结果 ①SIRS组、脓毒症组、严重脓毒症组、脓毒性休克组血浆pro-ADM浓度逐渐升高,分别为0.34、2.23、4.57和8.21 μg/L,其中以脓毒性休克组pro-ADM浓度最高(P均＜0.05);②在所有脓毒症患者中,与其他标志物相比,死亡患者的pro-ADM浓度比存活患者明显升高(2.01 μg/L比9.75 μg/L,P＜0.05),APACHE I评分也明显升高(23.44分比38.21分,P＜0.05);③在脓毒症存活患者的受试者工作特征曲线分析中,pro-ADM、PCT、APACHE I评分的曲线下面积(分别为0.87、0.81和0.81)较CRP和IL-6(分别为0.53和0.71)明显增多.结论 pro-ADM浓度测定在脓毒症的预测和危险分层中是一个新的有用的标志物.     

The study on pro-adrenomedullin as a new biomarker in sepsis prognosis and risk stratification

OBJECTIVE: To assess the clinical value of pro-adrenomedullin (pro-ADM) in the prognosis and risk stratification in sepsis. METHODS: Fifty-one critically ill patients admitted to the intensive care unit (ICU) were prospectively stratified into four groups according to internationally recognized criteria: systemic inflammatory response syndrome (SIRS, 25 cases), sepsis (12 cases), severe sepsis (9 cases) and septic shock (5 cases). The levels of plasma pro-ADM was determined in every patient using a new sandwich immunoassay, and compared with procalcitonin (PCT), C-reactive protein (CRP) and interleukin-6 (IL-6), and the acute physiology and chronic health evaluation II (APACHEII) score. RESULTS: (1) Median pro-ADM concentration was 0.34 mug/L for SIRS, 2.23 mug/L for sepsis, 4.57 mug/L for severe sepsis and 8.21 mug/L for septic shock. The plasma concentration of pro-ADM exhibited a gradual increase, and the median pro-ADM value was highest in the septic shock group (all P<0.05). (2) Compared with the other biomarkers, in the sepsis, severe sepsis and septic shock groups, the plasma concentration of pro-ADM and APACHEII score in the non-survivors was significantly higher than in the survivors (pro-ADM: 2.01 mug/L vs. 9.75 mug/L, APACHEII score: 23.44 scores vs. 38.21 scores, both P<0.05). (3) By the receiver operating characteristic (ROC) curve plot analysis of pro-ADM in sepsis, the area under the ROC curve for pro-ADM (0.87) in survivors was similar to the area under the ROC curve for PCT (0.81) and APACHEII score (0.81), and was significantly higher than the area under the ROC curve for CRP (0.53) and IL-6 (0.71). CONCLUSION: The measurement of pro-ADM is a new and useful marker in sepsis prognosis and risk strafification.     

Presepsin as a novel sepsis biomarker

BACKGROUND:

In 2004, a new biomarker sCD14-subtypes (presepsin) was found and its value was shown in the diagnosis and evaluation of sepsis. This article is a brief overview of the new biomarker.

DATA SOURCES:

A literature search using multiple databases was performed for articles, especially meta-analyses, systematic reviews, and randomized controlled trials.

RESULTS:

Compared with other markers, presepsin seems to have a better sensitivity and specificity in the diagnosis of sepsis. Presepsin as a biom1arker is not only suitable for the early diagnosis of sepsis, but also for the assessment of its severity and prognosis.

CONCLUSIONS:

Presepsin has a higher sensitivity and specificity in the diagnosis of sepsis as a new biomarker, and is a predictor for the prognosis of sepsis. More importantly, preseptin seems to play a crucial role as a supplemental method in the early diagnosis of sepsis. Since there is no multicenter study on the relationship between presepsin and sepsis, further studies on the clinical values of presepsin are needed.KEYWORDS: Presepsin, Sepsis, Diagnosis     

Development of metabolic and inflammatory mediator biomarker phenotyping for early diagnosis and triage of pediatric sepsis

IntroductionThe first steps in goal-directed therapy for sepsis are early diagnosis followed by appropriate triage. These steps are usually left to the physician’s judgment, as there is no accepted biomarker available. We aimed to determine biomarker phenotypes that differentiate children with sepsis who require intensive care from those who do not.MethodsWe conducted a prospective, observational nested cohort study at two pediatric intensive care units (PICUs) and one pediatric emergency department (ED). Children ages 2–17 years presenting to the PICU or ED with sepsis or presenting for procedural sedation to the ED were enrolled. We used the judgment of regional pediatric ED and PICU attending physicians as the standard to determine triage location (PICU or ED). We performed metabolic and inflammatory protein mediator profiling with serum and plasma samples, respectively, collected upon presentation, followed by multivariate statistical analysis.ResultsNinety-four PICU sepsis, 81 ED sepsis, and 63 ED control patients were included. Metabolomic profiling revealed clear separation of groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.89, area under the receiver operating characteristic curve (AUROC) of 0.96 (standard deviation [SD] 0.01), and predictive ability (Q²) of 0.60. Protein mediator profiling also showed clear separation of the groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.78 and AUROC of 0.88 (SD 0.03). Combining metabolomic and protein mediator profiling improved the model (Q² =0.62), differentiating PICU sepsis from ED sepsis with accuracy of 0.87 and AUROC of 0.95 (SD 0.01). Separation of PICU sepsis or ED sepsis from ED controls was even more accurate. Prespecified age subgroups (2–5 years old and 6–17 years old) improved model accuracy minimally. Seventeen metabolites or protein mediators accounted for separation of PICU sepsis and ED sepsis with 95 % confidence.ConclusionsIn children ages 2–17 years, combining metabolomic and inflammatory protein mediator profiling early after presentation may differentiate children with sepsis requiring care in a PICU from children with or without sepsis safely cared for outside a PICU. This may aid in making triage decisions, particularly in an ED without pediatric expertise. This finding requires validation in an independent cohort.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-1026-2) contains supplementary material, which is available to authorized users.     

Rapid diagnosis of sepsis using biomarker signatures

Diagnosis of sepsis is complicated by non-specific clinical definitions and delays in laboratory analysis using tests which may have very poor predictive values. The use of host biomarker signature sets, which when measured in combination have high predictive values, offers a paradigm shift forwards for rapid, near-patient diagnosis. These analyses more closely mirror the rapid blood chemistry and hematology analyses which often are used for near-patient testing and diagnosis.Diagnosis of severe sepsis is one area in which a laboratory confirmation could positively affect patient management but, owing to a lack of clear correlation between single biomarkers and disease, is often of little value. Sepsis is a significant health issue in many countries where invasive surgical procedures, for example, have become more frequent. Over 170 different biomarkers have been described as either diagnostic or prognostic for sepsis, but clinical trials in which these biomarkers are evaluated singly often give relatively low positive predictive value outcomes and tests based upon single biomarkers are therefore of limited value since diagnosis is made using clinical observations, and prophylactic antimicrobial therapy often is used as a preventative measure in case of infectious etiology.

Biomarker signatures

Recent discovery work on diagnostic biomarkers for sepsis concentrates efforts on two different approaches; the first is on using multiple host biomarker changes to define a ‘signature’ which is indicative of disease. In the previous issue of Critical Care, Ware and colleagues describe a clinical study using multiple host biomarkers to aid diagnosis of acute respiratory distress syndrome (ARDS), a particular complication of sepsis which is often under-diagnosed because of the difficulties in applying a non-specific definition of disease [1]. All of the patients enrolled in this clinical study had a diagnosis of severe sepsis, and 50% also met the definition of ARDS.Host biomarker signatures with potential for use as laboratory diagnostic markers can be either proteins which are easily measured, as in this case, or nucleic acids. The latter approach was recently described by Ma and colleagues [2], and microRNAs were sequenced and used to provide signature sequences which were shown to clearly distinguish between sepsis and systemic inflammatory response syndrome. The alternative to measuring changes in host biomarker(s) is the direct detection of the pathogen; one of the key microbiological analyses recommended for diagnosis of severe sepsis is the collection of blood cultures prior to commencement of broad-spectrum antimicrobial therapy and isolation of the pathogen [3] or detection of the pathogen nucleic acids by polymerase chain reaction assay. The direct detection of pathogens or nucleic acids in samples often provides little guidance to the clinician because of either delays while samples are transported to and analyzed in the laboratory or the sometimes low positive predictive value of such analyses which, therefore, cannot be used definitively as ‘rule out’ diagnostics.Although a number of sepsis diagnostic kits based on single biomarkers are commercially available, the value of the results obtained is limited and often does not clearly inform patient management. Here is the opportunity for biomarker signature sets. The advent of rapid diagnostic platforms means that, to start with, multiple biomarkers can be analyzed in parallel in a reproducible and rapid manner; such technologies have been available for blood chemistry and hematology for many years now, and it is high time microbiology caught up. Measurement of host biomarkers more closely resembles the analyses which are performed by clinical chemistry and hematology labs and which frequently are performed in intensive treatment units so that patient management can be rapidly changed on the basis of the results obtained. The major problem with measurement of host biomarkers and their ultimate use as diagnostic or prognostic indicators of infectious disease is not one of technologies, as these are plentiful, but of data interpretation. The difficulty arises not from the absolute measurement of such serum biomarkers, as described by Ware and colleagues [1], as this is very straightforward, but in analysis and assignment of a positive or negative test result, which is where the work now needs to be done. As we know, single biomarkers are often of low predictive value in the diagnosis of complicated conditions such as sepsis, not because they are difficult parameters to measure, but because it is not always clear when a biomarker is elevated (and when it is not) when used in the outbred population that humans are. The same issue of data interpretation occurs with analysis of multiple biomarkers, as an elevated level of a single biomarker can be abnormal in one person but normal in another. However, this is where the signature approach comes in; a large number of both ‘normal’ (that is, healthy) patient samples as well as samples from those diagnosed and proven to have the condition under investigation (in this case, sepsis) need to be analyzed and these data then need to be used to set the cutoff values for each biomarker and for the signature set so that high positive predictive and negative predicative values can be accurately assigned. The ability to rapidly measure multiple biomarkers, coupled with well-validated data sets, not only means that diagnosis of sepsis can for the first time be moved nearer to the patient but also has high value in subsequent patient management and therefore prognosis.     

Apolipoprotein M - a new biomarker in sepsis

ABSTRACT: Sepsis is one of the leading causes of mortality in non-cardiac intensive care units, and the need for markers of progression and severity are high. Also, treatment of sepsis is highly debated and potential new targets of treatment are of great interest. In the previous issue of Critical Care Kumaraswamy and colleagues have investigated whether plasma apolipoprotein M (apoM) is affected during different grades of sepsis, septic shock and systemic inflammatory response syndrome. Interestingly, plasma apoM was significantly decreased in all groups of patients with a relationship to severity of disease. This identifies apoM as a potential new biomarker in sepsis. It also underscores the possibility that altered high-density lipoprotein in sepsis patients can affect the course of disease. Thus, since apoM is the carrier of Sphingosine-1-P (S1P), a molecule with great influence on vascular barrier function, the study presented raises the interest and relevance for further studies of apoM and S1P in relation to sepsis and inflammation.     

《2004严重感染和感染性休克治疗指南》系列讲座(8)儿科严重感染的治疗

严重感染和感染性休克是以全身性感染导致器官功能损害为特征的复杂临床综合征。近年来，抗感染和器官功能支持技术虽然取得了长足的进步，但严重感染发病率和病死率仍居高不下。面对严重感染和感染性休克的严峻形势，在拯救全身性感染运动(SSC，2002年10月由欧洲危重病医学会和国际感染论坛发起)的倡导下，来自11个国际组织的专家以循证医学为基础制订了《成人和儿科重症感染治疗指南》，旨在改善严重感染和感染性休克患者的预后。     

Prognostic markers of pediatric meningococcal sepsis

Having available tools to determine the prognosis of pediatric meningococcal sepsis at admission to the Intensive Care Unit or during the course of the disease constitutes a clinical necessity. Recently, new readily measurable circulating biomarkers have been described as an additional tool for severity classification and prediction of mortality in meningococcal disease. These biomarkers have been associated with increased risk of mortality scores and a number of organ failures in heterogeneous samples of critically ill children. In future, genetic markers may be used for identification of high-risk patients by creating prediction rules for clinical course and sequelae, and potentially provide more insight in the complex immune response in meningococcal sepsis. We briefly summarize the data pointing at the emerging genome-wide expression profiling studies and review the prognostic value of the main markers investigated in pediatric meningococcal sepsis putting them in the current frame of sepsis in general.     

Blood transfusions are associated with increased risk for development of sepsis in severely burned pediatric patients

OBJECTIVE: To determine the risk of developing sepsis following transfusion of blood products in severely burned pediatric patients. DESIGN: Retrospective, cohort study. SETTING: Shriners Hospital for Children and University Hospital. PATIENTS: Severely burned pediatric patients with >30% total body surface area (TBSA) burn. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred seventy-seven pediatric burn patients over a period of 7 yrs (1997-2004) were included in the study, with 25 patients being septic at admission and therefore excluded. Patients were stratified according to TBSA burn and presence or absence of inhalation injury. The amounts of packed red blood cells (RBCs) and fresh frozen plasma (FFP) were recorded during hospital stay before the development of sepsis. Blood product administration was normalized for the number of surgeries and divided into two groups: high (RBCs>20/FFP>5) or low (RBCs<20/FFP<5) amount of blood products. Sepsis was diagnosed based on the criteria set by the Society of Critical Care Medicine in conjunction with positive blood culture or presence of organisms in the organs at autopsy. By stratifying the groups into low and high blood transfusion, we found that patients with >60% TBSA burn with inhalation injury have an 8% risk of developing sepsis in the low RBC group, which increases to 58% in the high RBC group (p<.05). Similar results were found for RBCs per operation, FFP, and FFP per operation (p<.05). There were no differences in age and gender between groups. CONCLUSIONS: Pediatric burn suffering from a 60% TBSA burn with concomitant inhalation injury are more likely to develop sepsis if they are given high amounts of blood products, indicating an immunocompromised state following blood transfusion.     

Biomarkers for pediatric sepsis and septic shock

Sepsis is a clinical syndrome defined by physiologic changes indicative of systemic inflammation, which are likely attributable to documented or suspected infection. Septic shock is the progression of those physiologic changes to the extent that delivery of oxygen and metabolic substrate to tissues is compromised. Biomarkers have the potential to diagnose, monitor, stratify and predict outcome in these syndromes. C-reactive protein is elevated in inflammatory and infectious conditions and has long been used as a biomarker indicating infection. Procalcitonin has more recently been shown to better distinguish infection from inflammation. Newer candidate biomarkers for infection include IL-18 and CD64. Lactate facilitates the diagnosis of septic shock and the monitoring of its progression. Multiple stratification biomarkers based on genome-wide expression profiling are under active investigation and present exciting future possibilities.     

The influence of early hemodynamic optimization on biomarker patterns of severe sepsis and septic shock

BACKGROUND: Despite abundant experimental studies of biomarker patterns in early severe sepsis and septic shock, human data are few. Further, the impact of the severity of global tissue hypoxia resulting from resuscitative strategies on these early biomarker patterns remains unknown. METHODS: The temporal patterns of interleukin-1 receptor antagonist, intercellular adhesion molecule-1, tumor necrosis factor-alpha, caspase-3, and interleukin-8 were serially examined over the first 72 hrs of hospitalization after early hemodynamic optimization strategies of early goal-directed vs. standard therapy for severe sepsis and septic shock patients. The relationship of these biomarker patterns to each hemodynamic optimization strategy, severity of global tissue hypoxia (reflected by lactate and central venous oxygen saturation), organ dysfunction, and mortality were examined. RESULTS: Abnormal biomarker levels were present upon hospital presentation and modulated to distinct patterns within 3 hrs based on the hemodynamic optimization strategy. The temporal expression of these patterns over 72 hrs was significantly associated with the severity of global tissue hypoxia, organ dysfunction, and mortality. CONCLUSION: In early severe sepsis and septic shock, within the first 3 hrs of hospital presentation, distinct biomarker patterns emerge in response to hemodynamic optimization strategies. A significant association exists between temporal biomarker patterns in the first 72 hrs, severity of global tissue hypoxia, organ dysfunction, and mortality. These findings identify global tissue hypoxia as an important contributor to the early inflammatory response and support the role of hemodynamic optimization in supplementing other established therapies during this diagnostic and therapeutic "window of opportunity."     

儿童脓毒症诊治研究进展

脓毒症是全球范围内造成儿童死亡的重要因素之一.儿童脓毒症的病原学特点、临床表现及治疗手段与成人脓毒症不尽相同,故详细了解儿童脓毒症的特点有助于早期识别和集束化管理脓毒症,从而进一步改善脓毒症患儿的预后,降低病死率.     

Protein C as an early biomarker to distinguish pneumonia from sepsis

Purpose

Patients with pneumonia often are unrecognized as also having sepsis. We evaluated protein C, as a potential biomarker, to differentiate between patients with pneumonia and sepsis.

Materials and Methods

A retrospective chart review was performed for all protein C tests over a 14-month period (January 11, 2007, to March 10, 2008) at an 8-hospital system with 1706 total beds. Charts were screened for the discharge diagnoses of sepsis, severe sepsis, septic shock, bacteremia, and pneumonia. Protein C levels were compared between patients with sepsis and pneumonia, and at time intervals of 0 to 12 hours, 12 to 24 hours, 24 to 48 hours, and more than 48 hours after diagnosis.

Results

One thousand forty-seven protein C levels were obtained in 980 patients. Thirty-two protein C levels met the inclusion and exclusion criteria for the sepsis group, and 34 for the pneumonia group. Overall, the mean protein C levels were significantly less in patients with sepsis at 59.2% (95% confidence interval [CI], 49.5%-68.9%) compared with patients with pneumonia at 108.9% (95% CI, 95.6%-122.3%; P < .001). In addition, levels within each of the time intervals were also significantly lower in the sepsis group.

Conclusions

In this study, protein C levels performed well in differentiating between patients with sepsis or pneumonia in the early period after diagnosis.     

The FOOTPRINTS model of pediatric palliative care

Little is known about the optimal context in which to provide care for the more than 53,000 children who die each year in the United States. Poor training in pediatric palliative care contributes to care that is often fragmented and may neglect the physical, psychosocial, and spiritual needs of the child and family. Pediatric hospice care is frequently not available or not chosen by the family or health care providers. In response to a critical need to move beyond the disease oriented, hospital-based model with a lack of continuity between hospital and community-based medical services, we developed FOOTPRINTS, an innovative program of advanced care planning and care coordination. A continuity physician directs the treatment plan regardless of site of care. Staff members coordinate follow up and communication among hospital and community-based care providers. Spiritual support continues through bereavement. Education in the hospital and community supports provision of excellent palliative care by current providers. Satisfaction with this model of care has been high. More than 90% of health care providers and families perceived that the child and family needs as well as the health care provider needs were met by the advanced care planning process and written care plan. All continuity providers would refer another patient. The FOOTPRINTS program promotes quality of care and family and health care provider satisfaction with care. It has been developed to serve as a "best practice" model for care at life's end.     

Novel biomarker for predicting sepsis mortality: vitamin D receptor

ObjectiveThere are currently no studies on the role of vitamin D receptor (VDR) levels as a cause of or risk factor for sepsis. We aimed to establish the association between VDR levels and 28-day mortality in critically ill patients with sepsis.MethodsThis prospective cross-sectional observational study included 148 patients diagnosed with sepsis who were treated in the intensive care unit. We measured VDR levels, laboratory characteristics, and health scores and related them to survival.ResultsThe 148 patients included 96 survivors and 52 non-survivors, with VDR levels of 1.92 and 1.36 ng/mL, respectively. Baseline VDR was a significant predictor of 28-day mortality, with an area under the curve of 0.778. A low VDR level was significantly associated with lower overall survival in patients with sepsis according to Kaplan–Meier curve analysis. VDR levels were also negatively correlated with lactate, C-reactive protein, acute physiological and clinical health evaluation (APACHE) II and sequential organ failure assessment (SOFA) scores, and disease severity.ConclusionsVDR levels were associated with high 28-day mortality and negatively correlated with lactate, C-reactive protein, APACHE II and SOFA scores, and disease severity in patients with sepsis. VDR levels can predict poor outcomes in patients with sepsis.