Sepsis biomarkers can have important diagnostic, therapeutic, and prognostic functions. In a previous review, we identified 3370 references reporting on 178 different biomarkers related to sepsis. In the present review, we evaluate the progress in the research of sepsis biomarkers. Using the same methodology as in our previous review, we searched the PubMed database from 2009 until September 2019 using the terms “Biomarker” AND “Sepsis.” There were no restrictions by age or language, and all studies, clinical and experimental, were included. We retrieved a total of 5367 new references since our previous review. We identified 258 biomarkers, 80 of which were new compared to our previous list. The majority of biomarkers have been evaluated in fewer than 5 studies, with 81 (31%) being assessed in just a single study. Apart from studies of C-reactive protein (CRP) or procalcitonin (PCT), only 26 biomarkers have been assessed in clinical studies with more than 300 participants. Forty biomarkers have been compared to PCT and/or CRP for their diagnostic value; 9 were shown to have a better diagnostic value for sepsis than either or both of these biomarkers. Forty-four biomarkers have been evaluated for a role in answering a specific clinical question rather than for their general diagnostic or prognostic properties in sepsis. The number of biomarkers being identified is still increasing although at a slower rate than in the past. Most of the biomarkers have not been well-studied; in particular, the clinical role of these biomarkers needs to be better evaluated.

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Biomarkers of sepsis: time for a reappraisal

The vascular blood-brain barrier is a highly regulated interface between the blood and brain. Its primary function is to protect central neurons while signaling the presence of systemic inflammation and infection to the brain to enable a protective sickness behavior response. With increasing degrees and duration of systemic inflammation, the vascular blood-brain barrier becomes more permeable to solutes, undergoes an increase in lymphocyte trafficking, and is infiltrated by innate immune cells; endothelial cell damage may occasionally occur. Perturbation of neuronal function results in the clinical features of encephalopathy. Here, the molecular and cellular anatomy of the vascular blood-brain barrier is reviewed, first in a healthy context and second in a systemic inflammatory context. Distinct from the molecular and cellular mediators of the blood-brain barrier's response to inflammation, several moderators influence the direction and magnitude at genetic, system, cellular and molecular levels. These include sex, genetic background, age, pre-existing brain pathology, systemic comorbidity, and gut dysbiosis. Further progress is required to define and measure mediators and moderators of the blood-brain barrier's response to systemic inflammation in order to explain the heterogeneity observed in animal and human studies.

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The blood-brain barrier in systemic infection and inflammation.

A biomarker describes a measurable indicator of a patient's clinical condition that can be measured accurately and reproducibly. Biomarkers offer utility for diagnosis, prognosis, early disease recognition, risk stratification, appropriate treatment (theranostics), and trial enrichment for patients with sepsis or suspected sepsis. In this narrative review, we aim to answer the question, "Do biomarkers in patients with sepsis or septic shock predict mortality, multiple organ dysfunction syndrome (MODS), or organ dysfunction?" We also discuss the role of pro- and anti-inflammatory biomarkers and biomarkers associated with intestinal permeability, endothelial injury, organ dysfunction, blood-brain barrier (BBB) breakdown, brain injury, and short and long-term mortality. For sepsis, a range of biomarkers is identified, including fluid phase pattern recognition molecules (PRMs), complement system, cytokines, chemokines, damage-associated molecular patterns (DAMPs), non-coding RNAs, miRNAs, cell membrane receptors, cell proteins, metabolites, and soluble receptors. We also provide an overview of immune response biomarkers that can help identify or differentiate between systemic inflammatory response syndrome (SIRS), sepsis, septic shock, and sepsis-associated encephalopathy. However, significant work is needed to identify the optimal combinations of biomarkers that can augment diagnosis, treatment, and good patient outcomes. 

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Biomarkers for sepsis: more than just fever and leukocytosis—a narrative review

Sepsis-associated cerebral dysfunction is complex pathophysiology, generated from primary infections that are developed elsewhere in the body. The neonates, elderly population and chronically ill and long-term hospitalized patients are predominantly vulnerable to sepsis and related cerebral damage. Generally, electrophysiological recordings, severity and sedation scales, computerized imaging and spectroscopy techniques are used for its detection and diagnosis. About the underlying mechanisms, enhanced blood-brain barrier permeability and metalloprotease activity, tight junction protein loss and endothelial cell degeneration promote the influx of inflammatory and toxic mediators into the brain, triggering cerebrovascular damage. An altered neutrophil count and phenotype further dysregulate the normal neuroimmune responses and neuroendocrine stability via modulated activation of protein kinase C-delta, nuclear factor kappa-B and sphingolipid signaling. Glial activation, together with pro-inflammatory cytokines and chemokines and the Toll-like receptor, destabilize the immune system. Moreover, superoxides and hydroperoxides generate oxidative stress and perturb mitochondrial dynamics and ATP synthesis, propagating neuronal injury cycle. Activated mitochondrial apoptotic pathway, characterized by increased caspase-3 and caspase-9 cleavage and Bax/Bcl2 ratio in the hippocampal and cortical neurons, stimulate neurocognitive impairments. Additionally, altered LC3-II/I and P62/SQSTM1, p-mTOR, p-AMPK1 and p-ULK1 levels and dysregulated autophagosome-lysosome fusion decrease neuronal and glial energy homeostasis. The therapies and procedures for attenuating sepsis-induced brain damage include early resuscitation, cerebral blood flow autoregulation, implantable electric vagus nerve stimulation, antioxidants, statins, glucocorticoids, neuroimmune axis modulators and PKCδ inhibitors. The current review enumerates the pathophysiology of sepsis-induced brain damage, its diagnosis, the role of critical inducers and mediators and, ultimately, therapeutic measures attenuating cerebrovascular degeneration.

Sepsis and Cerebral Dysfunction: BBB Damage, Neuroinflammation, Oxidative Stress, Apoptosis and Autophagy as Key Mediators and the Potential Therapeutic Approaches.

ObjectiveTo investigate the prognostic significance of serum procalcitonin (PCT) and C-reactive protein (CRP) in patients with sepsis and those with septic shock.MethodsFifty-nine patients were div...

https://journals.sagepub.com/doi/pdf/10.1177/0300060518822404

Prognostic significance of PCT and CRP evaluation for adult ICU patients with sepsis and septic shock: retrospective analysis of 59 cases.

Neuroinflammation often develops in sepsis along with increasing permeability of the blood-brain barrier (BBB), which leads to septic encephalopathy The barrier is formed by tight junction structures between the cerebral endothelial cells We investigated the expression of tight junction proteins related to endothelial permeability in brain autopsy specimens in critically ill patients deceased with sepsis and analyzed the relationship of BBB damage with measures of systemic inflammation and systemic organ dysfunction The case series included all (385) adult patients deceased due to sepsis in the years 2007–2015 with available brain specimens taken at autopsy Specimens were categorized according to anatomical location (cerebrum, cerebellum) The immunohistochemical stainings were performed for occludin, ZO-1, and claudin Patients were categorized as having BBB damage if there was no expression of occludin in the endothelium of cerebral microvessels Brain tissue samples were available in 47 autopsies, of which 38% (18/47) had no expression of occludin in the endothelium of cerebral microvessels, 34% (16/47) developed multiple organ failure before death, and 745% (35/47) had septic shock The deceased with BBB damage had higher maximum SOFA scores (16 vs 14, p = 004) and more often had procalcitonin levels above 10 μg/L (56% vs 28%, p = 0045) during their ICU stay BBB damage in the cerebellum was more common in cases with C-reactive protein (CRP) above 100 mg/L as compared with CRP less than 100 (69% vs 25%, p = 0025) In fatal sepsis, damaged BBB defined as a loss of cerebral endothelial expression of occludin is related with severe organ dysfunction and systemic inflammation

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Brain tight junction protein expression in sepsis in an autopsy series.

Background A high prevalence of delirium is observed in sepsis, yet specific markers for this brain dysfunction in sedated patients are still lacking. Cytoplasmic low molecular weight calcium-binding protein, S-100β, is a commonly used nonspecific marker for brain injury. Here, we evaluated whether delirium is associated with increases in S-100β levels. Methods This observational study included 22 patients with septic shock. Delirium was assessed by CAM-ICU and blood samples were obtained to measure inflammatory (CRP, PCT, IL-6, IL-17, TNF-α) and cerebral biomarkers (S-100β, NSE, HAB42, SUBP). Patients were categorized according to the presence of delirium. Results Delirium was present in 10/22 of the patients (45.5%). Serum S-100β levels were above the laboratory cutoff value of 0.15 μg/L in 13/22 (59.1%) of the patients. The odds ratio for risk of developing delirium in cases with an S-100β >0.15 μg/L was 18.0 (95%CI, 1.7-196.3, P = 0.011). Patients with delirium had higher plasma levels of IL-6 compared to those without; 138.3 pg/mL [28.0-296.7] vs 53.6 pg/mL [109.3-505, P = 0.050]. There was a positive correlation between S100 β and IL-6 levels (r = 0.489, P = 0.021). Delirium patients had higher SOFA scores; 10 [5-9] vs 7[8-10.5], P = 0.036. Conclusions Delirium in septic shock was associated with an elevated protein S-100β when using a laboratory cutoff value of 0.15 μg/L and with more severe organ dysfunction during the ICU stay.

Elevated serum S-100β in patients with septic shock is associated with delirium.

Although tissue perfusion is often decreased in patients with sepsis, the relationship between macrohemodynamics and microcirculatory blood flow is poorly understood. We hypothesized that alterations in retinal blood flow visualized by angiography may be related to macrohemodynamics, inflammatory mediators, and retinal microcirculatory changes. Retinal fluorescein angiography was performed twice during the first 5 days in the intensive care unit to observe retinal abnormalities in patients with sepsis. Retinal changes were documented by hyperfluorescence angiography; retinal blood flow was measured as retinal arterial filling time (RAFT); and intraocular pressure was determined. In the analyses, we used the RAFT measured from the eye with worse microvascular retinal changes. Blood samples for inflammation and cerebral biomarkers were collected, and macrohemodynamics were monitored. RAFT was categorized as prolonged if it was more than 8.3 seconds. Of 31 patients, 29 (93%) were in septic shock, 30 (97%) required mechanical ventilation, 22 (71%) developed delirium, and 16 (51.6%) had retinal angiopathies, 75% of which were bilateral. Patients with prolonged RAFT had a lower cardiac index before (2.1 L/kg/m2 vs. 3.1 L/kg/m2, P = 0.042) and during angiography (2.1 L/kg/m2 vs. 2.6 L/kg/m2, P = 0.039). They more frequently had retinal changes (81% vs. 20%, P = 0.001) and higher intraocular pressure (18 mmHg vs. 14 mmHg, P = 0.031). Patients with prolonged RAFT had lower C-reactive protein (139 mg/L vs. 254 mg/L, P = 0.011) and interleukin-6 (39 pg/ml vs. 101 pg/ml, P < 0.001) than those with shorter RAFT. Retinal angiopathic changes were more frequent and cardiac index was lower in patients with prolonged RAFT, whereas patients with shorter filling times had higher levels of inflammatory markers.

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Retinal arterial blood flow and retinal changes in patients with sepsis: preliminary study using fluorescein angiography

Objective When developing approaches for automatic preprocessing of electroencephalogram (EEG) signals in non-isolated demanding environment such as intensive care unit (ICU) or even outdoor environment, one of the major concerns is varying nature of characteristics of different artifacts in time, frequency and spatial domains, which in turn causes a simple approach to be not enough for reliable artifact removal. Considering this, current study aims to use correlation-driven mapping to improve artifact detection performance. Approach A framework is proposed here for mapping signals from multichannel space (regardless of the number of EEG channels) into two-dimensional RGB space, in which the correlation of all EEG channels is simultaneously taken into account, and a deep convolutional neural network (CNN) model can then learn specific patterns in generated 2D representation related to specific artifact. Main results The method with a classification accuracy of 92.30% (AUC = 0.96) in a leave-three-subjects-out cross-validation procedure was evaluated using data including 2310 EEG sequences contaminated by artifacts and 2285 artifact-free EEG sequences collected with BrainStatus self-adhesive electrode and wireless amplifier from 15 intensive care patients. For further assessment, several scenarios were also tested including performance variation of proposed method under different segment lengths, different numbers of isoline and different numbers of channel. The results showed outperformance of CNN fed by correlation coefficients data over both spectrogram-based CNN and EEGNet on the same dataset. Significance This study showed the feasibility of utilizing correlation image of EEG channels coupled with deep learning as a promising tool for dimensionality reduction, channels fusion and capturing various artifacts patterns in temporal-spatial domains. A simplified version of proposed approach was also shown to be feasible in real-time application with latency of 0.0181 s for making real-time decision.

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A Correlation-Driven Mapping For Deep Learning application in detecting artifacts within the EEG.

This paper introduces a simple approach combining deep learning and histogram contour processing for automatic detection of various types of artifact contaminating the raw electroencephalogram (EEG). The proposed method considers both spatial and temporal information of raw EEG, without additional need for reference signals like ECG or EOG. The proposed method was evaluated with data including 785 EEG sequences contaminated by artifacts and 785 artifact-free EEG sequences collected from 15 intensive care patients. The obtained results showed an overall accuracy of 0.98, representing high reliability of proposed technique in detecting different types of artifacts and being comparable or outperforming the approaches proposed earlier in the literature.

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Kristo Erikson

Papers

Brain tight junction protein expression in sepsis in an autopsy series.

Elevated serum S-100β in patients with septic shock is associated with delirium.

Retinal arterial blood flow and retinal changes in patients with sepsis: preliminary study using fluorescein angiography

A Correlation-Driven Mapping For Deep Learning application in detecting artifacts within the EEG.

Automatic detection of artifacts in EEG by combining deep learning and histogram contour processing