Biomarkers in Systemic Inflammatory Response Syndrome: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 3 by Jason Zhu.

Clinically useful biomarkers of SIRS (neutrophil extracellular traps, cell-free DNA, DAMP, TREMs, NGAL, miRNA, selected cytokines, ROS, and recognised markers of endothelial damage from the group of adhesins by means of immunohistochemical techniques) related to the neutrophils are presented, and their role in the diagnosing and forecasting of sepsis, burn disease, and COVID-19 is emphasised.

  • %MCEPASTEBIN%
  • neutrophils
  • SIRS
  • cytokines
  • ROS
  • biomarkers

1. Introduction

Maintaining a balance between activation and suppression of immune response is one of the most important clinical objectives of researchers and physicians in the field of clinical immunology worldwide. The body’s immune response is activated by an invasion of the organism by microbes and by all types of injuries (e.g., burns or mechanical trauma, surgical procedures). The complex system of this response includes general systemic reactions, among which people can distinguish the innate (natural) response and acquired (adaptive) response, with antigen-presenting cells being the common link between the aforementioned mechanisms. The condition for eliciting an immune system response to the activity of microorganisms is breaking the continuity of skin or mucous membranes; after an injury, the protective barriers of the organism are broken, with subsequent destruction of tissues and cells, which in turn start processes intended to restore homeostasis, stimulating the regeneration of destroyed tissues and preventing infection. Small injuries result in a local defensive reaction of the body, whereas widespread injuries lead to a response with a systemic character.

  • neutrophils
  • SIRS
  • cytokines
  • ROS biomarkers
  • neutrophils
  • SIRS
  • cytokines
  • ROS
  • biomarkers
Neutrophils, as cells of innate immune response, are capable of synthesising various types of cytokines, including proinflammatory (e.g., IL-1a, IL-1b, IL-6, IL-7, IL-18, MIF), anti-inflammatory (e.g., IL-1ra, TGF-b1, TGF-b2), immunoregulatory (e.g., IFN-β, IL-12, IL-21, IL-23, IL-27), colony-stimulating factors (e.g., G-CSF, GM-CSF, SCF), angiogenic and fibrogenic factors (e.g., VEGF, FGF2, TGF-a, HGF), CC chemokines and CXC chemokines, and TNF-superfamily members (e.g., TNF-α, FasL, TRAIL, APRIL, RANKL) [1][2]. Therefore, these cells, in addition to the ability to destroy pathogens, also demonstrate immunomodulatory and repair properties [3][4]. However, the molecular mechanisms which control the expression of cytokines in human neutrophils have not been yet fully explained. Although the understanding of the method by which neutrophils influence or modulate tissue injury and repair has only started evolving recently, their participation (beneficial or harmful) after local activation in tissue remains unclear. Additionally, precisely adjusted mechanisms that regulate the recruitment of neutrophils become dysregulated during SIRS in the form of sepsis or as a consequence of broadly understood injury. Although recruitment of neutrophils is of key importance to a host’s defence, excessive representation of neutrophils may potentially result in injury to tissues in which inflammatory processes may not be occurring. Frequently, the complete elimination of neutrophils is not possible, but potential clinical benefits may be obtained by regulating or modifying their response [5].

2. Neutrophil Extracellular Traps

It should be kept in mind that after detection of bacteria in the blood, neutrophils may release their DNA in a configuration similar to a mesh, forming neutrophil extracellular traps (NETs), thus increasing the capturing capacity of the organ in which the NETs are released. They are covered by neutrophil proteases (e.g., elastase), antimicrobial molecules (e.g., histones), and also by other toxic molecules that kill pathogens; therefore, absorbing and killing pathogens seems to be the primary function of NETs [4][6][7]. However, numerous studies have also revealed the detrimental role of NETs in sepsis [8][9]. It was demonstrated that the formation of NETs starts from the production of oxidizing agents by neutrophils, which leads to the degradation of nuclear envelope and release of DNA into the cell; initially, it was postulated that neutrophils undergo lysis and die off after formation of NETs [10], although the reports of other authors indicate that the release of DNA may occur through vesicular transport and degranulation [11]. In humans, an increased number of NETs in plasma has correlated with increased lung damage and mortality, whereas lowered level of deoxyribonuclease (DNase) in plasma has led to the development of ARDS caused by sepsis [12]. It was described that the release of NETs during NETosis has an adverse impact on various human diseases, including the diseases of the respiratory, circulatory, nervous, and musculoskeletal systems, kidneys, liver, cancer, and autoimmunisation [13][14][15].

3. Cell-Free DNA

Patients after severe organ injury are at risk of post-injury immunosuppression, the consequence of which may be the development of sepsis [16]. Therefore, for the prognosis of life-threatening complications and assessment of severity of these patients, the reliable biomarkers of SIRS have to be used. Among them, cell-free DNA (cfDNA) in the blood has recently gained increasing interest; elevated concentrations of this biomarker were found in serum and under physiological processes such as pregnancy and physical exercise, among others [17][18][19]. Increased levels of cfDNA have also been observed in pathological processes such as infections and sepsis [20] or thermal injuries [21], as well as trauma [22]. As a DAMP, cfDNA is increased after traumatic injuries and plays a major role in the pathophysiology of SIRS, generating various types of clinical complications [21][23]. Although the exact mechanism of cfDNA release from cells is still unclear, apoptosis, necrosis, suicidal, and vital NETosis with consecutive release of neutrophil extracellular traps (NETs) are considered as potential sources [19][22][24][25]. Trulson et al. showed, in their prospective study, that cfDNA levels in serum and plasma are highly elevated in trauma and are strongly associated with injury severity and poor prognosis of patients with multiple trauma [26]. Circulating free DNA/NETs seems to be a valuable additional marker for the calculation of injury severity and/or prediction of inflammatory second hit on intensive care units (ICUs) [27]. Finally, growing evidence supports the hypothesis that DAMPs, including high-mobility group box 1 protein (HMGB1), cell-free DNA (cfDNA), and histones, as well as neutrophil extracellular traps (NETs), may directly or indirectly contribute significantly to the development of MODS [28].

4. DAMPs

Another example of a DAMP with obvious clinical implications is HMGB-1. In the literature, increased levels of HMGB-1 have been demonstrated in children with MODS [29]. Similarly, increased concentrations of these markers were present in the blood of adults suffering from sepsis and multiorgan failure. However, the concentrations of HMGB-1 found in septic patients did not differ when compared in the groups of patients who survived and patients in whom the diseases had ended with death [29][30]. Currently, HMGB-1 is considered to be an important mediator of sepsis and potential therapeutic target in cases of MODS [31]. Both DAMPs and PAMPs activating the immune cells by TLRs lead, in consequence, to production of ROS, which promote damage to the endothelium. Cytokines and released ROS (the production of which is induced by hypoxia) lead to mitochondrial dysfunction with subsequent development of cellular disfunction and organ failure [32].

5. TREMs

Triggering receptors expressed on myeloid cells (TREMs) are a group of receptors expressed on myeloid cells (e.g., monocytes, macrophages, neutrophils). They are mainly involved in the regulation of inflammation and play an important role in the innate and adaptive immune response; activated phagocytes release the receptor that can be found as a soluble form in plasma [33]. In the literature, increased levels of sTREM-1 in septic patients have been reported, indicating that it is a reliable biomarker, the levels of which could predict survival rates in sepsis better than PCT or CRP [34][35][36]. German researchers demonstrated, in their small prospective study, that a combination of normalized IL1β plasma levels, responses to endotoxin, and soluble TREM-1 plasma concentrations at the end of surgery are predictive markers of SIRS development and could act as an indicator for starting early therapeutic interventions [37].

6. NGAL

Lipocalin-2 (LCN-2) is a glycoprotein also known in the literature under the name of siderocalin or neutrophil gelatinase-associated lipocalin (NGAL), which is secreted from the inflammatory cells and tissues as a result of neutrophil activation. NGAL has bacteriostatic properties, which play an important role in the destruction of iron during antibacterial innate immune response. In addition to its important role in the innate response, this property provides a protective role in case of injuries, systemic inflammations, and various other types of cellular stress; there are attempts to use this inflammatory biomarker in kidney and liver disorders, tumours, and inflammatory diseases of the colon [38][39]. Moreover, Chang et al. investigated the predictive value of plasma NGAL in patients with severe sepsis; according to the results of the study, this biomarker discriminated 28-day survivors from nonsurvivors on day 2 and 7 and was a relatively robust predictor of 28-day mortality prediction [40]. Chinese authors in experimental studies on animals showed that animals with septic acute kidney injury (AKI) have higher serum NGAL compared with animals with nonseptic AKI; monitoring the activities of TNF-α, NGAL, and IL-6 would make great contributions in discovering sepsis and evaluating the severity of sepsis [41]. In turn, Paul et al., in their prospective cohort study on patients with acute febrile episodes fulfilling the SIRS criteria, revealed that the NGAL sepsis screening tool with a score of >7 can be used in the emergency department to identify bacterial sepsis [42].

7. Immunohistochemistry Evaluation of Biomarkers

It is extremely important for the clinician to use reliable and available biomarkers that enable rapid diagnosis with subsequent treatment of sepsis. When fatal sepsis is suspected, autopsy and routine histology results are not very specific tools and remain unconvincing. Italian researchers, based on a review of the literature, reported that the use of immunohistochemical techniques may prove helpful and could be used in the diagnosis of postmortem sepsis, concluding that each of the studied biomarkers could prove useful in confirming or ruling out a diagnosis of sepsis in the postmortem examination, especially in the forensic setting [43]. An imbalance in the release of pro- and anti-inflammatory cytokines in response to an infectious stimulus underlies the pathophysiology of sepsis development. An intensified anti-inflammatory response of the organism may consequently lead to immunosuppression, which is particularly dangerous if it complicates any severe post-traumatic conditions. Endogenous inflammatory mediators released at that time, including chemokines and cytokines, cause the activation of the vascular endothelium with all histopathological consequences and the development of clinical entities, i.e., ARDS, DIC, or MODS. In their study, La Russa et al. reported that among a large group of recognized markers of endothelial damage from the group of adhesins, ICAM-1 (CD54), E-selectin (CD62E), and VE-cadherin are useful postmortem markers of sepsis; these authors also indicated the possibility of testing other markers for this purpose, such as angiotensin-I converting enzyme (ACE), TNF-α, PCT, VEGF, some antigens expressed on leukocyte surfaces (very late antigen-4 (VLA-4), i.e., CD49d/CD29), and enzymes contained in neutrophils granules (lysozyme (LZ), lactoferrin (LF), and s-TREM-1) [43].

8. MicroRNA

MicroRNAs (miRNAs) may play a role as prognostic and diagnostic markers in the early detection of septic patients or in the differentiation between sepsis and other inflammatory diseases. MiRNAs that can be detected in the blood represent the greatest arsenal for use as biomarkers due to their relatively easy identification and testing. However, the use of miRNAs as diagnostic and prognostic biomarkers in clinical practice is currently limited due to the low sensitivity and specificity of the methods used for their identification, with the exception of real-time quantitative PCR (RTq-PCR), which in turn is costly and time-consuming [44]. MicroRNA is still an unexplored field of knowledge, and a standardized method for identifying and measuring miRNAs has not yet been developed. This issue remains a challenge for researchers worldwide studying SIRS biomarkers for use in clinical practice. Despite these limitations, research on miRNAs continues with the imminent hope of their use in the clinic. It should be recalled that most biomarkers used for sepsis diagnosis are inflammatory biomarkers, the levels of which can be altered by other conditions such as trauma, surgery, or cancer. That is why the assessment of biomarker levels should be individualized in every clinical case. There are numerous research groups that have demonstrated an altered transcriptional expression of these small noncoding RNAs in the course of sepsis [45][46][47][48][49]. For example, miR-122 plays a crucial role in the septic process and has a higher diagnostic value than CRP and leukocyte count; it has also been shown to be a prognostic marker for sepsis, albeit with low specificity and sensitivity [48]. Guo et al. found that miR-495 was downregulated in blood samples from septic patients; the decrease was even more pronounced in patients who developed septic shock [45]. On the other hand, Sun et al. found a positive correlation between miR-328 serum levels and sepsis in human patients [46]. Zhang et al. even found that the serum level of miR-29c-3p was significantly increased in sepsis patients [47]. Han et al. evaluated the prognostic value of miR-155, finding that it could also be used for predicting the mortality and treatment outcome of sepsis-induced lung injury [49]. Thus, it was observed that certain miRNAs can be used as diagnostic or predictive markers for subsequent clinical outcome.
Up until now, no anti-inflammatory therapy has been effective in sepsis clinical trials, and little is known about the role of miRNAs in regulating neutrophil function. However, an in-depth understanding of the miRNA function within neutrophils will help to identify potential clinical applications of miRNAs as therapeutic agents. Numerous studies are being conducted around the world to answer the question of whether miRNA levels could alter inflammation. For example, Chen et al. reported in their research that miR-let-7b could regulate immunosuppression by targeting the neutrophilic TLR4/NF-κB signal during CLP-induced sepsis, which reveals novel mechanisms of the involvement of miR-let-7b in neutrophilic inflammatory activity and provides valuable therapeutic targets for severe inflammation-driven diseases, including sepsis and the current COVID-19 [50].

9. Assessment of Cytokine Concentrations

Shelhamer et al. have reported increased levels of IL-6 and IL-8 in ICU patients with a severe burn injury, which were an indicator prognostic of death [51]. There are also studies about the increase in IL-18 in burn patients, which appeared within 48 h after a burn [52]. Finnerty et al. observed that the profile of cytokines, which is characterised by increased concentrations of IL-6 and IL-12 and decreased TNF-α, in children with severe burns (>40% TBSA) was prognostic of increased risk of death due to sepsis [53]. Hur et al., assessing the concentrations of cytokines in patients with a burn injury, indicated that high (and increasing on the first day of the disease) blood levels of IL-6, antagonist of IL-1 receptor (IL-1RA), and monocyte chemotactic factor (MCP-1) are clinically useful prognostic markers of death [54]. The own prospective research in a group of children with burns demonstrated a significant decrease in concentrations of assayed cytokine inhibitors (sTNFR I, sTNFR II, IL-1 ra) and anti-inflammatory cytokine (IL-10) following the completion of treatment, compared to their initially high levels observed at 6–24 h after the injury [55]. Despite multiple studies assessing, in clinical practice, the levels of cytokines circulating in the blood from the aspect of diagnostics of post-injury infections, the use of these markers as singular indicators to identify sepsis is insufficient due to their low specificity and sensitivity. Gouel-Cheron et al., in a prospective study on 100 patients after severe injury, reported that a combination of the assessment of clinical and immune condition of the patient with measurement of circulating IL-6 improves both specificity and positive predictive value of the used marker [56]. A retrospective study of COVID-19 patients found that elevated serum ferritin and IL-6 correlated with nonsurvivors [57]. IL-6 is one of the key factors and its level is positively correlated with the severity of COVID-19. The increased systemic cytokine production contributes to the pathophysiology of severe COVID-19, including hypotension, ARDS, which might be treated with IL-6 antagonists, i.e., tocilizumab, sarilumab, and siltuximab. In severe COVID-19 patients, the use of tocilizumab was shown to be significantly associated with a reduced risk of invasive mechanical ventilation and death [58]. The meta-analysis by Chinese authors demonstrated the strong association between elevated circulating cytokines and COVID-19 severity and mortality; they revealed that circulating levels of IL-2R, IL-10, IL-1 , IL-4, IL-8, IL-17, TNF-alfa, and particularly IL-6, were elevated in severe and nonsurviving COVID-19 patients when compared with mild patients [59].       

10. Evaluation of ROS Generation

Even though adaptive mechanisms that the organism produces in response to the factor that initiates SIRS have been well studied, there is still an ongoing search for new immunological markers which would be useful in further prognoses for burn patients [60]. The part played by ROS in the pathomechanism of SIRS in patients after a burn injury is still not well documented. Isolated reports in the literature on this subject are fragmentary and varied. Dobke et al. indicated decreased activity of the NADPH:O2 oxidoreductase system in patients with thermal injury [61]. Similarly, Rosenthal et al. reported a decreased respiratory burst of neutrophilic granulocytes when studying the cytosol components (p47-phox and p67-phox) of this enzyme in burn patients [62]. Other authors have observed increased oxygen metabolism of granulocytes in an adequate group of patients [63]. According to reports from the literature, an impairment of chemotaxis, adherence, phagocytosis, and oxygen metabolism and intracellular destruction of microorganism by neutrophils occur in patients with a burn injury [61]. Moreover, the research demonstrated that children in whom, in the course of a burn disease, a hypovolaemic shock developed demonstrated significantly lower initial production of ROS compared to the children in whom shock did not occur. A one-time early analysis (at 6–24 h after the burn) established particularly high concentrations of IL-1 receptor antagonist (IL-1 ra) in patients who developed hypovolaemic shock in the first period of the burn disease [60]. Therefore, monitoring of IL-1 ra in parallel with the intensity of neutrophil respiratory burst indicates a prognostic value of the examined markers in the development of SIRS complications in children with severe burns.
For a physician, a very important issue is the possibility of prognosing future course of SIRS and occurrence of MODS in their patients (as a consequence of systemic infection or severe injury, among others), and also monitoring the clinical course of SIRS by multiple repeated assessment of concentrations of adequate biomarkers of inflammation. It should be emphasised that the assaying of concentrations may prove finally insufficient, which is why they always have to be considered in combination with the clinical data obtained from an interview and physical examination. For this purpose, the clinician should use various available research techniques (ELISA, chemiluminescence, flow cytometry), which prove very useful in the assessment of the aforementioned SIRS biomarkers [64][65]. Taking into account the imperfections of the laboratory markers of inflammatory reaction that have been used so far, there is still ongoing intensive research worldwide directed at discovering new, sensitive, and specific biochemical markers of systemic inflammatory reaction.

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