Ahuja N, Mishra A, Gupta R, Ray S. Biomarkers in sepsis-looking for the Holy Grail or chasing a mirage! World J Crit Care Med 2023; 12(4): 188-203 [PMID: 37745257 DOI: 10.5492/wjccm.v12.i4.188]
Corresponding Author of This Article
Sumit Ray, MBBS, MD, Director, Department of Critical Care Medicine, Holy Family Hospital, Okhla Road, Delhi 110025, India. drsray67@yahoo.co.in
Research Domain of This Article
Critical Care Medicine
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Minireviews
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: All the authors were equally involved in the designing, research methodology, data collection and writing of the manuscript.
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Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Sumit Ray, MBBS, MD, Director, Department of Critical Care Medicine, Holy Family Hospital, Okhla Road, Delhi 110025, India. drsray67@yahoo.co.in
Received: March 13, 2023 Peer-review started: March 13, 2023 First decision: April 28, 2023 Revised: May 12, 2023 Accepted: June 12, 2023 Article in press: June 12, 2023 Published online: September 9, 2023
Abstract
Sepsis is defined as a life-threatening organ dysfunction caused by the dysregulated host response to infection. It is a complex syndrome and is characterized by physiologic, pathologic and biochemical abnormalities in response to an infection. Diagnosis of sepsis is based on history, physical examination and other investigations (including biomarkers) which may help to increase the certainty of diagnosis. Biomarkers have been evaluated in the past for many diseases and have been evaluated for sepsis as well. Biomarkers may find a possible role in diagnosis, prognostication, therapeutic monitoring and anti-microbial stewardship in sepsis. Since the pathophysiology of sepsis is quite complex and is incompletely understood, a single biomarker that may be robust enough to provide all information has not been found as of yet. However, many biomarkers have been studied and some of them have applications at the bedside and guide clinical decision-making. We evaluated the PubMed database to search for sepsis biomarkers for diagnosis, prognosis and possible role in antibiotic escalation and de-escalation. Clinical trials, meta-analyses, systematic reviews and randomized controlled trials were included. Commonly studied biomarkers such as procalcitonin, Soluble urokinase-type plasminogen activator (Supar), presepsin, soluble triggering receptor expressed on myeloid cells 1, interleukin 6, C-reactive protein, etc., have been described for their possible applications as biomarkers in septic patients. The sepsis biomarkers are still an area of active research with newer evidence adding to the knowledge base continuously. For patients presenting with sepsis, early diagnosis and prompt resuscitation and early administration of anti-microbials (preferably within 1 h) and source control are desired goals. Biomarkers may help us in the diagnosis, prognosis and therapeutic monitoring of septic patients. The marker redefining our view on sepsis is yet a mirage that clinicians and researchers continue to chase.
Core Tip: Sepsis is defined as life threatening organ dysfunction caused by a dysregulated host response to infection. Early diagnosis of sepsis and prompt initiation of antimicrobials is essential. Biomarkers may be helpful in early diagnosis, prognostication and monitoring of response to therapy in septic patients. We review commonly used biomarkers such as procalcitonin, presepsin, soluble urokinase plasminogen activator, etc., and their utility in clinical practice.
Citation: Ahuja N, Mishra A, Gupta R, Ray S. Biomarkers in sepsis-looking for the Holy Grail or chasing a mirage! World J Crit Care Med 2023; 12(4): 188-203
Sepsis is defined as a life-threatening organ dysfunction caused by the dysregulated host response to infection. It is a complex syndrome and is characterized by physiologic, pathologic and biochemical abnormalities in response to an infection. It is a leading cause of mortality across the world and is a major healthcare concern[1]. Septic shock is a subset of sepsis in which the underlying cellular/metabolic abnormalities are profound enough to increase mortality. These patients are identified with the help of clinical criteria of hypotension requiring vasopressors to maintain a mean blood pressure of more than 65 mmHg and a serum lactate level of more than 2 mmol/L despite adequate fluid resuscitation. Initially, sepsis was defined in 1991 as infection or suspected infection leading to the onset of systemic inflammatory response syndrome (SIRS) where SIRS was defined as the presence of any two out of four criteria-tachycardia (heart rate > 90/min), tachypnoea (respiratory rate > 20 breaths per min), fever or hypothermia (temperature > 38 C or < 36 C), leukocytosis or leukopenia (Total Leukocyte Count > 12000/mm3 or < 4000/mm3 or immature forms or bands > 10%. Rudd et al[2] have attempted to estimate the global, regional and national incidence of sepsis and associated mortality using the Global Burden of Diseases, Injuries and Risk Factor Study estimates. They estimated an incidence of 48.9 million cases [95% uncertainty interval (UI): 38.9-62.9] of sepsis recorded worldwide in 2017. Almost 11 million (10.1-12) deaths were recorded as related to sepsis which is approximately 19.7% (18.2-21.4%) of all global deaths. In comparison from 1990 to 2017, age-standardized sepsis incidence decreased by 37% (95%UI: 11.8-54.5) and mortality decreased by 52.8% (47.7-57.5). The highest burden of sepsis was estimated to be in sub-Saharan Africa, Oceania, south Asia, East Asia, and Southeast Asia. Markwart et al[3] in their study have estimated that around 23.6 % of cases (95%CI: 17%-31.8%, range 16%-36.4%). Among the patients with sepsis associated with organ dysfunction in intensive care unit (ICU), 24.4% (95%CI: 16.7%-34.2%, range 10.3%-42.5%) were acquired during ICU stay while 48.7% (95%CI: 38.3%-59.3%, range 18.7%-69.4%) had a hospital origin. In ICU patients, with hospital-acquired sepsis associated with organ dysfunction, a mortality of 52.3% (95%CI: 43.4%-61.1%, range 30.1%-64.6%). With this huge burden of sepsis worldwide, there is a pressing need for early and accurate diagnosis of sepsis to allow early initiation of therapy.
The pathophysiology of sepsis is complex and is poorly understood. It involves the activation of various pro-inflammatory and anti-inflammatory pathways in response to a pathogen and its effects on the host. These pathways tend to disrupt the metabolomic profile and the identification of these metabolites can be helpful in diagnosis, therapy modification, and prognostication in sepsis patients.
Early recognition of sepsis and prompt management is essential and can help to reduce mortality in such patients. Differentiation of septic patients from other patients with a systemic inflammatory response due to non-infectious causes is difficult. Diagnosis of sepsis is based on history, physical examination and other investigations (including biomarkers) may help to increase the certainty of diagnosis. Early initiation of antibiotics is one of the cornerstones of the management of septic patients. However prudent antimicrobial therapy is required to prevent the emergence of drug-resistant organisms and hence an increased certainty in the diagnosis of sepsis will help to rationalize initiation of anti-microbials and also might help to de-escalate or discontinue them in critically ill patients, thereby reducing the chances of resistance. Biomarkers may serve as an aid for diagnosis, prognosis and therapy modification in septic patients. In the plethora of biomarkers, only a few have been recognized for their diagnostic abilities, but none have marked their presence as the absolute indicator of sepsis diagnosis.
A biological marker or a biomarker is defined as a character that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention. They may be used for diagnosis, staging of disease, prognostication, and for prediction and monitoring of clinical response to therapy. An ideal biomarker for sepsis should have the following characteristics: (1) Early identification of sepsis to initiate timely antibiotics; (2) High specificity to differentiate from noninfective causes of SIRS; (3) Identify bacterial sepsis from other causes of infection; (4) Prognostication of the patient's condition; and (5) Guide antibiotic therapy-escalation and de-escalation of antibiotics
A few biomarkers for sepsis have been described in Table 1. Our review aims to assess the role of biomarkers in diagnosis, prognosis and antibiotic stewardship in septic patients.
Precursor of hormone calcitonin secreted by C cells of thyroid gland
C-reactive protein
Acute phase protein secreted by hepatocytes in response to pathogen or tissue damage
IL6
A cytokine, mainly produced by macrophages and lymphocytes in response to infection and it can affect the activation of B and T lymphocytes
suPAR
A protein derived from cleavage and release of cell membrane bound urokinase plasminogen activator receptor
sTREM1
Mainly expressed on the surface of polymorphonuclear cells and mature monocytes
Presepsin (sCD14-ST)
sCD14 is cleaved by proteases during inflammation, to form an N terminal fragment-the sCD14 subtype (sCD14-ST)
Adrenomedullin
A 52 amino acid peptide initially isolated from phaeochromocytomas. It is secreted by mammalian tissues and endothelial cells in response to various stimuli such as hypoxia, angiotensin 2, inflammatory cytokine such as TNF-α, IL-1β, etc.
Mid regional Proadrenomedullin (MR-proADM)
A peptide secreted by multiple tissues in order to stabilize the microcirculation and protect against endothelial permeability
BIOMARKERS FOR DIAGNOSIS OF SEPSIS
In our review for biomarkers for the diagnosis of sepsis, we searched the PubMed database for sepsis biomarkers for diagnosis and narrowed the search by selecting biomarkers which have been studied in at least 300 patients or had a meta-analysis done with at least 1000 patients. Biomarkers with an area under the receiver operator characteristic curve (AUC) of at least 0.80 were then individually researched and included (Table 2). Few of the biomarkers and their utility in diagnosing sepsis, have been explained in our review.
Randomised control trial, Prospective, Secondary analysis
Gram negative vs Gram positive bacteremia and candidemia
PCT (Gram negative bacteremia)
0.72 (95%CI: 0.71-0.74)
Value was 10 ng/mL sensitivity 69%, specificity 35% for Gram negative bacteraemia
Streptococci, E. coli and other Enterobacteriaceae detected from BC were associated with three times higher PCT values. Urogenital or abdominal foci of infection were associated with twofold increased PCT
PCT was helpful in recognizing GNBSI, but the test results should be interpreted carefully with knowledge of patients' medical condition and should not serve as the only criterion for GNBSI
Patients suspected of having any infection in the ED, the accuracy of nCD64, sTREM1, and HMGB-1 was not significantly sensitive or specific for diagnosis of sepsis
Combining CRP and nCD64 expression, an abnormal result for both was associated with a 92% probability of sepsis, whereas sepsis was ruled out with a probability of 99% if both were normal. In nonseptic patients, an increase in nCD64 expression ≥ 40 MFI predicted ICU-acquired infection (n = 29) with a sensitivity of 88% and specificity of 65%
525 adult patients in emergency. Severe sepsis: 49; Sepsis: 302; SIRS: 58. Sirs with no bacterial infection: 53. Bacterial infection no SIRS: 63
PLA(2)GIIA
NA
OR: 1.48 (1.20-1.81, P < 0.001)
Differences in AUC between these parameters were not significant. On multivariate logistic regression analysis only PLA(2)GIIA could differentiate patients with severe sepsis from others (OR: 1.37, 95%CI: 1.05-1.78, P = 0.019
sTREM1, APACHES II higher in patients with positive culture than negative cultures. sTREM1, PCT and CRP levels, or WBC count performed equally to differentiate
PCT
0.65 (95%CI: 0.53–0.76)
PCT cut-off value of 1.57 ng/mL. Sens: 67.31; Spec: 65.79%; PPV: 72.92; NPV: 70
C-REACTIVE PROTEIN
C-reactive protein (CRP) is an acute phase reactant which rises early in any inflammatory response including sepsis. Though its specificity has been challenged repeatedly, it is still among the most frequently included parameter in clinical studies[4].
PROCALCITONIN
Procalcitonin (PCT) demonstrated better diagnostic accuracy and specificity compared to CRP[5,6]. Alongside CRP, it is the most extensively studied marker and the most common marker against which most other markers have been compared for their diagnostic and prognostic role in sepsis. It is now well established that its levels rise in sepsis. However, the increase in PCT levels is significantly influenced by the type of infection, the site of infection, the severity of the patient's illness and post-operative status and the type of surgery. It increases within 4 h of injection of endotoxin, so it has the potential to recognize Gram-negative sepsis early. Higher procalcitonin levels are seen in Gram-negative bloodstream infections compared to Gram-positive infections and candidemia[7,8].
Patients with Gram-negative bacteremia had higher procalcitonin levels than Gram-positive bacteremia or candidemia[9]. However, Goodlet et al[10] found that PCT failed to rule out bacteremia.
In burn patients, PCT has been shown to be effective for early diagnosis of sepsis (AUC: 0.92)[11].
PCT like many other sepsis biomarkers [CRP, interleukin 6 (IL6)] increases in response to surgery in the first 24 h. Major cardiac and abdominal surgeries have been found to have higher PCT values. Unlike CRP, PCT levels rapidly fall and any subsequent rise has been shown to corroborate with post-operative sepsis.
Dong et al[12] found in post-cardiac surgery that PCT was able to identify infective SIRS compared to CRP and white blood cell count (WBC) (P < 0.0001)[12].
Procalcitonin-based antibiotic initiation failed to show any short-term mortality benefit rather than a delay in antibiotic initiation in sepsis. Procalcitonin-based antibiotic protocol, though, has shown its role in the de-escalation of antibiotics[13]. Hence it is imperative to use procalcitonin within a clinical context rather than as a sole marker for the diagnosis of sepsis.
PRESEPSIN (SCD14-ST)
Presepsin is released from monocytes following infection and in a recent meta-analysis, it is as good as procalcitonin for diagnosis of sepsis with an AUC of 0.87 and sensitivity and specificity of 0.84 and 0.73, respectively. The major limitation was the inclusion of only observational studies and no randomized controlled trials (RCTs)[14].
Liu et al[15] evaluated 859 patients in a single center presenting in emergency and found that compared to SIRS, patients with sepsis had significantly presepsin values (P < 0.0001). The value increased with the severity of sepsis. Presepsin had significantly higher AUC than PCT in diagnosing sepsis (P < 0.01).
Following trauma; PCT, CRP, and total blood count[15] increase irrespective of infective status, unlike presepsin which was found to be significantly increased in infected trauma cases only[16].
Halıcı et al[17] found presepsin to be effective in differentiating chronic obstructive pulmonary disease exacerbation with and without pneumonia[17].
Thus, presepsin has the potential to diagnose sepsis early and also to differentiate sepsis from non-infective SIRS, thereby optimising antibiotic initiation. Further randomised control trials are needed.
Soluble urokinase-type plasminogen activator receptor (SuPAR) is normally present in blood and various other body fluids and is increased in states of inflammation. In the recent meta-analysis by Huang et al[18] SuPAR had a moderate diagnostic ability for sepsis similar to procalcitonin, but was inferior to PCT in differentiating from non-infective SIRS[18].
NEUTROPHILIC CD 64
Neutrophilic CD 64 (NCD64) is a surface receptor on the antigen-presenting cells which increases in response to infections and exposure to endotoxins.
In adult patients, Yeh et al[19] and Cong et al[20] found NCD64 outperformed procalcitonin, CRP and IL6 for sepsis diagnosis[19,20].
Liu et al[21] in their observational study found NCD64 to be significantly increased in bacterial and viral infections compared to fungal infections (P < 0.0005), and in DNA virus infections compared to RNA virus infections(P < 0.0071)[21]. Further studies may be needed to establish its role to distinguish bacteremia.
In critically ill patients, NCD64 when combined with other markers like CRP is useful for diagnosing sepsis, especially when combined with CRP. A normal CRP and NCD64 [cut off 230 mean fluorescence intensity (MFI)] ruled out sepsis with a 99% probability. An increase of ≥ 40 MFI may indicate ICU-acquired infection in a previously non-infected patient as per their results[22].
OTHER BIOMARKERS
Various markers like IL27, Soluble triggering receptor expressed on myeloid cells 1 (sTREM1), and high mobility group box 1 (HMGB-1) failed to perform as diagnostic markers in larger trials[23-26].
Group IIA secretory phospholipase A2 (sPLA2-IIA) in a prospective cohort analysis could differentiate severe sepsis but needs further studies. Bactericidal/permeability-increasing protein in the same study did not show a significant benefit[27].
COMBINATION OF BIOMARKERS
Recent researchers are now also focusing on using a combination of markers with promising results[28]. Novel markers when used with traditional/time-tested clinical tools like neutrophil count, CRP, etc. increases the probability of differentiating sepsis from non-infective SIRS and initiates timely management.
PCT when combined with CRP and IL6 significantly increased its diagnostic accuracy for sepsis[29]. NCD64 combined with CRP have shown similar results[22,30].
Timely antibiotic initiation remains the most important factor determining patient survival. At present, most biomarkers act as an aid to clinical judgement and not its replacement in the diagnosis of sepsis and antibiotics administration (Table 3).
Table 3 Biomarkers for diagnosis of sepsis-current understanding in diagnosis of sepsis.
Biomarker
Diagnosis of sepsis
Differentiating sepsis and SIRS
Guiding antibiotic initiation
Organism identification
Procalcitonin
Better than CRP; cannot be used independently; diagnosis based on clinical context
Better than CRP; cannot be used independently; diagnosis based on clinical context
Delays antibiotic administration; No short term mortality benefit
Higher in Gram negative bacteremia than Gram positive. Higher in bacteremia than in candidemia. No defined cutoffs. Treatment to be based on clinical judgement
Presepsin
Possible role
Possible role
No significant data
No significant data
nCD64
Possible role; when combined with CRP, higher diagnostic accuracy and high negative predictive value
No significant data
No significant data
Increased in bacterial and viral infection more than fungal
suPAR
Possible role
Performed poorly
No significant data
No significant data
IL6
Inferior to PCT, CRP
Inferior to PCT, CRP
No significant data
No significant data
BIOMARKERS FOR SEPSIS PROGNOSIS
Apart from diagnosis, biomarkers may also be used for prognostication in septic patients. We searched the PubMed database for biomarkers that have been previously described commonly in the literature. We searched for the biomarker in question in the context of prognosis in septic patients. Only clinical trials, meta-analyses, systematic reviews and randomized controlled trials were included. Some of the biomarkers studied in sepsis patients have been evaluated for prognostication in such patients and results have been promising.
PROCALCITONIN
In a meta-analysis conducted by Arora et al[31], procalcitonin levels were found to be significantly lower in survivors of sepsis than non-survivors. Another meta-analysis by Patnaik et al[32] that had 1974 patients evaluated for procalcitonin clearance had an overall mortality of 37.54%. They concluded that procalcitonin non-clearance can be used as a marker for mortality. However, optimal cutoff points for the same for septic patients in the ICU are unknown. An overall AUC of 0.708 (95%CI: 0.648-0.769) was observed for the same under the random effect model as a result of moderate variation (50.80%) in the studies included. So, procalcitonin clearance could be used as a predictor for mortality and prognostication in septic patients with non-clearance suggesting a higher risk of death (Table 4).
To compare changes in PCT and CRP concentration in critically ill septic patients to determine which marker better predicts outcome
157 patients; 171 episodes
CPCTc and CRPc are significantly associated with treatment failure (P = 0.027 and P = 0.03 respectively) and marginally significant with 28 d mortality (P = 0.064 and 0.062 respectively). AUC for prediction of treatment success-PCTc-0.71 (95%CI: 0.61-0.81); CRPc-0.71 (95%CI: 0.61-0.81); AUC for survival prediction-PCTc-0.77 (95%CI: 0.66-0.88); CRPc-0.77 (95%CI: 0.67-0.88)
Changes in PCT and CRP concentrations were associated with outcomes of critically ill septic patients. CRP may not be inferior to PCT in predicting outcomes in these patients
To evaluate the results of all non-clearance of serial PCT as a mortality predictor
10 studies, 1974 patients
AUC varied between the studies between 0.52 and 0.86. Overall AUC-0.711 (95%CI: 0.662-0.760) under fixed effect model and 0.708 (95%CI: 0.648-0.769) under random effect model. Overall proportion of mortality-37.54%
PCT non clearance is a marker for increased mortality. Optimal cut off points for PCT non clearance in septic patients admitted to ICU are not known
To evaluate the value of PCT in women with APN at ED
240
AUC for predicting 28 d mortality for PCT-0.68. For predicting mortality, a cut off value of 0.42 ng/mL, sensitivity was 80% and specificity was 50%. Disease classification systems were predicted to be superior to PCT in predicting 28 d mortality
By distinguishing the severity of sepsis related to APN mortality, PCT levels help clinicians in disease severity classification and treatment decisions at ED
To predict outcome with traditional and new inflammatory markers in septic patients
242
AUC for PCT was 0.878 which was highest as compared to other markers
PCT may be a better marker than other inflammatory markers, CRP, leukocyte count, body temperature to identify patients endangered by severe infection or sepsis
To study the procalcitonin levels in survivors and non survivors of sepsis
25 studies; 2353 patients
Mean difference in procalcitonin levels between survivors and non survivors on day 1 (P = 0.02) and day 3 (P = 0.03) was statistically significant
Significantly lower levels of procalcitonin were observed in survivors as compared to non survivors in early stages of sepsis
PRESEPSIN
Masson et al[33] evaluated presepsin (a soluble CD 14 subtype) and its relation with mortality in patients with septic shock enrolled in the multicenter ALBIOS trial. 997 patients were evaluated and their results showed that baseline presepsin concentrations increased with SOFA score, the number of prevalent organ dysfunction failures, and the incidence of new failures of respiratory, coagulation, liver and kidney systems. A rise in the concentration of presepsin from day 1 to day 2 predicted a significantly higher ICU and 90-d mortality. They concluded that presepsin is an early predictor of host response and mortality in septic patients (Table 5).
To evaluate the prognostic value of presepsin and comparison with procalcitonin
100
Presepsin levels at day 1 were higher in decedents (2269 pg/mL, median-1171 to 4300 pg/mL) than in survivors (1184 pg/mL, median-875 to 2113 pg/ml); P = 0.002) whereas PCT was not different (18.5 mcg/L, median 3.4 to 45.2) and 10.8 mcg/L (2,7 to 41.9 mcg/L) P = 0.13). The evolution of presepsin levels over time was significantly different in survivors compared to non survivors (P for time-survival interaction-0.03)
Presepsin showed better prognostic accuracy than procalcitonin in the range of SOFA. (AUC: 0.64-0.75 vs AUC: 0.53-0.65)
Evaluation of diagnostic and prognostic value of presepsin in sepsis and septic shock patients during the 1st wk of ICU treatment
116
AUC- 0.64 TO 0.71; Presepsin cut off values-Sepsis-530 pg/mL; Severe sepsis-600 pg/mL; Septic shock-700 pg/mL
Presepsin has good prognostic value in terms of prognosis for 30 d and 6 mo all cause mortality throughout the 1st wk of ICU stay and its prognostic value for all cause mortality is comparable to that of IL6 and better than that of PCT, CRP or WBC
To evaluate the mortality prediction value of presepsin in septic patients
10 studies; 1617 patients
Initial prespesin levels (within 24 h) were significantly lower in survivors as compared to non survivors. Pooled SMD (standardized mean difference) between survivors and non survivors-0.92 (95%CI: 0.62–1.22)
Some mortality prediction of presepsin; further studies may be needed to define optimal cut off points for presepsin to predict mortality in sepsis
To investigate the prognostic value of presepsin for elderly septic patients in ICU
142
Presepsin levels were significantly higher in infected patients. Day 3 presepsin levels showed a significant prognostic value for 30 d mortality but was not found to be superior to other biomarkers
Early diagnostic ability comparable to that of PCT; however not a perfect biomarker for prognosis of 30 d mortality in elderly patients
To compare presepsin with other conventional biomarkers (PCT, CRP, IL6) for evaluating the severity of sepsis
103
In patients with unfavorable prognosis: (1) Presepsin levels did not decrease significantly during follow up; (2) Higher duration of antibiotic therapy was used (P < 0.05); and (3) Higher 28 day mortality (P < 0.05)
Presepsin levels correlated with severity during follow up as compared to other conventional biomarkers
Evaluating the relationship between presepsin levels and host response, appropriateness of antibiotics, and mortality in severe sepsis patients
997 patients with severe sepsis or septic shock in ALBIOS trial
Baseline Presepsin concentrations increased with SOFA score, number of organ failures, and incidence of new organ failures; An increasing concentration of presepsin from day 1 to day 2 predicted higher ICU (P < 0.0001) and 90 d mortality (P < 0.01)
Presepsin is an early predictor of host response and mortality in patients with sepsis
ADRENOMEDULLIN (ADM) AND PRO ADRENOMEDULLIN
Adrenomedullin (ADM) and Pro adrenomedullin (proADM) are other markers that could be used for prognostication in septic patients and it is one of the biomarkers that has been evaluated for prognostication in community acquired pneumonia (CAP) patients (apart from IL6). Christ-Crain et al[34] have described its prognostic significance in CAP patients and concluded that proADM could be used as a risk stratification marker in patients with CAP. Ortqvist et al[35] in their observational trial found that higher IL6 levels were associated with higher mortality and bacterial pneumonia patients had the highest IL6 levels as compared to pneumonia of other aetiologies. Li et al[36] evaluated the ability of Adm and proADM for prognosis in septic patients in a meta-analysis and their results showed that increased AM or Pro ADM levels are associated with increased mortality (pooled RR: 3.31; 95%CI: 2.31-4.75) (Table 6).
Table 6 Adrenomedullin and pro adrenomedullin for prognosis of sepsis.
To evaluate the value of Pro ADM levels for severity assessment and outcome prediction in CAP
302
Pro ADM levels (as compared to CRP and leukocyte count) increased with increasing severity of CAP (calculated through PSI score). Pro ADM levels at admission significantly higher 2.1 (1.5 to 3) nmol/L compared to survivors 1 (0.6 to 1.6) nmol/L; P < 0.001. AUC for proADM was 0.76 (95%CI: 0.71–0.81)-significantly higher than PCT, CRP, TLC
Pro ADM is a useful biomarker for risk stratification in patients with CAP
To evaluate the prognostic value of adrenomedullin in septic patients and compare it with PCT and MEDS
837
Mean levels (at admission of AM were 28.66 ± 6.05 ng/L in 100 healthy controls, 31.65 ± 6.47 ng/L in 153 systemic inflammatory response syndrome patients, 33.24 ± 8.59 ng/L in 376 sepsis patients, 34.81 ± 8.33 ng/L in 210 severe sepsis patients, and 45.15 ± 9.87 ng/L in 98 septic shock patients. The differences between the 2 groups were significant. ADM levels significantly higher in non survivors; AUC for in hospital mortality-AM-0.773; PCT-0.701; MEDS-0.721
Adrenomedullin is valuable prognostic biomarker for septic patients in ED
Plasma bio ADM (day 1) was higher in and associated with higher 90 d mortality, multi organ failures, extent of haemodynamic support and serum lactate time course over the 1st wk. Bio ADM trajectory during the 1st wk of treatment predicted 90 d mortality; Reduction to levels below 110 pg/ml at day 7 was associated with reduction in 90 d mortality
Bio ADM levels may help individualize haemodynamic support therapy in septic patients
To evaluate role of MR Pro Adm compared to conventional biomarkers (PCT, CRP, lactate) and clinical scores to identify disease severity in sepsis
1089
MR Pro Adm had strongest association with mortality and high disease severity; A decreasing concentration of PCT by ≥ 20 % from baseline to day 1 or ≥ 50 % from baseline to day 4 but a persisting high level of Pro Adm had significantly increased mortality risk [HR (95%CI)-19 (8-45.9) and 43.1 (10.1-184)]
MR Pro Adm assesses disease severity and treatment response more accurately than conventional biomarkers and scores
SuPAR
suPAR has been evaluated in multiple trials and systematic reviews[18] to assess for prognostication in septic patients and has been validated to be a useful prognostic marker in adult septic patients (Table 7).
Table 7 Soluble urokinase plasminogen activator receptor for prognosis of sepsis.
To assess the usefulness of suPAR levels in critically ill patients with sepsis, SIRS, bacteraemia, focusing (diagnostic and prognostic value)
10 studies
Little diagnostic value in critically ill septic patients. Superior prognostic value in such patients as compared to other markers. Improved mortality prediction by combining suPAR with other markers or disease severity classifications. suPAR levels correlate positively with markers of organ dysfunction and severity of disease classification system scores
suPAR has a low diagnostic value for septic patients. It may add to prognostication with other markers and organ dysfunction scores
To evaluate the usefulness of suPAR for diagnosis and prognosis of bacterial infections
17 studies included
High suPAR levels were related with a significantly increased risk of death with a pooled risk ratio of 3.37 (95%CI: 2.6-4.38). Pooled sensitivity and specificity for predicting mortality were 0.7 and 0.72 respectively, with AUC of 0.77
suPAR can be used for prognosis of bacterial infection
sTREM1 could also be useful in predicting mortality in septic patients at an initial stage of infection and has also been used for prognostication in neonatal septic patients[37] (Table 8).
Table 8 Soluble triggering receptor expressed on myeloid cells 1 for prognosis of sepsis.
To determine prognostic value of sTREM1 in predicting mortality at the initial stage of infection
9 studies
High sTREM1 level was associated with higher risk of death in infection, with pooled RR 2.54 (95%CI: 0.61-0.86) using a random effects model; Pooled sensitivity and specificity of sTREM1 to predict mortality in infection were 0.75 (95%CI: 0.61-0.86) and 0.66 (95%CI: 0.54-0.75), respectively
Higher sTREM1 levels had a moderate prognostic significance in assessing the mortality of infection in adult patients; however sTREM1 alone is not sufficient to predict mortality as a marker
To study the association of sepsis prognosis with dynamic changes in sTREM1 and its polymorphisms
160
sTREM1 levels were significantly raised in non survivors than in survivors (P < 0.001); Logistic regression showed that sTREM1, APACHE 2, and rs2234237 polymorphisms are risk factors for prognosis
Dynamic changes in sTREM1 and rs2234237 polymorphism could be used for prognostication in septic patients
To observe dynamic changes in plasma sTREM1 levels and to study its effect on predicting outcome of septic patients combined with SOFA score
57
Non survivors-sTREM1 levels were highest on Day 1 and a gradual elevation was seen over days 1, 3 and 7). Survivor-sTREM levels were highest on day 1 and then showed a gradual reduction over days 1, 3 and 7. sTREM levels were significantly higher in non survivors as compared to survivors (P < 0.01)
High plasma levels of sTREM1 are detected at initial stages in septic patients and sTREM1 level combined with SOFA score may be helpful in predicting outcomes in septic patients
Various biomarkers as described above and, in the table, have been evaluated for prognostication in septic patients. Sepsis biomarkers by themselves can provide valuable information for prognostication and in conjunction with organ dysfunction scores and severity scoring systems for critically ill patients, can provide an improved assessment for mortality and prognosticating in such patients. However, costs associated with their use, limited availability and limited knowledge about them are a hindrance in the clinical application of these markers. The optimal cut-off for prediction for prognosis has not been well defined and there is considerable heterogeneity in the literature. Site-specific values of these biomarkers (such as urine, cerebrospinal fluid, etc.) have not been adequately studied. Procalcitonin is a biomarker that has been used relatively more frequently in many countries and its non-clearance is associated with a higher mortality. The domain of biomarkers for sepsis prognosis is a promising field and many new biomarkers are expected to be discovered with the use of omics technologies.
ROLE OF BIOMARKERS IN ANTIBIOTIC STEWARDSHIP/DE-ESCALATION
Longer and injudicious use of broad-spectrum antibiotics has been associated with a higher frequency of adverse effects and interference with the microbiome, more treatment costs and the emergence of antibiotic resistance. Ruling out sepsis with certainty and withholding antibiotics, especially in critically ill patients is a challenging task even for a highly experienced physician. Although a shorter treatment course instead of longer has been recommended by the current Surviving Sepsis guidelines, a definitive duration of treatment for different sites and severity of infection has not been clearly defined[38]. CRP and PCT have been studied extensively in the biomarker-based algorithmic approach including antibiotic initiation and discontinuation.
PROCALCITONIN
Based on the multiple RCTs that evaluated PCT to guide antimicrobial treatment in patients with lower respiratory tract infections (LRTI), the current guidelines by IDSA recommend a shorter treatment course for pneumonia under PCT guidance[39]. The ProHOSP trial conducted at tertiary care hospitals in Switzerland included 1359 patients with severe LRTIs and studied the role of PCT in the initiation and discontinuation of antibiotics. The trial concluded a lower mean duration of antibiotic exposure and less frequent antibiotic-associated adverse effects in the PCT group as compared to the control group [standard of care (SOC)] within 30 d from the time of presentation[40].
The PRORATA trial, which was a large trial conducted on 630 critically ill patients with a suspected bacterial infection in France aimed at studying the effectiveness of a procalcitonin-based algorithm to decrease antibiotic exposure. The algorithm included initiation of antibiotic if serum PCT was ≥ 0.5 ng/mL and continuation until the serial measurements showed levels less than 0.5 ng/mL or reduction by at least 80% of the baseline value. The trial results showed a statistically significant decrease in the duration of antibiotic treatment from 11.6 d in the PCT group to 14.3 d in the control arm (P < 0.0001). The rate of relapse and re-infection were comparable between the two arms but a trend towards higher mortality in the PCT group at 60 d[41]. On similar grounds, the SAPS trial was designed to study the discontinuation of antibiotic protocol based on serial PCT measurements. The results were similar to the PRORATA trial with a significant reduction in antibiotic exposure days in the PCT group [5 d vs 7 d in the SOC (P < 0.0001)]. However, in contrast to the PRORATA trial, the SAPS trial also found a reduction in 28-d (19.6% vs 25%, P = 0.0122) and 1-year mortality (34.8% vs 40.9%, P = 0.0158)[42].
CRP
A systematic review and meta-analysis published by Petel et al[43] evaluated the efficacy of CRP in septic patients. Based on the results of this analysis, the CRP cut-off recommended for antibiotic discontinuation was < 10 mg/L for neonatal sepsis. The majority of the studies on adults included patients with respiratory tract infection and cut-offs used were similar, with most of them withholding antibiotics if CRP was < 20 mg/L and initiating or continuing the use of CRP was > 100 mg/L. The physician's discretion was followed for CRP values between 20 mg/L and 100 mg/L. The meta-analysis concluded that CRP based algorithmic approach reduced the rate of antibiotic initiation with no significant differences in mortality, infection relapse and hospitalization rates[43].
A recent trial conducted in the critical care unit of a university hospital in Brazil by Borges et al[44] compared the days of antibiotic therapy between a CRP-guided protocol and an evidence-based judicious use strategy (not using the marker). The decision of antibiotic discontinuation in the intervention arm was based on serial CRP measurements (if CRP < 35 mg/dL or decrease to decrease ≥ 50%). The trial illustrated the efficacy of the CRP-based strategy in reducing the median duration of antibiotic use by 1 day for the index infection episode [6 (5-8) d in the CRP arm vs 7 (7-10) d in the control arm; P = 0.011]. However, despite such promising results, no significant differences were found in terms of antibiotic-free days and survival outcomes between the two arms[44].
Another multicenter RCT, including patients with Gram-negative bacteremia with randomization in a 1:1:1 ratio, compared an individualized CRP-guided antibiotic treatment (Duration based on the decrease in CRP levels ≥ 75% from its peak along with the absence of fever for 48 h) with a fixed 7-d and 14-d therapy. The primary outcomes of this trial in terms of incidence of clinical failure occurred in 2.4% of patients in the CRP arm, 6.6% in the 7-d arm, and 5.5% in the 14-d arm (difference in CRP vs 14-d arm was -3.1%; P < 0.001). The median duration of antibiotic therapy in the CRP-guided group was 7 d. The findings of this study hence concluded that antibiotic duration should not be predefined in the initial phase of illness and use of a biomarker-guided approach may prevent prolonged antibiotic exposure without increasing the failure rates[45].
Considering the results of these trials and meta-analysis, it may be inferred that CRP-guided protocolized therapy allows a lower antibiotic exposure and comparable rates of infection relapse and mortality with the control group.
NEWER BIOMARKERS WITH A ROLE IN ANTIBIOTIC STEWARDSHIP
Presepsin
Presepsin is a soluble form of CD14 that takes part in pathogen recognition by innate immunity. Masson et al[33] analyzed a subset of data from the ALBIOS trial and studied the relation between the circulating presepsin levels, the host response and mortality in patients with severe sepsis. The study concluded a direct correlation between a rise in presepsin concentration and a rise in SOFA score and the number of organ failures. Baseline levels of presepsin were found to be higher in patients who subsequently tested positive for bacterial infection (particularly with Gram-negative sepsis). The levels declined gradually in patients with negative cultures and appropriate antibiotic therapy[33]. Xiao et al[46], published a trial recently, comparing presepsin guidance to SOC in sepsis. In the intervention group, antibiotics were discontinued at serum presepsin concentration of < 350 pg/mL or a decline of more than 80% from baseline. Despite more antibiotic-free days in the presepsin group, there was no significant difference in mortality between the two arms[46]. These findings suggest a potential role of this biomarker in guiding antibiotic escalation and de-escalation strategies.
IL-1β and IL-18
The VAPrapid2 trial published in 2020 was the first trial to use biomarkers (IL-1β and IL-18 from the bronchoalveolar lavage fluid) to improve antibiotic stewardship by the early exclusion of infection in patients with suspected ventilator-associated pneumonia (VAP). Although the trial illustrated the efficacy of studied biomarkers (IL-1β and IL-18) in accurately excluding VAP, it could not achieve the endpoint of showing any statistically significant difference in the number of antibiotic-free days. Certain factors such as reluctance to BAL and non-adherence to the discontinuation protocol by treating clinicians could have contributed to the lack of difference in antibiotic duration between the intervention and control groups[47].
OMICS (GENOMICS, TRANSCRIPTOMICS, PROTEOMICS AND METABOLOMICS) IN SEPSIS
The host inflammatory response leads to the generation of by-products or metabolites and these have been used as the traditional biomarkers in sepsis. However, omics technology, including genomics, transcriptomics, proteomics and metabolomics are referred to as the systematic measurement at the level of DNA, RNA, protein and metabolite levels and the omics technology has resulted in the delineation of newer biomarkers in sepsis and sub-phenotyping in sepsis patients. We will explain omics in sepsis in a nutshell as a more comprehensive detail of omics in sepsis is beyond the scope of this review.
Genomics is the study of the genome to explain physiological or pathological processes. Variable response and susceptibility of individual patients to infection are different because of genetic factors. Genomics can be used to determine genetic polymorphisms and epigenetic markers that may be used as bioindicators in septic patients. Single Nucleotide Polymorphism (SNP) are a common type of genetic polymorphism and SNP genotyping of various genes may provide important information relevant to sepsis.
Tightly regulated gene expression leads to the regulation of pro and anti-inflammatory responses in septic patients and gene expression study forms the basis of transcriptomics. Micro RNAs (miRNAs) are short RNAs of 18 to 25 nucleotides that regulate gene expression in target mRNA. miRNA profiling of leukocytes and plasma in septic patients may be used to detect molecules that may be used as biomarkers. Similarly, long non-coding (involved in epigenetic control of gene expression) may be useful to detect diagnostic and therapeutic classes of biomarkers.
All sets of proteins expressed by an organism constitute a proteome and proteomics is the study of the expression, localization, function and interaction of the proteome. Proteomics may thus provide the basis for determining newer biomarkers in sepsis[48].
Metabolomics was defined way back in the 1990s and defines techniques aimed at measuring metabolites present within a cell, tissue or organism. The underlying principle in genetics describes the flow of information from DNA through mRNA transcripts and the subsequent translation of it into proteins. These proteins take part in tightly controlled metabolic pathways. Metabolome is the terminal downstream product of the genome and consists of all the low molecular weight molecules (metabolites) in a cell, tissue or organism required for growth, maintenance, or normal function in a specific physiological state. These metabolites generate the phenotype in an organism and these can be detected and measured to provide information about the particular process in question[49]. The pathophysiological pathways of sepsis may lead to inflammatory and anti-inflammatory metabolites being produced and identification of these metabolic products can help to detect sepsis early, and may also help to assess treatment response and estimate recovery[50].
Su et al[51] identified metabolic biomarkers that can be useful to differentiate sepsis from SIRS. They assessed 65 patients (35 patients with sepsis, 15 patients with SIRS, and 15 normal individuals). They used liquid chromatography-mass spectrometry to analyze metabolites in serum samples. They reported significantly lower levels of lactitol dehydrate and S-phenyl-D cysteine and increased S-(3-methylbutanoyl)-dihydrolipamide-E and N-nonanoyl glycine in septic patients as compared to SIRS patients. Patients with severe sepsis and septic shock had low glyceryl-phosphoryl-ethanolamine, Ne, Ne dimethyllysine, phenylacetamide and D-cysteine (P < 0.05) in serum. S-(3-methylbutanoyl)-dihydrolipoamide-E, phosphatidylglycerol (22:2 (13Z,16Z)/0:0), glycerlophosphocholine and S-succinyl glutathione were significantly lower (P < 0.05) in serum (collected 48 h before death) of patients who died. These metabolites are reflective of the ongoing metabolome during sepsis and may be used to diagnose sepsis and estimate severity and mortality. However, larger studies are needed for validation.
CONCLUSION
Sepsis and septic shock are life-threatening conditions requiring prompt resuscitation and antibiotic administration. The sepsis biomarkers are still an area of active research with newer evidence adding to the knowledge base continuously. Sepsis is the result of a complex interplay of various pathways. A single biological marker may not be an answer for diagnosis, prognostication, follow up and guide to antibiotic escalation/de-escalation in sepsis. Regardless, understanding these sepsis biomarkers and their role in the sepsis pathway can help to further rationalize sepsis management alongside clinical judgement. Early targets for sepsis treatment would be to administer anti-microbials within 1 h of presentation and source control as early as possible. The 2021 surviving sepsis campaign guidelines suggest against using procalcitonin and clinical judgement to start initial antibiotic vs clinical judgement alone as waiting for procalcitonin may delay antibiotic administration. However, it is suggested to use procalcitonin in addition to clinical evaluation as compared to clinical evaluation alone to discontinue antimicrobials in patients with septic shock with adequate source control. The values of the biomarkers (like procalcitonin, Supar, nCD64, presepsin, etc.) may help guide the therapy by differentiating noninfective SIRS from infective SIRS. A combination of biomarkers has been found to increase their diagnostic accuracy.
The marker redefining our view on sepsis is yet a mirage that clinicians and researchers continue to chase. Many have become redundant and many more are still in the running to prove their worth. "Omics" (including genomics, transcriptomics, proteomics and metabolomics) will lead to the discovery of newer biomarkers and their applications in diagnosis, prognosis and therapeutic monitoring are going to increase.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Corresponding Author's Membership in Professional Societies: Indian Society of Critical Care Medicine, No. 07-R/276.
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