Korean J Clin Lab Sci.

2021;53(4):309-316

https://doi.org/10.15324/kjcls.2021.53.4.309

Korean Society for

Clinical Laboratory Science

REVIEW ARTICLE

Diagnosis and Prognosis of Sepsis

Chang-Eun Park
Department of Biomedical Laboratory Science, Molecular Diagnostics Research Institute, Namseoul University, Cheonan, Korea

패혈증의 진단 및 예후예측
박창은
남서울대학교 임상병리학과·분자진단연구소

ARTICLE INFO ABSTRACT

Received November 28, 2021 Sepsis is a physiological response to a source of infection that triggers mechanisms that
Revised December 2, 2021 compromise organ function, leading to death if not treated early. Biomarkers with high sensitivity,
Accepted December 6, 2021
specificity, speed, and accuracy that could differentiate sepsis from non-infectious systemic
inflammatory response syndrome (SIRS) could bring about a revolution in sepsis treatment. Given
the limitations and time required for microbial verification of pathogens, the accurate diagnosis of
infection before employing antibiotic therapy is important and clinically necessary. Procalcitonin
(PCT), lactate, C-reactive protein (CRP), cytokines, and proadrenomedullin (ProADM) are the
common biomarkers used for diagnosis. The procalcitonin (PCT)-guided antibiotic treatment in
patients with acute respiratory infections effectively reduces antibiotic exposure and side effects
Key words while improving survival rates. The evidence regarding sepsis screening in hospitalized patients is
Biomarker limited. Clinicians, researchers, and healthcare decision-makers should consider these findings and
Cytokine limitations when implementing screening tools, future research, or policy on sepsis recognition in
Laboratory detection hospitalized patients. The use of biomarkers in pediatric sepsis is promising, although such use
Multi-markers should always be correlated with clinical evaluation. Biomarkers may also improve the prediction of
Sepsis
mortality, especially in the early phase of sepsis, when the levels of certain pro-inflammatory
cytokines and proteins are elevated.
Copyright Ⓒ 2021 The Korean Society for Clinical Laboratory Science.

INTRODUCTION for in intensive care units (ICUs), but this is now

changing with more septic patients being cared for in
Sepsis is defined as life-threatening organ dysfunction hospital wards [1]. The response to sepsis is the result of
caused by a dysregulated host response to infection. complicated interactions between mechanisms of
Organ dysfunction can be identified as an acute change inflammation, anti-inflammation, humoral and cellular
in total sequential organ failure assessment (SOFA) adaptive mechanisms and circulatory changes, the
score at least two points consequent to the infection. accurate detection of procalcitonin (PCT) in serum is
Septic patients were previously predominantly cared crucial for effective early diagnosis and very helpful for
further treatment guidance.
Acute respiratory infections are caused by bacteria,
Corresponding author: Chang-Eun Park
Department of Biomedical Laboratory Science, Molecular Diagnostics Research
viruses, and other causes and are often treated with
Institute, Namseoul University, 91 Daehak-ro, Seonghwan-eup, Seobuk-gu,
Cheonan 31020, Korea
antibiotic therapy. Sepsis has contributed to the
E-mail: [email protected] development of multidrug-resistant bacterial pathogens [2].
ORCID: https://orcid.org/0000-0003-4259-7928

pISSN 1738-3544 eISSN 2288-1662

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/
licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
310 Chang-Eun Park. Diagnosis Sepsis

The infection blood biomarker procalcitonin has been effective method of screening patients in acute care is
proposed as an adjunct to clinical judgment and not clear, therefore the purpose of this review was to
traditional clinical parameters to guide antibiotic examine the application of sepsis screening tools or
prescribing practices in patients with acute respiratory alert mechanisms for early recognition of sepsis in
infections. PCT measurements increase within 6∼12 hr general hospitalized.
of infection in response to pro-inflammatory mediator
release after bacterial invasion, are highest in patients MAIN BODY
who have bacteraemia, and correlate with disease
severity and clinical outcome of patients with infection Overall the frequency and time to use of diagnostic
[3]. measures (lactate orders, blood cultures) improved
PCT concentrations rapidly fall by about 50% each significantly, whereas results pertaining to treatment
day during resolution of infection and are therefore (fluids and vasopressors) were inconsistent across
useful in monitoring the clinical course and supporting studies with some but not all demonstrating improve-
decisions to discontinue antibiotic treatment. A large ment [8]. A biomarker may be defined as a character-
US study, found PCT kinetics over 72 hr to be a strong istic that can be objectively measured and assessed as
and independent predictor of mortality. Early identifi- an indicator of normal biological processes, pathological
cation of non-responders to antibiotic and other processes, and/or pharmacological responses to a
medical treatment might also help to prevent adverse therapeutic intervention.
events [4]. It has been argued that sepsis has no
reference standard for identification and diagnosis, 1. Procalcitonin (PCT)
with early signs and symptoms being non-specific [5]. PCT is thought to have pro-inflammatory effects
The known presence of specific biomarkers during the similar to CRP. PCT, a sensitive biomarker of in-
response to an infectious insult makes possible the flammation, is a U.S. Food and Drug Administration
potential clinical use of such biomarkers in screening, (FDA) approved marker of blood infection for guiding
diagnosis, prognosis (risk stratification), therapeutic antibiotic therapy [9]. PCT should always be interpreted
response monitoring, and rational use of antibiotics carefully in the context of medical history and other
(determination of adequate treatment length, for clinical information as recommended in the Surviving
example). Sepsis Campaign (SSC) [10].
C-reactive protein (CRP), one of the biomarkers that Normal serum values are below 0.05 ng/mL, and a
has been in longer use in pediatric sepsis, is a value of 2.0 ng/mL suggests a significantly increased
non-specific, acute-phase protein that increases 4∼6 risk of sepsis and/or septic shock. Values ＜0.5 ng/mL
hr after exposure to an inflammatory trigger (infectious represent a low risk while values of 0.5∼2.0 ng/mL
or not) and has an 8 hr doubling time, peaking from 36 suggest an intermediate likelihood of sepsis and/or
∼50 hr after the trigger stimulus. Elevation of PCT levels septic shock.
usually occurs earlier during the course of infection
than elevation of CRP levels, peaking at approximately 2. Lactate
24∼36 hr. Recently, The interleukin-6 (IL-6) and IL-8 to Sepsis may progress rapidly to septic shock that is
increase its specificity in the diagnosis of infections [6]. often associated with micro-and macro-circulatory
Sepsis alerts mediated by technology embedded in dysfunction Lactate levels have been a useful marker for
electronic medical records have also been proposed as organ dysfunction and may also serve as an endpoint
an effective screening mechanism [7]. The most for resuscitation in patients with sepsis. The 2013 SSC

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 Korean J Clin Lab Sci. Vol. 53, No. 4, December 2021 311

international guidelines lists a lactate level ＞2 mmol/L

as one of the criteria defining severe sepsis and a lactate 5. D-dimer
level ＞4 as defining septic shock [11]. Serial lactate D-dimer was shown to predict the presence of
measurements may be useful in monitoring treatment bacteremia in septic patients and was correlated with
effectiveness to various therapeutic interventions, and sepsis severity [16].
therefore, is recommended in the sepsis bundle for
septic shock, especially when the initial level is high. A 6. Proadrenomedullin (ProADM)
normal lactate level is often interpreted as indicating a ProADM is a potent vasodilator that belongs to the
good prognosis in sepsis, but studies suggest that this calcitonin peptide superfamily with PCT. ProADM has
may be a false assurance. Elevated levels of lactate are been shown to improve clinical pneumonia risk scores
not considered specific for either the diagnosis of ProADM has been used as a prognostic marker, either
sepsis, or predicting mortality, unless thoughtfully alone or in risk stratification with other hormonal
coupled with the overall clinical trials. propeptides in patients with sepsis and severe
pneumonia [17]. Correlation with severity and potential
3. C-reactive protein (CRP) use as a risk stratifier ProADM was promising marker of
Serum concentrations can increase up to 1,000-folds diagnosis of infection in febrile neutropenic patients.
during acute inflammatory events, which increases its
value as a biomarker of infection and inflammation 7. Multi-marker approach to sepsis

compared to other acute phase reactants. In patients When used as a single marker, failed to provide useful
with CRP concentrations ＞10 mg/dL, decreasing information, no single marker accurately reflects the
concentrations in the first 48 hr was associated with a rapid immunological changes of sepsis. With optimal
mortality of 15%, whereas mortality reached 61% for cutoff values, the combination of baseline alpha-2
patients in whom the CRP concentration increased macroglobulin and 72 hr PCT offered a 75% negative
[12]. An increase in CRP concentration above 2.2 mg/dL predictive value (95% CI 54∼96%), and differentiated
over the 48 hr period was predictive of inadequate bacterial sepsis from systemic inflammatory response
antibiotic therapy with a sensitivity of 77% and a syndrome (SIRS) [17]. When combined with another
specificity of 67% [13]. biomarker, including interleukin 8 (IL-8), increased
CRP levels are apparently a good diagnostic predictor in
4. Cytokines the first 24 hr. The different biomarkers down to a panel
Interleukin-6 (IL-6), IL-8 and IL-10 have been the 3 markers that best predicted the development of
most widely studied cytokines to diagnose sepsis, sepsis: IL-1 receptor antagonist (IL-1ra), protein C and
evaluate the level of the inflammatory response and neutrophil gelatinase associated lipocalin (NGAL). For
help determine the prognosis for the patient. IL-6 is a accuracy to predict severe sepsis (0.80) [19]. NGAL was
prototype of proinflammatory cytokine, IL-8 is a major promising biomarker of acute kidney injury (organ
chemokine, and IL-10 represents an important anti- dysfunction) also, using the early increase in cases of
inflammatory cytokine. IL-6 and IL-10 levels are acute kidney failure (48 hr prior to the increase of
correlated with the mortality rate in septic patients [14]. creatinine) and early introduction of renal protection
IL-8 has been used to predict the severity of sepsis in measures. The utilizing the results of three more
pediatric patients, although the utility of IL-8 has not traditional biomarkers (PCT, CD64 and soluble
been confirmed in adults [15]. triggering receptor expressed on myeloid cells 1
(sTREM-1) [20]. A risk model for estimating mortality in

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312 Chang-Eun Park. Diagnosis Sepsis

children with septic shock using five biomarkers (C-C flammatory receptor expressed on monocytes/macro-
chemokine ligand 3 (CCL3), IL- 8, heat shock protein 70 phages and neutrophils [25]. Vaspin, a visceral adipose
kDa 1B (HSPA1B), granzyme B (GZMB), and matrix tissue-derived serpin, was first identified as an insulin-
metallopeptidase 8 (MMP8) was created and validated sensitizing adipose tissue hormone, and its anti-
[21]. inflammatory function has recently been demonstrated
a weak positive correlation between the concentration
8. Sepsis-related sequential organ failure assessment of vaspin and CRP [26]. A recent study showed that
(SOFA) score using a panel of biomarkers consisting of angiopoietin-1,
The SOFA score is a mortality prediction score that is angiopoietin-2, and bicarbonate was a better predictor
based on the degree of dysfunction of six organ of severity in pediatric septic patients [27]. The miRNAs
systems. The score is calculated on admission and every have been suggested as biomarkers in the context of
24 hr until discharge using the worst parameters sepsis, In patients with sepsis, which are most likely due
measured during the prior 24 hr. The scores can be used to a lack in standardization of sample collection, data
in a number of ways: As individual scores for each organ normalization, and analysis [28]. Recently, there have
to determine progression of organ dysfunction. As the been increasing data indicating that kallistatin, testican-
sum of scores on one single ICU day. As the sum of the 1, presepsin, and mid-regional pro-adrenomedullin or
worst scores during the ICU stay. It is believed to bio-ADM are promising biomarkers significant in
provide a better stratification of the mortality risk in diagnosis and monitoring of sepsis. The HMGB-1 is
ICU patients given that the data used to calculate the promptly released subsequent to the infection. Also, it
score is not restricted to admission values. These has been reported to have pro-inflammatory effects,
changes may be quantified by calculating the SOFA and high plasma levels have been associated to sepsis.
score [22]. Clinical laboratory tests are essential in Further, it has been correlated directly to sepsis
determining pulmonary function (arterial blood gases), severity and organ dysfunction [29]. Initial neutrophil
hepatic function (bilirubin) and renal function to lymphocyte ratio (NLR) may be a helpful prognostic
(creatinine). The status of the coagulation system is biomarker for sepsis and that high NLR may indicate
determined by measuring the number of platelets. unfavorable prognoses in patients with sepsis. However,
these findings should be interpreted with caution due to
9. Experimental analytes the aforementioned limitations. The types of recently
Several new biomarkers have been proposed recently reported circulating biomarkers for evaluating sepsis
ranging from cytokines to small cellular proteins. These were classified and arranged (Table 1).
markers offer the potential to improve the diagnosis
and treatment of sepsis. High IL-3 levels are associated 10. Molecular diagnosis kits
with poor prognosis and high mortality rate, even after A commercially available kit for molecular diagnosis
adjusting for prognostic indicators [23]. Tumor necrosis of sepsis has been reported, has high specificity and
factor (TNF)-α converting enzyme (TACE) is a trans- sensitivity, and is used as a rapid diagnostic method
membrane protease enzyme that cleaves membrane- [38]. SeptiCyte Lab (Immunexpress Inc., Seattle, WA,
bound TNF to produce soluble TNF. Patients with sepsis USA) is the first RNA-based technology that targets
had substantially elevated levels of basal TACE activity specific human inflammatory markers using 2.5 mL
that were refractory to lipopolysaccharide stimulation whole blood for sepsis determination in 4∼6 hr.
[24]. The peptidoglycan (PGN) recognition protein 1 SeptiCyte provides a robust way to detect whether a
(PGLYRP1) as a ligand for TREM-1, a known proin- pathogen is present based on the host response but

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 Korean J Clin Lab Sci. Vol. 53, No. 4, December 2021 313

Table 1. The outlined markers were classified into relevant circulating biomarkers being evaluated within sepsis

Category Biomarker Characteristic References

Chemokines Interleukin (IL-8) Pro-inflammatory cytokines are involved in chemotaxis [30]

during the inflammation for diagnosis
Monocyte chemoattractant protein Role in the progression of sepsis to the [31]
(MCP-1) immunosuppressive phase to predict
Macrophage inflammatory protein Highly related members of the CC chemokine subfamily, [32]
(MIP)/Macrophage CC chemokine (or β-chemokine) proteins have two adjacent
migration inhibitory factor (MIF) cysteines (amino acids), near their amino terminus
Osteopontin (OPN) Matricellular protein that mediates diverse biological functions. [33]
OPN is involved in normal physiological processes and is
implicated in the pathogenesis of a variety of disease states
Regulated on Activation, Valuable sensitivity and specificity [34]
Normal T Cell (RANTES)
Cell markers Triggering receptor expressed on Expression increases after the exposition of neutrophil to bacteria [35]
myeloid cells-1 (TREM-1) showed better prognostication than procalcitonin and C-reactive protein
Presepsin (the receptor of Measured during the first week of treatment in [36]
lipopolysaccharide-lipopoly-saccharide ICU patients to predict all-cause mortality with
binding protein [LPS-LBP] complexes) respect to 30 days and 6 months
Toll-like receptor (TLR) 2 and 4 Induced organ failure [37]

requires a higher volume of blood and initial sample CONCLUSIONS

preparation SeptiCyte Lab is a host response-targeted,
reverse transcription-quantitative PCR (RT-qPCR)-based Septic shock is a subset of sepsis in which underlying
test that quantifies the relative expression levels of four circulatory and cellular/metabolic abnormalities are
RNA biomarkers (carcinoembryonic antigen-related profound enough to substantially increase mortality.
cell adhesion molecule 4 [CEACAM4], lysosomal- Septic shock defined by hypotension despite fluid
associated membrane protein 1 [LAMP1], phospholipase resuscitation and serum lactate level ＞2 mmol/L.
A2 group VII [PLA2G7] and placenta-specific protein 8 Clinical diagnotic severe sepsis or septic shock type of
[PLAC8]) known to be involved in innate immunity and PCT algorithm and procalcitonin cutoffs used
the host response to infection. discontinuation at day 4, 7, and 10; recommendation
An emerging technology termed “integrated com- against antibiotic: ＜1.0 μg/L or ＞50% drop to previous
prehensive droplet digital detection” (IC3D) (Velox value [39]. Serial measurements of CRP are useful in
Biosystems, Irvine, CA, USA) claims to selectively detect assessing the response to antimicrobial treatment. CRP
individual bacterial species directly from small values that fail to decrease or continue to rise after 48
quantities of whole blood within 1 to 4 hr (190). The hours of antibiotic therapy suggest treatment failure.
IC3D technology is limited in the number of targets that On admission and 24 hours later, the diagnostic
it can detect in a single sample but is capable of accuracy of CRP alone for severe sepsis in children with
skipping sample preparation entirely to accomplish the febrile neutropenia was lower than that of PCT and
simplest and most direct testing from blood samples. IL-6. The 40% of the sepsis patients remain culture
This may be of significant value for rapidly tracking the negative [40]. It is important to differentiate culture
spread of individual organisms in the context of negative sepsis patients from those with noninfectious
outbreaks. In a one-step, culture- and amplification- SIRS, as these disease conditions require different
free process, the IC3D method provides quantitative therapeutic regimens. An accurate and timely diagnosis
bacterial detection with single-cell sensitivity. IC3D of sepsis allows prompt and appropriate treatment.
combines DNAzyme-based sensors with real-time Sepsis screening and response are complex processes
droplet microencapsulation and a particle counter. of care that involve various disciplines necessitating

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314 Chang-Eun Park. Diagnosis Sepsis

roles of each of the professionals be made explicit. This Acknowledgements: Funding for this paper was provided
immunosensor could be promisingly used for clinical by Namseoul University year 2021.
early diagnosis of bacterial infections and also for Conflict of interest: None
guiding antibiotic therapy due to its ability for highly Author’s information (Position): Park CE, Professor.
sensitivity detection. Use of procalcitonin to guide
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