10/9/17

BIO & PICTURE – MEDLAB 2016

Adhi Kristianto Sugianli
Adhi Kris)anto Sugianli, M.D
(clinical pathologist, lecturer) (Faculty of Medicine Universitas Padjadjara
Dr. Hasan Sadikin General Hospital Bandung
Office:
Departement of Clinical Pathology, Adhi Kristianto Sugianli is a clinical patholo
Faculty of Medicine Universitas Padjadjaran, Departement of Clinical Pathology of Dr. H
Dr. Hasan Sadikin General Hospital Bandung Faculty of Medicine Universitas Padjadjara
acquiring his medical degree, he complete
Academic qualifica)on:
of Laboratory Medicine from Universitas
•  Medical degree : Universitas Kristen Maranatha (2000 - 2007)
•  Clinical training/Specialist : Universitas Padjadjaran (2008 - 2011)
training in Laboratory of Clinical Pathology
•  Postgraduate degree : Universitas Padjadjaran (2010 - 2011) Hospital - Faculty of Medicine Univerista
•  Sub-specialist clinical training on InfecQous Disease : Collegium of ISCPaLM (2014 – 2016) involved as a member of Hospital Infecti
Resistance-control program at Dr. Has
•  PhD candidate: AMC Universiteit van Amsterdam / Amsterdam InsQtute for Global Health and Development
(AIGHD) (2012 – present) Bandung. Now he is become a PhD stud
Center of the University of Amsterdam
Organiza)on: entitled: “Novel strategies and tools
•  AnQmicrobial Resistance-control Program Dr. Hasan Sadikin General Hospital surveillance”. His PhD research focuses o
•  Indonesian Society of Clinical Pathology and Laboratory Medicine infectious diseases, including antibiotic re
•  Indonesian AssociaQon of Clinical Chemistry
and laboratory capacity building.

Current ac)vi)es:
ScienQfic Project Indonesia Netherlands – Joint Research Project, enQtled: “Novel strategies and tools for anQmicrobial

resistance surveillance”, with research focuses on the microbiology aspect of infecQous diseases, including anQbioQc
resistance surveillance methods and laboratory capacity building.

Laboratory Approach to Sepsis

Adhi Kris)anto Sugianli

1
 receptors on the cell surface
rial substances in the extra-
ptor for LPS was the first TLR
s of receptors in the cytoplasm
lycans and/or nucleic acids.
ands, these receptors stimulate
mor necrosis factor (TNF),
-6. These three pro-inflamma-
temic inflammatory response
ly sepsis, and for many years
sis essentially represented an
he part of the innate immune
.
1991 defined ‘‘sepsis’’ as the
h two or more features of what
mmatory response syndrome’’ •  The first scienQfic definiQon of sepsis proposed
erature, elevated pulse rate,
abnormal white blood cell
iginal definition, published in
to include other signs and
n critical illness (Table 1).
mended that physicians make
nfection is strongly suspected,
ing. This change reflected the •  Sepsis: as the host's immune response [systemic
icult to identify an infection in
c clinical signs and symptoms,
earlier definition problematic.
at most of the clinical features
of the nature of the infection.
at the immune response, not the
problem.
Dr Roger C. Bone with the
re to sepsis than the exuberant
Bone helped to stress the
ry anti-inflammatory response
equired:
"
C
in (or arterial pCO2 532 mmHg,
# 109/L or 54.0 # 109/L (or 410%
f organ dysfunction
ns stresses that documentation of
r the diagnosis of sepsis if strong
ria, such as altered mental status,
nce of diabetes, and elevated CRP or
evitch and Tobias4.
often the terminal event of severe sepsis.
The cause of the organ failure in severe sepsis is unknown,
but it resembles the multiple organ dysfunction syndrome
(MODS) seen in patients who survive serious traumatic
injury10. Many investigators now consider both sepsis and
post-traumatic MODS to represent the same stereotypical 10/9/17
immunologic response to a severe insult. In this paradigm, the
innate immune system initially generates a pro-inflammatory
state in response to PAMPs, or in the case of tissue injury, in
response to similar molecules called damage-associated
molecular patterns (DAMPs) that are derived from damaged
host cells. In most patients, this pro-inflammatory response is
What is Sepsis ?
self-limited, even in the absence of effective treatment. But, in
patients who develop sepsis, the response is exaggerated (or
‘‘hyper-inflammatory’’) and leads to a compensatory down-
regulation of the immune system. It is not clear why this
by Schoa-muller in 1914:
happens in some patients and not others. A major risk factor
appears to be some degree of pre-existing immune dysfunc-
sepsis is a state caused by microbial invasion
tion. For instance, elderly patients (who usually have some
from a local infec4ous source into the
degree of immunodeficiency) and immunosuppressed patients
bloodstream which leads to signs of systemic
both have a higher incidence of sepsis, as well as a higher
illness in remote organs
mortality rate. Some other underlying factor or genetic
predisposition may also be involved. This subject has been
recently reviewed by Chung and Waterer11.
inflammatory response syndrome (SIRS)] to injury
As the paradigm of sepsis pathogenesis has evolved over
and/or infecQous sQmuli in the presence of a
time and as different therapeutic approaches to sepsis have
known (or strongly suspected) infecQon
been tried, different biomarkers have been used for diagnosis
of sepsis and monitoring of treatment. The initial focus in the
1980s was Dolores Limongi et al./Asian Pac J Trop Biomed 2016; 6(6): 516–519
on the early hyper-inflammatory phase, and high-
dose corticosteroids were an important component of sepsis
treatment12. TNF, IL-1b and IL-6, the three pro-inflammatory
cytokines that produce SIRS, as well as C-reactive protein
(CRP), a well-established member of the group of proteins
whose synthesis in the liver is up-regulated by IL-6, were all
Figure 1. Sepsis may be divided into two phases. Following infection, a
hyper-inflammatory phase is characterized by SIRS. This may resolve or
the patient may progress to what is called severe sepsis. During this
phase, there is evidence of CARS with immunosuppression and multiple
organ dysfunction. This may also resolve, especially with appropriate
support, but it often leads to death.
Crit Rev Clin Lab Sci, 2013; 50(1): 23–36
2
 10/9/17

Newest Guideline
HHS Public Access
Author manuscript
JAMA. Author manuscript; available in PMC 2016 August 01.
Author Manuscript

Published in final edited form as:

JAMA. 2016 February 23; 315(8): 801–810. doi:10.1001/jama.2016.0287.

The Third International Consensus Definitions for Sepsis and

Septic Shock (Sepsis-3)
Mervyn Singer, MD, FRCP, Clifford S. Deutschman, MD, MS, Christopher Warren Seymour,
MD, MSc, Manu Shankar-Hari, MSc, MD, FFICM, Djillali Annane, MD, PhD, Michael Bauer,
MD, Rinaldo Bellomo, MD, Gordon R. Bernard, MD, Jean-Daniel Chiche, MD, PhD, Craig M.
Coopersmith, MD, Richard S. Hotchkiss, MD, Mitchell M. Levy, MD, John C. Marshall, MD,
Author Manuscript

Greg S. Martin, MD, MSc, Steven M. Opal, MD, Gordon D. Rubenfeld, MD, MS, Tom van der
Poll, MD, PhD, Jean-Louis Vincent, MD, PhD, and Derek C. Angus, MD, MPH
Bloomsbury Institute of Intensive Care Medicine, University College London, London, United
Kingdom (Singer); Hofstra–Northwell School of Medicine, Feinstein Institute for Medical
Research, New Hyde Park, New York (Deutschman); Department of Critical Care and Emergency
Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Seymour);
Department of Critical Care Medicine, Guy’s and St Thomas’ NHS Foundation Trust, London,
United Kingdom (Shankar-Hari); Department of Critical Care Medicine, University of Versailles,
France (Annane); Center for Sepsis Control and Care, University Hospital, Jena, Germany
(Bauer); Australian and New Zealand Intensive Care Research Centre, School of Public Health
and Preventive Medicine, Monash University, Melbourne, and Austin Hospital, Melbourne,
Victoria, Australia (Bellomo); Vanderbilt Institute for Clinical and Translational Research,
Author Manuscript

Vanderbilt University, Nashville, Tennessee (Bernard); Reanimation Medicale-Hopital Cochin,

Sepsis-3 DefiniQons
Descartes University, Cochin Institute, Paris, France (Chiche); Critical Care Center, Emory
University School of Medicine, Atlanta, Georgia (Coopersmith);Washington University School of
Medicine, St Louis, Missouri (Hotchkiss); Infectious Disease Section, Division of Pulmonary and
Critical Care Medicine, Brown University School of Medicine, Providence, Rhode Island (Levy,
Opal); Department of Surgery, University of Toronto, Toronto, Ontario, Canada (Marshall); Emory
•  Sepsis: Life-threatening organ dysfuncQon
University School of Medicine and Grady Memorial Hospital, Atlanta, Georgia (Martin); Trauma,
Emergency & Critical Care Program, Sunnybrook Health Sciences Centre, Toronto, Ontario,
caused by dysregulated host response to
Canada (Rubenfeld); Interdepartmental Division of Critical Care, University of Toronto
(Rubenfeld); Department of Infectious Diseases, Academisch Medisch Centrum, Amsterdam, the
infecQon
•  Sep&c Shock: Subset of sepsis with circulatory
Corresponding Author: Clifford S. Deutschman, MD,MS, Departments of Pediatrics and Molecular Medicine, Hofstra–Northwell
Author Manuscript

School of Medicine, Feinstein Institute for Medical Research, 269-01 76th Ave, New Hyde Park, NY 11040 (cdeutschman@nshs.edu).
Author Contributions: Drs Singer and Deutschman had full access to all of the data in the study and take responsibility for the

and cellular/metabolic dysfuncQon associated

integrity of the data and the accuracy of the data analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data: All authors.

with higher risk of mortality

Drafting of the manuscript: Singer, Deutschman, Seymour, Shankar-Hari, Angus.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Shankar-Hari, Seymour.
Obtained funding: Deutschman, Chiche, Coopersmith.
Administrative, technical, or material support: Singer, Deutschman, Chiche, Coopersmith, Levy, Angus.
Study supervision: Singer, Deutschman. Drs Singer and Deutschman are joint first authors.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of
Interest. No other disclosures were reported.
Disclaimer: Dr Angus, JAMA Associate Editor, had no role in the evaluation of or decision to publish this article.

JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287

3
 10/9/17

Singer et al. Page 21

Author Manuscript
Author Manuscript

Figure.
Operationalization of Clinical Criteria Identifying Patients With Sepsis and Septic Shock
The baseline Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score should be
assumed to be zero unless the patient is known to have preexisting (acute or chronic) organ
dysfunction before the onset of infection. qSOFA indicates quick SOFA; MAP, mean arterial
Author Manuscript

pressure.

JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287

Author Manuscript

Common Approach for Sepsis

•  Culture -- blood culture
•  CBC -- Diff. count + NLR
JAMA. Author manuscript; available in PMC 2016 August 01.

•  PBS -- white blood cell abnormaliQes

•  Immunological respond acQviQes / sepsis
marker
–  CRP, PCT
–  IL-1, IL-6
–  Presepsin, suPAR, sTREM

4
 [35–37].
Sepsis markers can be helpful in answering three types of general questions (Table 1).
• The first question relates to their role in helping to identify—or perhaps more importantly
rule out—an infection. Infection is not an all-or-none phenomenon, and there are "gray
areas" where one can never really be certain that an infection was present or absent. Because
of their high sensitivity, sepsis markers are usually more helpful at ruling out than at ruling
in an infection. This is particularly true in critically ill patients, who often have some inflam-
matory response, but do not always have infection or require antibiotic administration.
Hence, sepsis markers, by ruling out infection, could help decrease the use of unnecessary
10/9/17
antibiotics, limit the use of excessive imaging procedures in search of a possible source, and
encourage the clinician to search for alternative diagnoses. One example of this use for bio-
markers was demonstrated by Christ-Crain and colleagues using PCT to rule out infections
in febrile patients presenting to an emergency department [38]. In patients with suspected
lower respiratory tract infection, use of antibiotics was more or less discouraged (<0.1 mcg/L
or <0.25 mcg/L) or encouraged (!0.5 mcg/L or !0.25 mcg/L) based on the PCT concentra-
tion. The result was a significant reduction in antibiotic use [38].
• The second question relates to their role in assessing the severity of disease, primarily for tri-
aging decisions. For example, whether or not to admit a patient from the emergency room or
general ward to the ICU. An example of this use for biomarkers was demonstrated by Gia-
marellos-Bourboulis et al. [39] in 1,156 hospitalized patients, showing that mortality rates
ESSAY were 2.6 times higher in patients presenting with sepsis on the general ward with a PCT con-
The Clinical Challenge of Sepsis
centration >0.12 ng/mL than in those with lower PCT levels. The authors suggested that
PCT concentrations could thus be used to help identify which patients may benefit from ICU
Identification and Monitoring
admission [39].
• The
Jean-Louis third
Vincent* question relates to their role in monitoring a patient's response to therapy. For this
Department ofrole in particular,
Intensive trendsUniversité
Care, Erasme Hospital, in concentrations over
libre de Bruxelles, timeBelgium
Brussels, are clearly
of more value than single
measurements. Again, PCT and CRP are the most widely studied biomarkers in this context.
* jlvincent@intensive.org

Summary
Table 1. How a biomarker, levels of which Points
increase in sepsis, can be used to answer clinically important questions.
ESSAY • Early treatment of sepsis is associated with improved outcomes so that rapid diagnosis is
Clinical question Sepsis Marker
important.
The Clinical Challenge of Sepsis
Increases
• The diagnosis or stays
of sepsis highill patients is challenging, because it can be Low
in critically or decreasing
compli-
Identification
Is the patient infected?
and Monitoring
cated by the
Suggests
and prior
Suggests needuse
presenceshould
antibiotics
toof
of inflammation
antibiotics
search for amaking
as a result of other underlying disease
be considered
sourcecultures negative.
of infection
processes
Suggests may not need antibiotics
Suggests additional investigations for infection could be
Jean-Louis Vincent* • Culture-dependent diagnosis of infection is slow, and biomarkers may provide a more postponed
Is the condition serious? Suggestsrapid means of to
admission ruling in or out
hospital infection.care unit
or intensive Suggests patient discharge home or transfer to regular floor
Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium
may be warranted
• Given the complexities could
of the sepsis response, no one biomarker will be sufficient to be considered
Is the patient responding to
* jlvincent@intensive.org Suggests
diagnoseantibiotic therapy may
sepsis. Combinations of need to be are needed, and
biomarkers Suggests treatment
new technology is effective and could be continued
is helping
treatment? reassessed
to speed the development of such panels. (reassurance)
Summary Points Suggests
• However, such tools cannot be used alone, and they must be seen as complementary to a could perhaps be stopped?
may need to assess need for (re)operation Suggest antibiotic therapy
a11111
careful clinical assessment and other laboratory signs.
•doi:10.1371/journal.pmed.1002022.t001
Early treatment of sepsis is associated with improved outcomes so that rapid diagnosis is
important.
• The diagnosis of sepsis in critically ill patients is challenging, because it can be compli-

Rhodes et al
cated by the presence of inflammation as a result of other underlying disease processes
and prior use of antibiotics making cultures negative.
PLOS Medicine | DOI:10.1371/journal.pmed.1002022 May 17, 2016 4 / 10
• Culture-dependent
OPEN ACCESS diagnosis of infectionIntroduction—The
is slow, and biomarkers may Clinical
provideProblem
a more
rapid means of ruling in or out infection.
Citation: Vincent J-L (2016) The Clinical Challenge Infections are common in people of all ages and around the globe. In most individuals, the host
•ofGiven the complexities of the sepsis
Med response, no one biomarker will with
be sufficient to threat, and little treatment is needed other than
13(5): after the Sepsis-3 definition (1) or septic shock demonstrated
Sepsis Identification
e1002022.
diagnose
and Monitoring. PLoS
doi:10.1371/journal.pmed.1002022
sepsis. Combinations of biomarkers
response
a short
is adequate
arecourse
needed,
to deal the potential
and new technology
of appropriate is helping
antibiotics if the origin is bacterial. However, in some cases, infec- clinical examination clear
to speedMay
Published: the17,development
2016 of such panels.tion can be associated with an inadequate or inappropriate host response, and when this results

a11111
a 36%–40% reduction of the odds of dying in the hospital with
However,
•Copyright: such
© 2016 tools cannot
Jean-Louis be used
Vincent. This is an alone, in and
the development
ated with
they must be of organ
seen dysfunction, thetoterm
as complementary a “sepsis” is used [1–3]. Sepsis can be associ-
viral or fungal infections, but the inflammatory response is generally less marked in
infection, cultures of othe
careful
open accessclinical assessment
article distributed under theand other
terms of the laboratory signs.
compliance with either the 3- or 6-hour SSC bundles (48). This
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
these cases, and the majority of patients with sepsis will have a bacterial infectious source. Such
patients are critically ill and likely to rapidly deteriorate into septic shock and multiple organ
ally unnecessary. We sugg
may be considered to be
medium, provided the original author and source are
credited.recommendation met the prespecified criteria for a BPS. The
failure if not treated quickly and effectively. Indeed, sepsis is associated with mortality rates of
around 30%, although these vary according to geographical location [4]. Most of the available
Funding: The author received no specific funding for epidemiological data on sepsis come from developed countries, and few data are available
OPEN ACCESS specifics of performance improvement methods varied mark-
this work.
Introduction—The Clinical Problem describing sepsis patterns and outcomes in poorer income and lower resource countries [5]. of antimicrobial therapy w
Competing Interests: The author has declared that There is no specific treatment for patients with sepsis, and management therefore relies on
Citation: Vincent J-L (2016) The Clinical Challenge
of Sepsis Identification and Monitoring. PLoS Med
13(5): e1002022. doi:10.1371/journal.pmed.1002022
edly between studies; thus, no single approach to performance
Infections are common in people of all ages and around the globe. In most individuals, the host
no competing interests exist. infection control—with source removal and effective antibiotics—and organ function support
response is adequate to deal with the potential threat, and little treatment is needed other than
Provenance: Commissioned; externally peer- [6]. There is good evidence that early treatment is associated with improved outcomes in these
Two or more sets (aero
a short course of appropriate antibiotics if the origin is bacterial. However, in some cases, infec-
reviewed.
improvement could be recommended (Supplemental Digital
patients [6–8], and the ability to recognize the condition as soon as possible is therefore
are recommended before
Gold Standard in Sepsis
Published: May 17, 2016 tion can be associated with an inadequate or inappropriate host response, and when this results
Copyright: © 2016 Jean-Louis Vincent. This is an in the development of organ dysfunction, the term “sepsis” is used [1–3]. Sepsis can be associ-
open access article distributed under the terms of the
Creative Commons Attribution License, which permits these
PLOS
Content 5, http://links.lww.com/CCM/C326).
ated with viral or fungal infections, but the inflammatory response is generally less marked in
cases, and the
Medicine majority of patients with sepsis will
| DOI:10.1371/journal.pmed.1002022 Mayhave a bacterial infectious source. Such
17, 2016 1 / 10
in all patients with suspe
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited.
patients are critically ill and likely to rapidly deteriorate into septic shock and multiple organ
failure if not treated quickly and effectively. Indeed, sepsis is associated with mortality rates of cultures may be drawn to
around 30%, although these vary according to geographical location [4]. Most of the available
culture yield has not been
C. DIAGNOSIS
Funding: The author received no specific funding for epidemiological data on sepsis come from developed countries, and few data are available
this work.
describing sepsis patterns and outcomes in poorer income and lower resource countries [5].
Competing Interests: The author has declared that
no competing interests exist.
There is no specific treatment for patients with sepsis, and management therefore relies on
infection control—with source removal and effective antibiotics—and organ function support
tial draws or timing to
Provenance: Commissioned; externally peer-
reviewed.
1. We recommend that appropriate routine microbiologic
[6]. There is good evidence that early treatment is associated with improved outcomes in these
patients [6–8], and the ability to recognize the condition as soon as possible is therefore on appropriate methods
cultures (including blood) be obtained before starting samples are enumerated i
PLOS Medicine | DOI:10.1371/journal.pmed.1002022 May 17, 2016
antimicrobial therapy in patients with suspected sepsis or 1 / 10
In potentially septic pa
septic shock if doing so results in no substantial delay in (in place > 48 hours) in w
the start of antimicrobials (BPS). cally apparent or a suspic
ated infection exists, at le
Remarks: Appropriate routine microbiologic cultures always
obtained from the cathet
include at least two sets of blood cultures (aerobic and
eral blood cultures). This
anaerobic).
a potential catheter-relat
Rationale: Sterilization of cultures can occur within minutes to inconsistent regarding th
hours after the first dose of an appropriate antimicrobial (49, 50). culture positivity (i.e., eq
Crit Care Med 2017; 45:486–552
Obtaining cultures prior to the administration of antimicrobials the vascular access devic
significantly increases the yield of cultures, making identification the peripheral blood cult
of a pathogen more likely. Isolation of an infecting organism(s) access device is the source
allows for de-escalation of antimicrobial therapy first at the tant to note that drawing
point of identification and then again when susceptibilities are lar catheter in case of pos
obtained. De-escalation of antimicrobial therapy is a mainstay eliminate the option 5 of re
of antibiotic stewardship programs and is associated with less tunneled catheters) imme
resistant microorganisms, fewer side effects, and lower costs (51). In patients without a s
Several retrospective studies have suggested that obtaining cul- tion and in whom anothe
 who need more careful monitoring so that the condition may immunoassays, including some design
be diagnosed and treated as soon as possible. This review will the patient’s bedside, are commerciall
discuss all the major types of biomarkers of sepsis which have like TNF and IL-1b, IL-6 is not spec
been proposed, and will try to place them within the context major role as a biomarker of sepsis ap
of both the different stages of sepsis and the targeted not diagnostic. Numerous studies hav
therapeutic approaches. levels of IL-6 in septic patients a
increase in mortality22–24. This has b
Pro-inflammatory cytokines as markers of the 10/9/17
more powerfully in a mouse model of
hyper-inflammatory phase of sepsis (cecal ligation and puncture, or CLP) i
TNF, IL-1b and IL-6 are the cytokines that mediate the initial only predict survival, but also are ab
response of the innate immune system to injury or infection. that could benefit most from treatme
XML Template (2013) [6.3.2013–12:46pm] [23–36]
//blrnas3/cenpro/ApplicationFiles/Journals/TandF/3B2/BCLS/Vol05001/130001/APPFile/TF-BCLS130001.3d (LAB) TNF and IL-1b both activate endothelial cells, attracting
[INVALID Stage] one of the desired attributes of an ide
circulating polymorphonuclear leukocytes (PMNs) to the site. because it may be able to identify tho
They also enter the circulation, causing fever and other who are at increased risk of developing
systemic symptoms. IL-6 enhances therefore need supportive therapy.
28 J. D. Faix Crit Rev Clinthe liver’s
Lab Sci, production
2013; 50(1): 23–36 of
the Heparin-binding
so-called acuteprotein
phase(HBP,
reactants, including CRP, and also Another group of pro-inflammatory
also known as azurocidin) been investigated as biomarkers of sep
stimulates a shift
is released from PMNingranules
the production
when the surfaceof cells in the
integrins of bone
marrow cytokines called chemokines. Althoug
the PMNssoengage
that more PMNs
selectins on theareendothelial
produced. cellTherefore,
surface73. these
three cytokines
It alters are essentially
endothelial cytoskeletalresponsible
structure for and the features of
induces chemokines is based on the arrange
disassembly
SIRS of the
and could intercellular useful
be potentially junctions, enhancing the
as biomarkers of sepsis terminal cysteine residues, there are t
M. Holub et al. on function26. Homing chemokines
ability of
(Figure 2).the PMNs to pass through the endothelial cell
barrier. One study showed it to be an excellent predictor of the adaptive immune system, especially
severe edema and vascular collapse seen in severe sepsis74. tissue, while inflammatory chemoki
This would make HBP an excellent biomarker for severe monocytes to sites of inflammatio
sepsis, but there has not been any significant follow-up to movement through the blood vessel
these initial reports.
inflammatory chemokines are pot
Activation markers such as CD64, CD11b and TREM-1
coli (15), are Streptococcus
also expressed on monocytes. pneumoniae However, (4), investigation
Haemophilus of sepsis, and some have been shown t
parainfluenzae (1) andmarkers
monocyte activation Staphylococcusas potential biomarkers hominis (1). In
of sepsis These include the chemokine IL-8 fo
has focused on the soluble form of the receptor for advanced and monocyte chemoattractant protein
three patients, the etiology of IMD was confirmed using
glycation end-products (RAGE). Just as the receptor for of sepsis mortality28. Although it p
a polymeraseendotoxinchain reaction
is an excellent example(PCR) of aanalysis
PAMP receptor, of theRAGE blood by attracting monocytes to sites o
or cerebrospinal
may be considered fluid. Three the prototype patients of awith DAMP pneumonia
receptor. MCP-1 may also promote the synthe
had anAlthoughetiologic originally believed to be specific for oxidized cross-
diagnosis that was established by a
linked glycated protein (hence its name), it appears to also be
inflammatory cytokine discussed be
significant increase in variety
specific IgG antibodies may represent a key element in th
able to bind a large of DAMPs. These includeagainst high-
from the pro-inflammatory phase to t
Chlamydophila
mobility group pneumoniae
box 1 (HMGB1), (2) aand Legionella
non-histone DNA-binding pneu-
protein and other proteins released by necrotic, but not phase.
mophilaapoptotic,
(1). The cohort of patients with viral infection
cells75. In 2008, detection of elevated circulating
included
Figure 3. Activated inflammatory cells up-regulate a number of proteins 24 2.
soluble
Figure
patients
RAGE (8 females,
(sRAGE),
Sepsis begins with produced
16 males)
either infection by either with
or tissue
ainjury.
alternative mean PAMPs
which may be detected as biomarkers of sepsis, either on theage cell of from PCT and CRP as biomarkers of s
41.5invading
splicing yrs spanning
or proteolytic
organisms cleavageor19–69
DAMPs ofyrs. the In
from these
extracellular
injured tissue patients,
domain
cells (or both)
surface or as soluble forms in plasma. (a) An unstimulated PMN; (b) a of recognized
the membrane receptor, receptorswas ablesuch to aspredict survival
are by macrophage the TLRs. This results PCT and CRP are both proteins pr
stimulated PMN with darker (‘‘toxic’’) granules and a Dohle the body following diagnoses 76 were established: tick-borne
(arrow); (c) frequently utilized biomarkers of sepsis related to PMNs inthe
in severe sepsisof
production .pro-inflammatory
Recently, elevated sRAGE
cytokines suchlevels
as TNF, were IL-1b and
infection and/or inflammation. They
include CD64, the soluble forms of TREM-1 and CD11b, and HBP. encephalitis
IL-6 and
similarly (15),
chemokinesenteroviral
predictive suchof aspoor meningitis
IL-8 and
survival MCP-1. in(4),
IL-6 viral
stimulates
patients hepa-
with the liver
to produce CRP and complement proteins.
77 Manyiscells in the body also most widely used clinical tests to
(d) Frequently utilized biomarkers of sepsis related to macrophages titis A (2),
or
produce
chicken
community-acquired
PCT
pox (2)to and
in response
pneumonia parvovirosis
. There (1). In the
controversy
patients with sepsis, with the exceptio
monocytes include the soluble forms of CD14 (which facilitates about the potential use of both sRAGE infection and injury. of sepsis
as a biomarker
control ingroup,
recognition of bacterial lipopolysaccharides) and the receptor for RAGE. 18 healthy adult persons were enrolled
patients with pneumonia, however. Lung alveolar type 1
(5 females cells and 13 males) withlevels a mean
Crit Rev Clin Lab Sci, 2013; 50(1): 23–36
normally express high of RAGE age and, 43 yrs therefore,span-
using the optimal cut-off68. It is likely that this test ning will 23–69 sRAGE yrs. The
levels may details
be elevated describingin pulmonary the infection
inclusion and
in the
78
receive more widespread acceptance, especially because it is absence of sepsis .
available on some of the automated hematology analyzers
exclusion criteria and clinical diagnostics
The TLR on the surface of macrophages and monocytes
have been re-
used to measure the total WBC count, a commonly ordered ported elsewhere
that recognizes[5]. endotoxin requires the assistance of another
test in sepsis evaluations. Neutrophil
membrane-boundand lymphocyteprotein, CD14, countsas wellwere as an determined
acute phase
The expression of the integrin CD11b, which enhances the reactant (lipopolysaccharide-binding protein or LBP) which
ability of neutrophils to adhere to the endothelium in sites
using afacilitates
CoulterendotoxinSTKS clinical analyzer (Coulter Elec-
binding to CD14. Although several
of inflammation, is also increased in bacterial infection,tronics and Inc., Miami,
studies have shown USA). NLCR levels
that elevated was expressed
of LBP can identify as the
some have proposed the use of both CD64 and CD11b
69
absolute number
patients with of neutrophils
infection, at very divided by the absolute
elevated concentrations this
together to diagnose sepsis . Several other neutrophil protein effectively neutralizes LPS, and may even be anti-
activation markers have been investigated as potential
number of lymphocytes79 [6].
inflammatory . Therefore, LBP may be less
Statistical analyses
Cent. Eur. J. Med. • 7(2) • 2012
DOI: discriminating
were • 258-261
10.2478/s11536-012-0002-3

biomarkers of sepsis but they have been measuredperformed in by abiomarkers

than other certifiedwith statistician.
regard to risk The data were
of developing severe ex-
plasma by immunoassay, either as soluble versions ofpressed 80 Central European Journal of Medicine Figure 1. ROC curve of NLCR values d
the as the
sepsis medianshowever,
. Recently, (interquartile there has ranges).
been interest Receiver in
diagnostic value for discrimina
cell-surface proteins or because the proteins are released measuring a soluble form of CD14 as a biomarker of sepsis.
during degranulation. Most of these have been investigated operating
in characteristic
Soluble CD14 levels were (ROC) shown curves to be comparable were drawn to PCT forfor and viral infections.
M. Holub et al.
experimental models of sepsis and reports of their usefulness NLCR diagnosis
as aNeutrophil
measure
of bacterial of discriminating
to
infection lymphocyte
81
power
and correlated count between
with the ratio
in clinical settings are limited.
The best studied is probably the triggering receptor
bacterial and
degree
asviral
of severity infections
a biomarker and
in septic patients
of as
82
.a measure of capa-
bacterial infections 4. Discussion
expressed on myeloid cells-1 (TREM-1). TREM-1 is a bility to detect bacterial infections. The ROC curve dem-
Research Article Detection of infectious organisms and their
coli (15), Streptococcus pneumoniae (4), Haemophilus member of the immunoglobulin superfamily which, onstrated like the false positive rate (x axis) and the sensitiv- Diagnostic markers that are currently
products in sepsis
parainfluenzae (1) and Staphylococcus hominis (1). In 70
ity of . the test (y axis). The areas under Michal Holub1, Ondřej Beran1,
Nikolathe curves (AUC)Chalupa1* nation of bacterial etiology are not s
CD64, is up-regulated when PMNs are exposed to bacteria
three patients, the etiology of IMD was confirmed using Kaspříková 2
, Pavel
However, clinical studies of the ability of the soluble form If sepsis is defined as SIRS in a patient with infection, then
a polymerase chain reaction (PCR) analysis of the blood
of TREM-1 to reliably identify patients with sepsis have were also evaluated.
the ultimate biomarker Department of Infectious and
would be the identification of the Tropical Diseases, First
1
Faculty of Medicine, Moreover, the markers that have be
or cerebrospinal fluid. Three patients with pneumonia Charles University in Prague and University Hospital Bulovka, CZ-180 81, Czech Republic
had an etiologic diagnosis that was established by not a been promising71. A recent report in which soluble microorganism responsible. This would not only confirm the duced into clinical practice are ass
significant increase in specific IgG antibodies against Institute of Biophysics and Informatics, First Faculty of Medicine,
2

TREM-1 predicted poor survival in ED patients more diagnosis; it would also provide a specific target
Charles University for
in Prague, CZ-120 00, Czech Republic costs that serve as major limitation
therapy.
Chlamydophila pneumoniae (2) and Legionella pneu-
accurately
mophila (1). The cohort of patients with viral infection
included 24 patients (8 females, 16 males) with a mean
than
this biomarker72.
either PCT or CRP may renew interest in Despite the fact that
3. Results
sepsis
Received 22 November 2011; Accepted 20 December 2011
may represent
to infection which might not be successfully treated by
an unusual response
include PCT, which is considered a
age of 41.5 yrs spanning 19–69 yrs. In these patients, Abstract: The implementation of new markers of bacterial infection into clinical practice is hindered by their costs. We assessed the potential
use of the neutrophil to lymphocyte count ratio (NLCR) to discriminate between bacterial and viral infections. NLCR was evaluated
marker for infection in critically ill patie
the following diagnoses were established: tick-borne
encephalitis (15), enteroviral meningitis (4), viral hepa- The medians of NLCR were 11.73 (7.73–21.87) in
in 45 patients with bacterial infections: 24 patients with viral infections and 18 healthy adults. The medians of NLCR were 11.73 in
bacterial infections, 2.86 in viral infections and 1.86 in controls. The NLCR cut-off value of 6.2 exhibited a sensitivity value of 0.91 and
ly implemented in routine diagnostic p
titis A (2), chicken pox (2) and parvovirosis (1). In the a specificity value of 0.96 for bacterial infection. These results suggest a diagnostic potential for NLCR.
control group, 18 healthy adult persons were enrolled
patients with bacterial infections, 2.86 (1.95–4.15) in
Keywords: Bacterial infection • Viral infection • Laboratory diagnosis • Marker • Neutrophil to lymphocyte ratio
versely, the NLCR is a low-cost and
(5 females and 13 males) with a mean age 43 yrs span- patients
© Versita Sp. zwith
o.o. viral infections and 1.86 (1.44–2.73) in parameter that does not require any
ning 23–69 yrs. The details describing the inclusion and
exclusion criteria and clinical diagnostics have been re- healthy adults. The optimal cutoff value for NLCR was for NLCR measurements. Similar to
ported elsewhere [5].
Neutrophil and lymphocyte counts were determined
determined as 6.2, which exhibited
1. Introduction a sensitivity
emergency care settings [7]. However, there value
is a lack of of WBC populations have rapid kine
information about the potential use of NLCR to discrimi-
using a Coulter STKS clinical analyzer (Coulter Elec-
The idealofmarker
0.91 and
for rapid a specificity
discrimination between bac-value of bacterial
nate severe 0.96.from The viral AUC
infections. was
Therefore, role of neutrophils in the early stage
tronics Inc., Miami, USA). NLCR was expressed as the terial and viral infection has not been determined for the aim of our study was to assess the sensitivity and
absolute number of neutrophils divided by the absolute routine 0.971 forC-reactive
use. Currently, predicting bacterial
protein (CRP), infection
white specificity of NLCR for inthealldiagnosis
87 enrolled
of community-ac- tory response. Neutrophilia is usually
number of lymphocytes [6]. Statistical analyses were
performed by a certified statistician. The data were ex- subjects and 0.956 for differentiating between bacte-
blood cell (WBC), and neutrophil counts are the most quired bacterial infections in patients who were hospital-
frequently used parameters for early diagnosis of bac- ized with febrile illness.
lymphocytopenia, which has also be
Figure 1. ROC curve of NLCR values demonstrating the high
pressed as the medians (interquartile ranges). Receiver diagnostic value for discrimination between bacterial rial and viral infections. The ROC curve is presented
terial infection [1]. However, these parameters do not
always reliably differentiate among bacterial, fungal,
a good predictor of bacteremia [11].
operating characteristic (ROC) curves were drawn for and viral infections.
NLCR as a measure of discriminating power between in Figure
and severe viral infections1.[2]. Therefore, other param- 2. Methods probably develops because of the nee
bacterial and viral infections and as a measure of capa- 4. Discussion eters have been recommended, including serum levels
bility to detect bacterial infections. The ROC curve dem-
of procalcitonin (PCT), interleukin (IL)-6, and IL-8 [3,4]. In all, 87 adults were enrolled in the prospective study. adaptive immune response in favor o
PCT has become a widely used marker in recent years. The study was approved by the ethics committee, and
onstrated the false positive rate (x axis) and the sensitiv-
ity of the test (y axis). The areas under the curves (AUC)
Diagnostic markers that are currently used for discrimi-
nation of bacterial etiology are not sufficiently reliable.
The superiority of PCT over CRP, WBC and neutrophil the patients signed informed consent forms before en- This notion is supported by data sho
counts for predicting the bacterial etiology of infection rollment. The cohort with bacterial infection comprised
were also evaluated. Moreover, the markers that have been recently intro- was also shown in our previous study [5]. 45 patients (22 females and 23 males) with a mean age cells are the most altered lymphocyte
duced into clinical practice are associated with high Neutrophilia and lymphocytopenia are well-estab- of 45 yrs spanning 18–80 yrs. The following clinical di-
costs that serve as major limitations. These markers lished markers of severe bacterial infection. Zaho- agnoses were established in the patients: community- vere bacterial infections and sepsis
3. Results include PCT, which is considered a fast and specific rec et al. [6] have documented the neutrophil to lym- acquired pneumonia (19), urosepsis (10), pyelonephritis
the NLCR that was observed in our
marker for infection in critically ill patients and is current- phocyte count ratio (NLCR) as an easily measurable (9), cellulitis (2), erysipelas (1), invasive meningococcal
The medians of NLCR were 11.73 (7.73–21.87) in ly implemented in routine diagnostic panels [9,10]. Con- parameter that indicates the severity of systemic inflam- disease – IMD (3) and sepsis (1). The bacterial etiol-
patients with bacterial infections, 2.86 (1.95–4.15) in versely, the NLCR is a low-cost and easily obtainable mation and sepsis in 90 oncology patients. Moreover, ogy was confirmed in 24 patients (53.9%). The following
NLCR is a useful parameter for predicting bacteremia in etiological agents were detected by culture: Escherichia
patients with viral infections and 1.86 (1.44–2.73) in parameter that does not require any special equipment
healthy adults. The optimal cutoff value for NLCR was for NLCR measurements. Similar to PCT, the changes
* E-mail: pavel.chalupa@lf1.cuni.cz

determined as 6.2, which exhibited a sensitivity value
of 0.91 and a specificity value of 0.96. The AUC was
0.971 for predicting bacterial infection in all 87 enrolled
subjects and 0.956 for differentiating between bacte-
rial and viral infections. The ROC curve is presented
in Figure 1.
6
of WBC populations have rapid kinetics, reflecting258 the
role of neutrophils in the early stage of the inflamma-
tory response. Neutrophilia is usually accompanied with
lymphocytopenia, which has also been suggested as
a good predictor of bacteremia [11]. Lymphocytopenia
probably develops because of the need to suppress the
adaptive immune response in favor of innate immunity.
This notion is supported by data showing that CD4+ T
cells are the most altered lymphocyte subset during se-
vere bacterial infections and sepsis [12]. The AUC for
the NLCR that was observed in our study was similar
 10/9/17

REVIEWREVIEW
Virulence 5:1, 154–160; January 1, 2014; © 2014 Landes Bioscience

Rapid diagnosis of sepsis

Frank Bloos and Konrad Reinhart*
Department of Anesthesiology and Intensive Care Medicine; Jena University Hospital; Jena, Germany

Keywords: sepsis, diagnosis, biomarker, cytokines, procalcitonin, PCR

Abbreviations:
Table 1. CRP,
Diagnostic value andC-reactive protein;
limitations of ICU,tointensive
biomarkers separate care unit; from
infectious IL, interleukin; LBP,
non-infectious lipopolysaccharide
causes of inflammation binding protein; MD2,
myeloid differentiation factor 2; PCR, polymerase chain reaction; PCT, procalcitonin; sTREM-1, soluble triggering receptor
Biomarker Source Sens. Spec. AUC LR+ LR− Limitations
expressed on myeloid cells 1; suPAR, soluble urokinase plasminogen activator receptor; TNF, tumor necrosis factor
Metaanalysis Slow kinetic, independent of infection severity,
C-reactive protein21 0.75 0.67 – 2.43 0.42
(n = 1386) increased in many inflammatory diseases
Biomarkers in sepsis diagnosis
Metaanalysis
Fast and
Procalcitonin 35 appropriate therapy is 0.77the cornerstone0.79 in the 0.89 antimicrobial
4.0 therapy Increased
0.29
in various non-infectious causes of8-10
is an independent predictor for death. SIRS
(n = 3244) (i.e., cardiac arrest, severe trauma)
therapy of sepsis. However, the discrimination of sepsis from Conventional diagnosis relies on the recognition of SIRS caused
non-infectious causes Cohort of inflammation may be difficult.
study
0.86 by infection and– the new onsetLimitedof organ dysfunction. However,
6
Interleukin-657 0.82 0.75 – data, conflicting results
Biomarkers have Materials
been suggestedand
(n = 327) to aidmethods
physicians in this this concept has been criticized after it has been published
decision. There is currently no biochemical technique available
Metaanalysis and study design because SIRS lacks specificity to be clinically meaningful. The
Downloaded by [202.152.151.234] at 10:26 05 September 2017

which alone
sTREM-1 78
allowsPatients
a rapid and reliable0.79discrimination 0.80between 0.87 4.0 0.26 Present in inflammatory disease without infection
(n = 1795) discrimination of SIRS with and without infection remains
sepsis and non-infectious inflammation. Procalcitonin (PCT) is
currently the most This
Cohort study
study
investigated isbiomarker
part of afor prospective
this purpose. the main study
observational problemofincommunity-onset
the clinical setting.11-13 Thus,
severe confirming
sepsis and
LBP57 0.57 0.85 0.73 infection
– – Non-specific marker ofresponse
inflammation
C-reactive protein septic(n =interleukin
and 327)
shock in adults inferior
6 perform conducted to PCTfrom
in Septemberas2011 cause toofJune
a severe
2012inflammatory
at Skaraborg Hospital, is the
a
most studies and their value in diagnosing sepsis is640
not beds,
defined. main challenge in the diagnosis of sepsis. A group of experts
secondary
Cohort study hospital with in the western region of Sweden. All patients 18 years con-
suPAR 98
All biomarkers including PCT are also –released after– various 0.62 revisited
– the original
– sepsis guidelines
Limited data; lowand developed
diagnostic valuetheforPIRO
sepsis
(n = 273) admitted to the emergency department for suspicion of a community-onset sepsis
secutively
non-infectious inflammatory impacts. This shortcoming (predisposition, infection, response, organ dysfunction) concept
Data give sensitivity
needs to be(sens.), specificity
takenwere asked
into account(spec.), area under the in
to participate
when biomarkers curve
arethe(AUC)
tofromOnly
study.
used receiver
for an operating
those characteristics,
patients
improved who gave positive
characterization their +
) and negative
and(LRstaging
written ofinformed(LR−) likelihood
patients with
ratios ofaid
a biomarker
the physicianfor differentiation
in the of infectious
diagnosis of sepsis. vs. non-infectious
Polymerase chaincausessepsis.
of inflammation.
14
Detection LBP, lipopolysaccharide
of microbial binding
nucleic Review
acids protein; suPAR,
by polymerase soluble
chain
urokinase plasminogen
consent
activator
were
receptor;
enrolled.
sTREM 1,may
The
soluble
study
triggering
was approved by the Regional
receptor expressed on myeloid cells 1.
Ethical Board of Goth-
reaction (PCR) based pathogen detection improve time to reaction (PCR) and biomarkers were named as future tools to
enburg
cannot(376–11).
Downloaded by [202.152.151.234] at 10:26 05 September 2017

adequate therapy but rule out the presence of infection describe the conditions infection and response within the PIRO
surgerywhen and negative.
pancreatic surgery. At the 19,20
A metaanalysis
time of admission showed to theonlyemergency
a A recent metaanalysis including 3244 clinical
patients and from 30
system. department,
PCR-based pathogen signs detection
and symptoms,
as well as measurement of
sensitivity 0.75 and a specificity laboratory of 0.67
data to weredifferentiate
collectedbacterialand recorded. studies
biomarkers Thecalculated
sampling
should a sensitivity
allow wasa more of 0.77
performed
rapid and a ofspecificity
according
diagnosis to as
sepsis rou- of 0.79
they
from noninfectious causes tine hospital procedures and prior to administration of antibiotic therapy. All medical records It
of infection. 21
to
are discriminate
available within sepsis
one from
working non-infectious
day. The aim causes
of this of
review sepsis.
is to
35

In the SepsisICU-setting,
is amongwere thetheperformance
most common of CRP causesto discriminate
of death in was concluded
summarize the that PCTabout
literature is a helpful
the marker (see
biomarkers for early
Table diagnosis
1 for an in
retrospectively reviewed by two senior specialists in infectious diseases (LL and GJ) to
patients with and
hospitalized without
patients. sepsis mortality
Hospital is only moderate.of patientsInwith sepsis sepsis
a recent overview) bothand in medical
PCR-based as well
pathogenas in surgical
detectionpatients.
currentlyThis confirms
proposed
studyrangeson critically
from 28.3illtopatients
determine
41.1% in with whether
North SIRS, America
the
elevatedpatients fulfilled
Europe. In aforformer
and CRP-levels 1 Sepsis-2 and Sepsis-3
metaanalysis
the diagnosis of sepsis.
criteria,
on Thepatients respectively.
after surgery
publications
According
for thisorreview
trauma havewhere
on ICU the Unitedday 1 States,could to Sepsis-2
differentiate
Martin et al.criteria,
reported bacterial
between apatients sepsisand
with
yearly increase was
of defined
PCT as verified
identified
been identified sepsis
by bacterial
better PubMed
systematic infection
than CRP. 36and systemic
A third
searches. Onlymetaanalysis
studies
without8.7%sepsis. in the However,
occurrence of sepsis
inflammatory
CRP wasresulting
response
inferior in to a syndrome
sepsis incidence
procalcitonin (SIRS), comparing
did whereas
not find sepsis
severe to bacterial
a sufficient non-infectious sepsisinflammation
diagnostic was defined
accuracy for have
as veri-
the been
diagnosis
and of 240.4 cases
sTREM-1 andpercould 100
fied000
not inhabitants
predict sepsis
bacterial in 2000.
prognosis 2
Many
andorsepsis-induced patients
positivity included
of hypotension
of sepsis.for37 evaluation of the diagnostic value.
However,
or tissue the hypoperfusion
latter analysis was orbiased
organby the choice
dysfunc-
with sepsis
blood culture. Similarly, may remain unrecognized as occurrence of infection
tion CRP had some ability to correctly of selection criteria. PCT levels between 0.1occurrence
and 0.5 ng/ml
22 35,38
according to the Swedish criteria (Fig 1; S1 Text) [50]. SIRS was
Biomarkers defined as the
related
diagnose organ with
patients dysfunction
severe is poorly
sepsis in the documented
emergency outside
departmentof the suggest presence
ICU.significantly
Sepsis is especially of at least two ofthethe following criteria:to fever >38.0˚C orofhypothermia bacterial infection <36.0such ˚ as lower respiratory
C, tachypnea >20
inferiorcommon to PCTinand elderly andprospective
is likely
3
but was IL-6. No tract infections requiring antimicrobial therapy. 39
For critically
increase substantially breaths/min, tachycardia >90 beats/min, leucocytosis C-reactive protein >12x109 cells/L or leucopenia <4x109
randomized studies aboutas the the population
impact of CRP ages.4
guided treatment ill patients, cut-offs for sepsis diagnosis differ considerably and a
Sepsis is defined as invasionAccording of pathogensto into the blood stream bacterial C-reactive (CRP) is an acute as phase protein and is released
algorithms on outcomecells/L. are available. Reasons Sepsis-3
for the moderate criteria, median cut-off sepsis was
of 1.1defined
(interquartile bacterial infection-in-
range 0.5–2.0) ng/ml across
together with the host duced response
organto this invasion.5characterized
dysfunction Thus, sepsis by from the liver
astudies
rise in after stimulation
total SOFA predominantly of IL-6 and other
35 2 (Fig 1) [1]. For both Sepsis-
discrimination of infectious from noninfectious patients may the
consists of the systemic inflammatory response syndrome (SIRS) cytokines.15 During infection, CRP has both pro-inflammatory was reported. Patients with septic shock have the
includecaused (1) the slow kinetic
by infection. 2Sepsis
and of CRP
Sepsis-3,
may be levels after onset
verified
complicated of
bacterial
by infection,
remote infection
organ highest
andwas PCT levels
defined
anti-inflammatory as averagingeffectsbetween
a clinical infection 4 and
as it mediates and45identification
ng/ml.38 of
elimination
(2) CRPdysfunctionincreases during
(severe of
sepsis)minor
relevant infection
or arterial bacteria and may
by culture,
hypotension
RESEARCH ARTICLE not or
(septic reflect
as typical
shock), Aclinical
pathogensmetaanalysis also reported
butsymptoms, inhibits such that moderately
interactionas erysipelas.
between increased PCT
Bacteraemia
endothelial values
cells
severity
which of infection,
significantly and (3)defined
worsens
was CRP outcomeis elevated
as of after with
patients
a positive noninfectious
blood infection.
culture 6 around
and
result. 1 ng/mlSecretion
leukocytes. in critically ill patients
is started 4 to 6 are suspicious
h after stimulationfor invasive
and
causes of inflammation
Current guidelines recommend such as trauma,
Diagnostic
that anti-infectious
accuracy
surgery or rheumatic therapy fungal
of procalcitonin,
peaks atrather36 h. CRPthanisbacterial
frequently infections. 40
However,ofthe
used for the diagnosis number of
infection.
disorders.
such as 23-25
antimicrobial therapy andneutrophil-lymphocytesurgical source control should studies In primarycount care,ratio,
included into theC-reactive
addition metaanalysis
of CRP to a was set oflowdiagnostic
and the statistical
rules
CRP be initiated as soonBiomarker
levels decrease asover
possiblethe to first measurements
48 h outcome.
optimize when successful
7
Indeed, heterogeneity
improved the recognitionconsiderable. of The authors concluded
pneumonia. 16
In surgical that further
patients,
compliancetherapy to sepsis is
protein,
guidelines improvesThe outcome
and lactate
and time to studies
in
CRP can
patients with suspected
antimicrobial CRPinitiated.
levels were
26,27
measured SACiUCI-study
with the ADVIA are aid
Chemistry
to differentiate
necessary to decideacute
Instrument (Siemens
appendicitis
on empirical from other
antifungal
Healthcare therapy
Diag-
bacterial
investigated patients with community acquired sepsis. The study based on PCT levels. sepsis noninfectious causes of40 lower abdominal pain17 and may predict
nostics Inc.) and plasma lactate on an ABL 800 Flex (Radiometer Medicalsurgery. ApS). 18NLCR were
*Correspondence
demonstrated in 891to:patients
Konrad Reinhart;
that CRP Ljungström
declined during1 the first infectious complications
2 Circulating PCT
after colorectal
1,3 levels decrease
However,
3,4 with a half-time of about
data
5 d after determinedLars
Email: konrad.reinhart@med.uni-jena.de
successful implementation on
of an
Barbara
ADVIA
antimicrobial
, Anna-Karin Pernestig
2120i
Usener5, Dianatherapy.
(Siemens
Tilevik2*
28
24
, Gunnar
about theJacobsson
hHealthcare
when diagnostic , accuracy
Rune Andersson
Diagnostics
the infection of CRP,counting
Inc.),
is sufficiently to treated.
distinguish infectionPCT
neutrophils
Dropping
Submitted: 08/28/2013; Revised: 11/29/2013; Accepted: 12/02/2013 from noninfection are ambivalent. Prediction of infectious
However, CRP-levels are and
http://dx.doi.org/10.4161/viru.27393 poorlymphocytes
predictors ofusing
1 Department mortality.the 29,30
white blood levels
of Infectious Diseases, Skaraborg
cell differential
Hospital, are therefore
Skövde,
methods
Sweden,associated
towith
2 Systems Biology
calculate
improved
Research
the survival
NLCR. CRP,while
rates
a1111111111 complication was insufficient after gastroesophageal cancer
Procalcitonin
a1111111111
Centre, School of Bioscience, University of Skövde, increasing or persistent
Skövde, Sweden, 3 CARe–Center elevated PCT levels are predictive for an
for Antibiotic
Resistance Research, Gothenburg University, Gothenburg, Sweden, 4 Department of Infectious Diseases,
Procalcitonin
a1111111111 (PCT) is the prohormone of calcitonin
Institute of Biomedicine, which
Sahlgrenska Academy,unfavorable
Gothenburg Universityoutcome. 41-43
and Sahlgrenska The sufficient
University Hospital,discrimination between
a1111111111produced in the C-cells
is normally of the
Gothenburg, Sweden,thyroid glands.
5 Department of Clinical infectious
Chemistry, UnilabsandAB,noninfectious
Skövde, Sweden conditions by PCT and the drop of
154
a1111111111 Virulence Volume 5 Issue 1
In healthy humans, all PCT is cleaved to calcitonin
* diana.tilevik@his.se and only PCT-levels in appropriately treated patients raised the hypothesis
< 0.1 ng/ml is measured in the blood. Regulation of PCT is that PCT levels can aid the physician in determining duration
changed during infection.31 This results in a massive release of of antimicrobial therapy. Several prospective randomized studies
PCT into Abstract
OPEN the ACCESS bloodstream which depends on sepsis severity.32 have been undertaken comparing a PCT-guided antimicrobial
In 1993, AssicotL,and
Citation: Ljungström Pernestigcoworkers
A-K, Jacobsson were the first to describe PCT therapy with a control group without a PCT algorithm. In patients
as a G,potential biomarker
Andersson R, Usener for sepsis Background
B, Tilevik D (2017) and infection.33 PCT shows presenting with lower respiratory tract infections in the primary
Diagnostic accuracy of procalcitonin, neutrophil-
a more favorable
lymphocyte count ratio,kinetic profile
C-reactive protein, and than CRP and cytokines as its
Early recognition is a key factor to achieve care or emergency
improved outcomes fordepartment
septic patients.setting,
Combina-a PCT-guided therapy
levelslactate
increase within
in patients with suspected4 bacterial h aftertions
to 12sepsis. onset of biomarkers,
of infection. as opposed
34 to singleresulted
ones, mayinimprove timely diagnosis
a significant reductionand survival.
in duration of antimicrobial
PLoS ONE 12(7): e0181704. https://doi.org/ We investigated the performance characteristics of sepsis biomarkers, alone and in combi-
10.1371/journal.pone.0181704 nation, for diagnosis of verified bacterial sepsis using Sepsis-2 and Sepsis-3 criteria,
Editor: Luciano Cesar Pontes Azevedo, Hospital respectively.
Sirio-Libanes, BRAZIL
www.landesbioscience.com
Received: April 13, 2017 Methods Virulence 155
Procalcitonin (PCT), neutrophil-lymphocyte count ratio (NLCR), C-reactive protein (CRP),
Accepted: July 4, 2017
Fig 1. Definitions of verified bacterial sepsis,
and lactate severe bacterial
were determined sepsis,
in a total of 1,572 and of
episodes bacterial septic
adult patients shock
admitted according to Sepsis-2
to the
Published: July 20, 2017
and Sepsis-3, respectively. SIRS, systemic
emergency inflammatory
department response
on suspicion syndrome;
of sepsis. MAP,
All sampling mean arterial
were performed prior topressure.
antibi-
Copyright: © 2017 Ljungström et al. This is an
https://doi.org/10.1371/journal.pone.0181704.g001
open access article distributed under the terms of otic administration. Discriminant analysis was used to construct two composite biomarkers
the Creative Commons Attribution License, which consisting of linear combinations of the investigated biomarkers, one including three se-
permits unrestricted use, distribution, and lected biomarkers (i.e., NLCR, CRP, and lactate), and another including all four (i.e., PCT,
reproduction in any medium, provided the original
NLCR, CRP, and lactate). The diagnostic performances of the composite biomarkers as
author and source are credited.
well as the individual biomarkers were compared using the area under the receiver operat-
PLOS ONE | https://doi.org/10.1371/journal.pone.0181704
Data Availability Statement: All data is available July
ing 20, 2017 curve (AUC).
characteristic 3 / 17
from the Zenodo database (https://doi.org/10.
5281/zenodo.823967).
Results
Funding: This study was supported by research
grants from the Swedish Knowledge Foundation For diagnosis of bacterial sepsis based on Sepsis-3 criteria, the AUC for PCT (0.68; 95% CI
(grant no20130307, www.kks.se), regional funds 0.65–0.71) was comparable to the AUCs for the both composite biomarkers. Using the Sep-
in Västra Götaland (www.vgregion.se), internal
sis-2 criteria for bacterial sepsis diagnosis, the AUC for the NLCR (0.68; 95% CI 0.65–0.71)

7
Clinical Research Fund Skaraborg Hospital (http://
www.vgregion.se/s/skaraborgs-sjukhus/om- but not for the other single biomarkers, was equal to the AUCs for the both composite bio-
skaraborgs-sjukhus/forskning-och-utveckling/ markers. For diagnosis of severe bacterial sepsis or septic shock based on the Sepsis-2

PLOS ONE | https://doi.org/10.1371/journal.pone.0181704 July 20, 2017 1 / 17

 Biomarker (cut-off) Sensitivity (95% CI) Specificity (95% CI) Accuracy (95% CI) DOR (95% CI) PPV (95% CI) NPV (95% CI)
PCT (2.0 ng/mL) 46.8% (39.2–54.3) 85.5% (83.7–87.4) 81.3% (79.4–83.3) 5.19 (3.70–7.27) 28.1% (22.9–33.4) 92.3% (91.6–94.4)
PCT (10.0 ng/mL) 26.6% (20.0–33.3) 95.5% (94.4–96.6) 88.1% (86.4–89.7) 7.68 (5.02–1.74) 41.7% (32.4–51.0) 91.5% (90.1–92.9)
CRP (20 mg/L) 87.3% (82.2–92.4) 13.5% (11.7–15.3) 21.4% (19.4–23.5) 1.07 (0.66–1.74) 10.8% (9.1–12.5) 89.9% (85.7–94.0)
CRP (100 mg/L) 56.4% (48.8–63.9) 49.4% (46.7–52.0) 50.1% (47.6–52.6) 1.26 (0.91–1.74) 11.8% (9.5–14.0) 90.4% (88.3–92.5)
Lactate (2.5 mmol/L) 66.5% (59.2–73.7) 85.1% (83.2–87.0) 83.1% (81.2–85.0) 11.36 (7.94–16.23) 35.3% (30.0–40.6) 95.4% (94.2–96.6)
Lactate (3.5 mmol/L) 67.1% (61.4–72.7) 96.5% (95.5–97.5) 91.7% (90.3–93.0) 56.23 (38.15–82.89) 79.0% (73.7–84.4) 93.7% (92.5–95.0)

10/9/17
NLCR (3.0) 96.4% (93.6–99.2) 10.0% (8.4–11.6) 19.4% (17.4–21.3) 2.98 (1.29–6.95) 11.5% (9.9–13.2) 95.8% (92.5–99.1)
Fig 4. AUC for the biomarkers evaluated in the present study. Error bars represent 95% CI. The red
NLCR (10.0) 79.0% (72.9–85.2) 55.6%
dotted (53.0–58.2)
lines represent a58.2% (55.7–60.6)
reference 4.73 (3.21–6.96)
line corresponding to AUC = 0.5. 17.8% (15.1–20.6) 95.6%
The three-biomarker (94.2–97.0)
consists of a
combination of CRP, lactate, and NLCR, whereas the four-biomarker consists of a combination of PCT, CRP,
CRP, C-reactive protein; DOR, diagnostic odds lactate,
ratio; NLCR, neutrophil-lymphocyte
and NLCR. count of
(A) AUC for diagnosis ratio; NPV, negative
bacteraemia. predictive
(B) AUC value; PCT,
for diagnosis procalcitonin;
of verified bacterialPPV,
infection.
predictive positive value. (C) AUC for diagnosis of verified bacterial sepsis using Sepsis-2 criteria irrespective severity (i.e., sepsis,
severe sepsis, and septic shock). (D) AUC for diagnosis of verified severe bacterial sepsis/septic shock using
https://doi.org/10.1371/journal.pone.0181704.t003 Sepsis-2 criteria. (E) AUC for diagnosis of verified bacterial sepsis using Sepsis-3 criteria irrespective severity
(i.e., sepsis and septic shock). AUC, area under receiver operating caracteristic curve; CI, confidence interval;
CRP,
to C reactive protein;
inconsistent results NLCR, neutrophil-lymphocyte
[56]. In the present study, ratio; PCT,investigated
we have procalcitonin.the diagnostic value of
https://doi.org/10.1371/journal.pone.0181704.g004
known biomarkers, i.e., PCT, the NLCR, CRP and lactate, alone as well as in combination
using a large sample consisting of 1,572 episodes of adult patients suspected with sepsis.
Recently, the criteria for sepsis were updated [1] and the definition of sepsis was changed
from a systemic inflammatory response syndrome caused by an infection (Sepsis-2) to a life-
Table 2. Performance characteristics of single biomarkers for diagnosing verified bacterial sepsis using Sepsis-2 criteriaa.
threatening organ dysfunction due to a dysregulated host response to infection (Sepsis-3).
Biomarker (cut-off) Sensitivity (95% CI) Changing
Specificitythe (95% CI) may
criteria Accuracy (95% CI)
ultimately DOR (95%
also affect CI) PPV (95%
the performance CI)
of diagnostic NPV (95% CI) In
biomarkers.
PCT (2.0 ng/mL) 26.4% (23.0–29.7) 88.6%
the (86.5–90.7)
present 61.6% that
study, we found (59.2–64.0) 2.79 (2.13–3.66)
CRP at a cut-off of 20 mg/mL 64.0%
had(58.3–70.0)
the highest 61.0% (58.4–63.8)
sensitivity
PCT (10.0 ng/mL) 11.1% (8.7–13.5) 96.4% (95.2–97.7) 59.4 (57.0–61.9) 3.38 (2.19–5.20) 70.5% (61.8–79.2)
(88%) for bacterial sepsis as defined by Sepsis-3 criteria, whereas both PCT at a cut-off 58.6% (56.0–61.1)
10.0 ng/
CRP (20 mg/L) 88.1% (85.7–90.6) 14.5% (12.1–16.8) 46.4% (43.9–49.0) 1.26 (0.93–1.70) 44.1% (41.4–46.8) 61.4% (54.7–68.1)
mL and lactate at a cut-off of 4.0 mmol/L showed high specificity (97%). Considering the
CRP (100 mg/L) 57.1% (53.3–60.9) 52.3% (49.9–56.6) 54.9% (52.4–57.4) 1.51 (1.23–1.86) 48.3% (44.8–51.8) 61.8% (58.3–65.3)
AUCs, all single biomarkers except for the NLCR performed slightly better in diagnosing bac-
Lactate (2.5 mmol/L) 24.9% (21.5–28.2) 82.7% (80.1–85.2) 57.4% (54.9–59.9)
terial sepsis based on Sepsis-3 criteria than1.58 (1.22–2.03) 52.6% (47.0–58.2) 58.7% (55.9–61.5)
Sepsis-2 criteria (Fig 4). PCT showed a moderate
Lactate (3.5 mmol/L) 11.9% (9.4–14.4) 94.4% (92.8–95.9) 58.4% (55.9–60.9) 4.84 (2.69–8.71) 62.1% (53.6–70.6) 58.0% (55.4–60.6)
AUC (0.68), but was nonetheless the single biomarker with the highest AUC and comparable
NLCR (3.0) 95.9% (94.4–97.4) 13.2% (10.9–15.5) 49.0% (46.5–51.6) 3.54 (2.29–5.45) 45.8% (43.2–48.4) 80.7% (74.2–87.3)
to the AUCs for the composite variables (Fig 4E). However, more studies based on the updated
NLCR (10.0) 64.3% (60.6–67.9) 64.0% (60.8–67.2) 64.1% (61.7–66.6) 3.20 (2.59–3.96) 57.8% (54.2–61.3) 70.1% (66.9–73.3)
Sepsis-3 criteria are needed to further assess the diagnostic performance of these biomarkers.
CRP, C-reactive protein; DOR, diagnostic odds ratio; The NLCR
NLCR, has been reported count
neutrophil-lymphocyte to correlate withnegative
ratio; NPV, the severity of disease
predictive [41–43]
value; PCT, and has PPV,
procalcitonin;
predictive positive value. gained interest as a predictor of survival in various clinical circumstances ranging from onco-
a
Including all episodes fulfilling the Sepsis-2 criteria for patients
logical bacterial sepsis irrespective
to patients severity (i.e., sepsis,
with cardiovascular severe
diseases sepsis, In
[62–67]. andthe
septic shock).
context of sepsis, the
https://doi.org/10.1371/journal.pone.0181704.t002
Table 4. Performance characteristics of single biomarkers for diagnosing verified bacterial sepsis using Sepsis-3 criteriaa.
Biomarker (cut-off) Sensitivity (95% CI) Specificity (95% CI) Accuracy (95% CI) DOR (95% CI) PPV (95% CI) NPV (95% CI)
PCT (2.0 ng/mL) 32.1% (28.3–36.0) 89.5% (87.6–91.4) 69.1% (66.8–71.4) 4.05 (3.10–5.29) 62.9% (57.3–68.5) 70.5% (68.0–72.9)
PLOS ONE | https://doi.org/10.1371/journal.pone.0181704 July 20, 2017 8 / 17
PCT (10.0 ng/mL) 15.4% (12.4–18.3) 97.4% (96.5–98.4) 68.2% (65.9–70.5) 6.88 (4.38–10.81) 76.8% (69.0–84.6) 67.5% (65.1–69.9)
CRP (20 mg/L) 88.4% (85.8–91.1) 14.4% (12.2–16.5) 40.8% (38.4–43.3) 1.28 (0.93–1.75) 36.4% (33.9–39.0) 69.0% (62.8–75.4)
CRP (100 mg/L) 59.7% (55.6–63.8) 53.3% (50.2–56.4) 55.6% (53.1–58.1) 1.69 (1.37–2.09) 41.5% (38.1–44.9) 70.4% (67.2–73.7)
Rhodes et al (2.5 mmol/L)
Lactate 29.5% (25.7–33.4) 84.2% (81.9–86.5) 64.6% (62.2–67.1) 2.23 (1.73–2.87) 51.0% (45.4–56.5) 68.2% (65.6–70.9)
Lactate (3.5 mmol/L) 14.9% (11.9–18.0) 95.3% (94.0–96.6) 66.6% (64.2–68.9) 3.54 (2.43–5.18) 63.8% (55.4–72.1) 66.8% (64.3–69.3)
APPENDIX 1. Recommendations
NLCR (3.0) and Best11.7%
95.1% (93.3–96.9) Practice Statements
(9.7–13.7) 41.5% (39.1–44.0) 2.58 (1.67–3.97) 37.5% (35.0–40.0) 81.1% (74.7–87.5)
A. NLCR
INITIAL(10.0) 64.7% (60.8–68.7)
RESUSCITATION 60.8% (57.9–63.9) 62.2% (59.8–64.6) 2.85 (2.30–3.54) 47.9% (44.3–51.5) 75.6% (72.6–78.6)

1. Sepsis and septic shock

CRP, C-reactive are medical
protein; emergencies,
DOR, diagnostic and ratio;
odds we recommend that treatment and resuscitation
NLCR, neutrophil-lymphocyte begin NPV,
count ratio; immediately (BPS).
negative predictive value; PCT, procalcitonin; PPV,
2. We recommend
predictive that, in
positive the resuscitation from sepsis-induced hypoperfusion, at least 30 mL/kg of IV crystalloid fluid be given
value.
within
a the first 3 hours (strong recommendation, low quality of evidence).
Including all episodes fulfilling the Sepsis-3 criteria for bacterial sepsis irrespective severity (i.e., sepsis and septic shock).
3. We recommend that, following initial fluid resuscitation, additional fluids be guided by frequent reassessment of hemodynamic
status (BPS).
https://doi.org/10.1371/journal.pone.0181704.t004
Remarks: Reassessment should include a thorough clinical examination and evaluation of available physiologic variables (heart rate,
blood pressure, arterial oxygen saturation, respiratory rate, temperature, urine output, and others, as available) as well as other
noninvasive or invasive monitoring, as available.
4. We
PLOS recommend further hemodynamic assessment (such as assessingJuly
ONE | https://doi.org/10.1371/journal.pone.0181704 cardiac function) to determine the type of shock if the
20, 2017 9 / 17
clinical examination does not lead to a clear diagnosis (BPS).
5. We suggest that dynamic over static variables be used to predict fluid responsiveness, where available (weak recommendation,
low quality of evidence).
6. We recommend an initial target mean arterial pressure of 65 mm Hg in patients with septic shock requiring vasopressors (strong
Special Article
recommendation, moderate quality of evidence).
7. We suggest guiding resuscitation to normalize lactate in patients with elevated lactate levels as a marker of tissue hypoperfusion
(weak recommendation, low quality of evidence).
B. SCREENING FOR SEPSIS AND PERFORMANCE IMPROVEMENT
1. We recommend that hospitals and hospital systems have a performance improvement program for sepsis, including sepsis
Surviving
screening for acutely ill,Sepsis Campaign: International
high risk patients (BPS).

Guidelines for Management of Sepsis and Septic

C. DIAGNOSIS
1. We recommend that appropriate routine microbiologic cultures (including blood) be obtained before starting antimicrobial therapy Special Article
Shock: 2016
in patients with suspected sepsis or septic shock if doing so results in no substantial delay in the start of antimicrobials (BPS).
Remarks: Appropriate routine microbiologic cultures always include at least two sets of blood cultures (aerobic
Special Article
APPENDIX
and anaerobic).
1. (Continued).
Andrew Rhodes, Recommendations
MB BS, MD(Res) (Co-chair)1 and
; Laura E. Evans, MD, MSc, Best
FCCM Practice
(Co-chair)2
; Statements
D. ANTIMICROBIAL THERAPY
9. IfWaleed Alhazzani,
combination MD, MSc,
therapy FRCPC
is used for(methodology chair)
septic shock, ; Mitchell M. Levy,
we recommend 3
MD, MCCMwith
de-escalation ; discontinuation of combination therapy within
4
1. We recommend that administration of IV antimicrobials should be initiated as soon as possible after recognition and within one
APPENDIX 1. (Continued). Recommendations and Best Practice Statements
the
hour for first
Massimo few
both sepsis days
Antonelli, in response
MD
and septic
5
; Ricard
shock to clinical
Ferrer,
(strong improvement
MD, PhD
recommendation,
6
; Anandquality
moderate and/or
Kumar, MD,evidence
FCCM7; of infection resolution.
This applies to both targeted (for
of evidence).

9.culture-positive
Jonathan E.empiric infections)
Sevransky, MD,isFCCM and;for
empiric
Charles (for
oneL.or culture-negative
Sprung, MD, JD, MCCM infections)
; Mark combination
E. Nunnally, MD, therapy
FCCM ; (BPS).
8 9 2
2. We recommend
If combination broad-spectrum
therapy therapy
used with
septic more
shock,antimicrobials
we recommendfor patients presenting
de-escalation with sepsis
with or septic
discontinuation of combination therapy within
shock
Bramto cover all likely pathogens
Rochwerg, MD, (including
(Epi)3;bacterial and
D.potentially fungal or viral coverage) (strong recommendation,
aninMSc Gordon Rubenfeld, MD (conflict
10ofdays
interest chair) ; resolution.
10
10. We the
moderate first
qualityfew
suggest days
that
of evidence). response
antimicrobial to clinical
treatment improvement
duration and/or
of 7 to evidence of adequate
is infection This applies
for most serious to both
infections targeted (for
associated with
culture-positive
Derek
sepsis C. Angus,
and MD,
septic infections)
MPH,(weak
shock and recommendation,
MCCM empiric
11 (for
; Djillali culture-negative
Annane, MD 12
; Richard
low quality infections)
ofJ.evidence).combination
Beale, MD, MB BS ; therapy (BPS).
13
3. We recommend that empiric antimicrobial therapy be narrowed once pathogen identification and sensitivities are established
10. Geoffrey
and/or
We adequate J. Bellinghan,
suggest clinical
that an MRCP
improvement
14
; Gordon
is noted
antimicrobial (BPS). R. Bernard,
treatment
15
MD ;of
duration Jean-Daniel
7 to 10 days Chiche,
16
MD ; for most serious infections associated with
is adequate
11. We suggest that longer courses are8 appropriate in patients who 17 have a slow clinical response, undrainable foci of infection,
4. We Craig
sepsis Coopersmith,
and septic MD,
shock FACS,
(weak FCCM ; Daniel
recommendation, P. DeinBacker,
low MD,
quality PhDevidence).
; Craig J. French,
states ofMB BS18;
and of
recommend against sustained systemic antimicrobial prophylaxis patients with severe inflammatory noninfectious
bacteremia
origin (e.g., severe with Staphylococcus
pancreatitis, burn
19 injury) (BPS).
aureus, some fungal viral infections, or immunologic 21deficiencies, including neutropenia
Seitaro Fujishima, MD ; Herwig Gerlach, MBA, MD, PhD ; Jorge Luis Hidalgo, MD, MACP, MCCM ;
20

5. 11.
(weak
We suggest
We Steven
recommend
recommendation,
that longer lowantimicrobials
courses quality
are of evidence).
appropriate in patients who have a slow clinical response, undrainable foci of infection,
M.that dosing
Hollenberg, strategies
MD, ofFCCM 22
AlanbeE.optimized
;aureus, Jones, based
MD23on accepted
; Dilip pharmacokinetic/pharmacodynamic
R. Karnad, MD, or FACP 24
;
bacteremia
principles and specific drugStaphylococcus
with properties in patients with sepsis some
or septicfungal and viral
shock (BPS). infections, immunologic deficiencies, including neutropenia
12. We Ruth suggest
(weak that PhD,
M.recommendation,
Kleinpell, shorter courses
RN-CS,
low FCCM
quality are
25 appropriate in some patients,
; Younsuck
of evidence). Koh, MD, PhD, FCCM26;particularly Thiago Costathose Lisboa,with
MDrapid
27
; clinical resolution following
6. Weeffective
suggest empiric
sourcecombination
control therapy
of (using at least two antibiotics
intra-abdominal or of different
urinary sepsisantimicrobial
and classes)
those aimed
with at the most likelyuncomplicated pyelonephritis (weak
anatomically
Flavia
bacterial R. Machado,
pathogen(s) for theMD, PhD ; Johnof J.septic
28
initial management Marini,
shockMD(weak;recommendation,
29
John C. Marshall, MD,ofFRCSC
low quality evidence).;
30
12.recommendation,
We suggest that shorter low quality courses 31are appropriate in some patients, particularly
of evidence). those with rapid clinical resolution following
John
Remarks: E. Mazuski,
Readers should MD,Table
review PhD, FCCM
6offor ; Lauralyn
definitions A.
of empiric,or McIntyre, MD, MSc, FRCPC
targeted/definitive,
32
;
effective
therapy before
source
reading
control
thisdaily
section.
intra-abdominal urinary sepsisbroad-spectrum,
and those with combination, and multidrug
anatomically uncomplicated pyelonephritis (weak
13. We recommend
Anthony S.
recommendation,McLean, MBassessment
low ChB,
quality MD, of FRACP,for de-escalation
evidence). FJFICM33; Sangeeta of antimicrobial
Mehta, MD34; therapy in patients
Rui P. Moreno, MD, PhD with
35
; sepsis and septic shock (BPS).
7. We John
suggest that combination
Myburgh, therapyMD,
MB ChB, not be routinely
PhD, used for ongoing
FANZCA, FCICM, treatment
FAICDof36most otherNavalesi,
; Paolo serious infections,
MD37; including
14.13.WeWesuggest
bacteremiarecommend that
and sepsis measurement
daily
without shockassessment of for
procalcitonin
de-escalation
(weak recommendation, levels
low quality ofof can be 31usedtherapy
antimicrobial
evidence). to support shortening
in patients the duration
with sepsis of antimicrobial
and septic shock (BPS).therapy in
Osamupatients
sepsis Nishida, (weak
MD, PhD 38
; Tiffany M. Osborn, quality MD, MPH, FCCM ; Anders Perner, MD39;
Remarks: This does not preclude the recommendation,
use of multidrug therapy low of evidence).
to broaden antimicrobial activity.
14.Colleen
We suggest that measurement
M. Plunkett 25
; Marco Ranieri, of procalcitonin
MD40; Christalevels can be
A. Schorr, MSN,used to FCCM
RN, support 22 shortening the duration of antimicrobial therapy in
;
8. WeWe
15. recommend
suggestagainst
thatcombination therapy for
procalcitonin the routine
levels canlowtreatment
be used of to
neutropenic sepsis/bacteremia (strong
sepsis
Maureen patients
recommendation, A.moderate
Seckel,(weak
CCRN, recommendation,
quality of CNS, MSN,
evidence). FCCM 41 quality
; Christopherofsupport
evidence). the discontinuation
W. Seymour, MD42; Lisa Shieh,ofMD, empiric
PhD43antibiotics
; in patients who initially
appeared
Khalid to haveMD
A.does
Shukri, sepsis, but subsequently
; Steven MDhave limitedSinger,
clinical evidence of Thompson,
infection (weak 47 recommendation, low quality of
the useQ. Simpson, ; Mervyn MD ; B.activity.
Taylor MD ;
44 45 46
15.evidence).
Remarks:WeThis
suggest that
not procalcitonin
preclude levels
of can therapy
multidrug be used to to support
broaden the discontinuation
antimicrobial of empiric antibiotics in patients who initially
appeared
Sean to haveMD
R. Townsend, sepsis,
48
but subsequently
; Thomas Van der Poll,have MD49limited clinical
; Jean-Louis evidence
Vincent, MD, ofPhD,
infection
FCCM (weak
50
; recommendation, low quality of
(Continued)
evidence).
E. SOURCE
W. CONTROL
Joost Wiersinga, MD, PhD51, Janice L. Zimmerman, MD, MACP, MCCM52;
540 1.E.
R. Phillip Dellinger, MD, MCCM
SOURCE CONTROL
22
We recommend that a specific
www.ccmjournal.org anatomic diagnosis of infection requiring emergent
March 2017 • Volume 45source
• Number control
3 should be identified or
1.excluded
Copyright © 2017
We recommend as by
rapidly
thethat asa possible
Society in patients
of Criticalanatomic
specific Care Medicine with sepsis
and Wolters
diagnosis or septic
Kluwer
of infection Health,shock, and
Rightsthat
Inc. All emergent
requiring any
Reserved. required
source control source
shouldcontrol intervention
be identifiedCopyright
or should
© 2017 by the Society of Critical Care Medicine and Wolters Kluwer H
beexcluded
implemented as soon as medically and logistically practical after the diagnosis is made
as rapidly as possible in patients with sepsis or septic shock, and that any required source control intervention should (BPS).
be implemented as soon as medically and logistically practical after the diagnosis is made (BPS).
2. We
*See also p.recommend
553. prompt removal of intravascular access
Emory devices
University that GA.
Hospital Atlanta,
Crit Care Med 2017; 45:486–552
are a possible source of sepsis or septic shock after other
8

St. George’s Hospital London, England, United Kingdom.

2.vascular access has been established (BPS). Hadassah Hebrew University Medical Center Jerusalem, Israel.
1 9

2
We recommend prompt removal
New York University School of Medicine New York, NY.
of intravascular
10
access devices that are a possible source of sepsis or septic shock after other
Sunnybrook Health Sciences Centre Toronto, Ontario, Canada.
vascular access has been established (BPS). University of Pittsburgh Critical Care Medicine CRISMA Laboratory
3
F. FLUID
McMaster THERAPY
University Hamilton, Ontario, Canada. 11

4
Brown University School of Medicine Providence, RI. Pittsburgh, PA.
F. FLUID THERAPY Hospital Raymond Poincare Garches, France.
1. We recommend that a fluid challenge Cattolica deltechnique be applied where fluid administration is continued as long as hemodynamic
12
5
Instituto di Anestesiologia e Rianimazione, Università Sacro
Cuore, Rome, Italy. 13
Saint Thomas Hospital London, England, United Kingdom.
6
1. We
factors recommend
continue that
to a fluid
improve
Vall d’Hebron University Hospital Barcelona, Spain.
challenge
(BPS). technique be applied where fluid administration is continued as long as hemodynamic
14
University College London Hospitals London, England, United Kingdom.
7 factors
University continue
of Manitoba Winnipeg,toManitoba,
improve (BPS).
Canada. 15
Vanderbilt University Medical Center Nashville, TN.
2. We recommend crystalloids as the fluid of choice for initial resuscitation and subsequent intravascular volume replacement in
Copyright © 2017 by the Society of Critical Care Medicine and the 16
Service de Reanimation Medicale Paris, France.
2.patients
European We recommend
Society ofwith sepsis
Intensive crystalloids
Care and septic
Medicine as theshock fluid(strong
of choice for initial resuscitation
recommendation, moderate andquality
subsequent intravascular volume replacement in
of evidence).
17
CHIREC Hospitals Braine L’Alleud, Belgium.
patients with sepsis
DOI: 10.1097/CCM.0000000000002255 and septic shock (strong recommendation, moderate quality of evidence).
18
Western Hospital Victoria, Australia.
3. We suggest using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock (weak
3. We suggest usinglow either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock (weak
486 recommendation,
www.ccmjournal.org quality of evidence).
recommendation, low quality of evidence).
Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
March 2017 • Volume 45 • Number 3

4. We suggest using albumin in addition to crystalloids for initial resuscitation and subsequent intravascular volume replacement
8
Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer
4.inWe suggest
patients using
with albumin
sepsis in addition
and septic shock,to crystalloids
when patients for initial
require resuscitation
substantialand subsequent
amounts intravascular
of crystalloids volume
(weak replacement low
recommendation,
in patients with sepsis and septic shock, when patients require substantial amounts of crystalloids (weak recommendation, low
quality of evidence).
quality of evidence).
5.5.We Werecommend
recommendagainst against using hydroxyethylstarches
using hydroxyethyl starchesfor forintravascular
intravascular volume
volume replacement
replacement in patients
in patients withwith sepsis
sepsis or septic
or septic shockshock
(strong
(strongrecommendation,
recommendation, high quality of
high quality of evidence).
evidence).
6.6.We
Wesuggest
suggestusing
using crystalloids over gelatins
crystalloids over gelatinswhen
whenresuscitating
resuscitatingpatients
patients with
with sepsis
sepsis or or septic
septic shock
shock (weak
(weak recommendation,
recommendation, low low
uPA dengan uPAR membutuhkan 3 domain uPAR yang utuh, sehingga apabila

uPAR dipecahkan menjadi bentuk terlarut (suPAR) maka efek fibrinolisis yang

diakibatkan karena ikatan uPA-uPAR tidak akan terjadi. Mekanisme fibrinolisis 10/9/17
yang diakibatkan uPA akan berkurang sehingga akan terjadi deposit fibrin dalam

jumlah besar yang akhirnya akan membentuk mikrotrombus sehingga terjadi

hipoksia jaringan yang akhirnya akan menyebabkan disfungsi organ yang

memperburuk hasil akhir sepsis14,53,54. Gambar 2.9 menjelaskan mengenai

suPAR & SOFA

hubungan koagulasi dengan suPAR pada keadaan sepsis

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Gambar 2.9 Gambar Hubungan Koagulasi dengan suPAR Pada Sepsis
Dikutip dari Wiersinga50
Keterangan : IL Interleukin; NFNuclear Factor; TAFIThrombin Activable Fibrinolysis Inhibitor; TFPITissue
Factor Pathway Inhibitor; TMThrombomodulin; TNFTumor Necrotic Factor; tPA tissue-type Plasminogen
Activator. Garis tegas menunjukan efek stimulasi, garis putus-putus menunjukan efek inhibisi
mendapatkan korelasi positif yang bermakna dengan kekuatan korelasi sedang
Gurasim, IndraQ, Prihatni, Suraya, 2017
yaitu sebesar 0,576 (derajat kepercayaan 95%). Korelasi antara kadar suPAR
2.1.6 Kadar suPAR Dalam Tubuh
serum dengan disfungsi organ berdasarkan skor SOFA disajikan dalam Tabel 4.2
Identifikasi sel pada darah perifer dan cairan ascites menggunakan metode
dan Gambar 4.1

flowcytometrymenunjukan bahwa diantara subset lekosit, hanya monosit,

Tabel 4. 2 Korelasi Antara Kadar suPAR Serum Dengan Disfungsi Organ

Berdasarkan Skor SOFA
Korelasi Variabel Penelitian r Nilai p
Korelasi antara kadar suPAR serum dengan 0,576 <0,001*
disfungsi organ pada penderita sepsis

Gambar 4. 1Grafik Korelasi Antara Kadar suPAR Serum Dengan Disfungsi Organ
Berdasarkan Skor SOFA

Gurasim, IndraQ, Prihatni, Suraya, 2017

Garis korelasi pada Gambar 4.1 memperlihatkan arah korelasi positif yang

menunjukkan bahwa terdapat hubungan antara kadar suPAR serum dengan skor

SOFA. Peningkatan kadar suPAR serum yang semakin tinggi akan diikuti dengan

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sTREM-1 & SOFA

Perbandingan Kadar sTREM-1 pada Kelompok Sepsis
dan Non Sepsis

Skor SOFA Skor SOFA

Variabel ≥ 2 <2 Nilai p
N= 42 n= 31
Kadar sTREM-1
(pg/mL) 0.000*
Median 256 128
Range 137-1025 66-248

* nilai p<0,05 berbeda bermakna secara

Frissyerly, TjandrawaQ, TrisQna, Turbawaty, 2017

Korelasi antara Kadar Presepsin dengan Skor

SOFA

Variabel Peneli)an r Nilai p

Presepsin & skor SOFA 0,660 0,000*

r = koefisien korelasi Spearman; * bermakna secara staQsQka (p<0,05)

Dwiyani, IndraQ, LismayanQ, Sugianli, 2017

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Summary
•  Obtaining suitable sepsis marker is sQll
difficult
•  Several approach should be address to get
proper diagnosis and beaer paQent outcome
•  Good communicaQon between clinician,
laboratory and paramedic -- as teamwork

Thank You

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