review article sepsis: from pathophysiology to...

Review ArticleSepsis From Pathophysiology to Individualized Patient Care

Ildikoacute Laacuteszloacute1 Domonkos Traacutesy1 Zsolt Molnaacuter1 and Jaacutenos Fazakas2

1Department of Anaesthesiology and Intensive Therapy Faculty of Medicine University of Szeged Szeged 6725 Hungary2Department of Transplantation and Surgery Faculty of Medicine Semmelweis University Budapest 1082 Hungary

Correspondence should be addressed to Ildiko Laszlo officeaitimedu-szegedhu

Received 12 March 2015 Revised 24 June 2015 Accepted 2 July 2015

Academic Editor Jacek Tabarkiewicz

Copyright copy 2015 Ildiko Laszlo et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Sepsis has become a major health economic issue with more patients dying in hospitals due to sepsis related complicationscompared to breast and colorectal cancer together Despite extensive research in order to improve outcome in sepsis over the last fewdecades results of large multicenter studies were by-and-large very disappointing This fiasco can be explained by several factorsbut one of the most important reasons is the uncertain definition of sepsis resulting in very heterogeneous patient populations andthe lack of understanding of pathophysiology which is mainly based on the imbalance in the host-immune response However thisheroic research work has not been in vain Putting the results of positive and negative studies into context we can now approachsepsis in a different concept which may lead us to new perspectives in diagnostics and treatment While decision making basedon conventional sepsis definitions can inevitably lead to false judgment due to the heterogeneity of patients new concepts basedon currently gained knowledge in immunology may help to tailor assessment and treatment of these patients to their actual needsSummarizing where we stand at present and what the future may hold are the purpose of this review

1 Introduction

One of the most challenging tasks in critical care medicineis the treatment of serious infection related multiple organdysfunction termed in general as sepsis severe sepsis andseptic shock However sepsis means a very heterogeneouspatient population which varies in etiology and severitytherefore universally applicable diagnostic criteria and treat-ment algorhythms are difficult to be definedThis heterogene-ity proved to be one of the most difficult hurdles that mostprospective randomized trials could not concur hence theyfailed to show either clear survival benefit or positive resultsof single center studies that were later contradicted by largemulticenter trials [1] Nevertheless sepsis has become a veryimportant health economic issue all around the world

Furthermore treating sepsis is a multidisciplinary taskEarly recognition and commencing initial steps of resuscita-tion are inevitable to give the best possible chance for survivalwhich has to be started on the primary care level outside thehospital in the emergency department or on thewards In theabsence of adequate initial management providing even thehighest level of intensive care would be in vain

Although the results of prospective randomized clinicaltrials may be disappointing as far as survival is concernedit is beyond doubt that we have learned a lot about thepathophysiology of sepsis during performing these studiesover the last few decades Understanding the immunologicalbackground of the clinical picture is of utmost importancewhich enables the clinician to interpret results of diagnostictests and rationalize treatment modalities in the most appro-priate way To highlight a few of the current novelties insepsis pathophysiology and potential new perspectives is thepurpose of this review

2 Sepsis Is Not a (Definitive) Disease

In medical school we were brought up in the world ofldquodefinitive diagnosesrdquo This means that patients come inwith a certain complaint the physician after taking medicalhistory performing physical examination and diagnostictests defines the diagnosis and treat the patient accordinglyIn the case of a well-defined disease more-or-less the sameor similar diagnostic tests and therapeutic interventionsare performed all around the world (such as stroke and

Hindawi Publishing CorporationJournal of Immunology ResearchVolume 2015 Article ID 510436 13 pageshttpdxdoiorg1011552015510436

2 Journal of Immunology Research

myocardial infarction) This holds true for most diseases inclassical medicine and surgery However defining sepsis isnot that simple The term we call ldquosepsis syndromerdquo wasconceived in a hotel room in Las Vegas in 1980 during theprotocol writing of one of the first prospective randomizedtrials in sepsis performed by a group of scientists led bythe late Roger Bone [2 3] Based on the inclusion criteria ofthis study a statement paper was later published by the sameauthors titled ldquoSepsis Syndrome A Valid Clinical Entityrdquo[3] However these classical signs of the ldquosepsis syndromerdquosuch as feverhypothermia leukocytosisleukopenia tachy-cardia and hypotension meant a very large and nonspe-cificnoninfectious cohort of patients For this reason a fewyears later a consensus conference was brought together anddefined the so called ldquoconsensus criteriardquo of sepsis [4] whichhas also been recently questioned and criticized by Vincentet al [5] In the most current Surviving Sepsis CampaignGuideline a more robust more detailed definition has beencreated in order to ldquosaverdquo the previous concept of the Bone-criteria [6]

These efforts clearly show that finding the appropriatedefinition of sepsis has been a continuous challenge for morethan 30 years The difficulty in defining sepsis originatesfrom its pathophysiology to be discussed in Section 4 Thishas been recognized by international societies and currentlyan international Task Force has been working on a newpathophysiology based sepsis definition Nevertheless inmost specialties the disease itself is easily diagnosed bya laboratory or radiological test However in the case ofsepsis it is different which makes not just the diagnosis butthe interpretation of the results of clinical trials and alsoepidemiological data very difficult

3 Epidemiology

According to recent surveys we treat several folds morecritically ill patients on the intensive care units (ICU)worldwide these days as compared to the figures from morethan 10 years ago [7] There seems to be an increase inthe incidence of sepsis with mortality rates of 20ndash50and according to recent data from the United States sepsisis the single most expensive reason for hospitalization atpresent [8 9] However it is important to note that reportedmortality shows considerable variation across the globe Arecent retrospective analysis fromAustralia andNewZealandshowed an increase in the number of critically ill and septicpatients over the last 12 years with a mortality reductionfrom more than 30 to less than 20 [7] In the PROCESStrial from the United States mortality was around 20 [10]According to these data outcome has improved dramaticallyover the years However results from Europe both retro-spective and prospective indicate greater mortality of 45ndash55 which was also accompanied by a 2- to 3-fold longerICU and hospital stay [11 12] as compared to that reportedby the two previously mentioned studies This raises thequestion ofwhether the care is better in those countrieswhichreported lower mortality rate or is it the patient selectionthat causes this difference Although it is difficult to give adefinitive answer referring to our previous chapter due to

the difficulties in defining sepsis severe sepsis and septicshock one cannot exclude that this difference can be theresult of the uncertainties in patient selection and in thosecountries reporting higher mortality rates sicker patientswere included in the ldquoseptic shockrdquo cohort

Indeed patients with the same diagnosis of ldquoseptic shockrdquocould have completely different severity and prognosis Thesame holds true for every potential ldquoinsultrdquo in critical caresuch as trauma sterile inflammation (acute pancreatitis)ischemia-reperfusion injury major surgery burns and infec-tion These conditions share the same feature in their patho-physiology namely that it is not the insult per se but the hostrsquosresponse especially the immune response which determinesseverity and outcome (Figure 1)

4 Pathophysiology

41 From Localized Insult to ldquoCytokine Stormrdquo The immunesystem is a ldquoteam effortrdquo that involves many different playersinteracting with each other as an orchestra The immuneresponse to pathogens relies on both innate and adaptivecomponentsThefirst line of defense against invaders consistsof physical barriers such as the skin [13 14] the mucousmembranes of our gastrointestinal [15] and respiratory [16]and genitourinary [17] tracts The second line is the rapiddefense by the innate immune system (including complementproteins sentinel phagocyte cells and natural killer cells)which plays an activator and a controller role of the adaptiveimmune system [18] The innate system acts by broad recog-nition of antigens mainly by sensing pathogen-associatedmolecular patterns (PAMP) of carbohydrates and fatty acidslocated on the surfaces of common pathogens By-and-largewhen a local response spread systemically the activation ofseveral classes of pattern recognition receptors will generatea ldquocytokine-chemokine stormrdquo [19] However very similarmolecules are released due to cell injury after trauma burnsischemia-reperfusion pancreatitis major surgery and soforth derived fromnecrotic cells mainly from themitochon-dria These are called ldquodamage-associated molecular pat-ternsrdquo (DAMP) It was a very important recognition that aftercellular injury similar proteins will be released during bacte-rial infection because the genetic background of the bacteriaand the mitochondria is very similar [20]This highlights thefact that the Bone-concept inevitablymixed patients who suf-fered insults due to PAMP DAMP or the mixture of the two

Activation of neutrophils macrophages and monocytesby costimulatory molecules at the site of infection will turnthe local adaptive immune system on and give ldquopermissionrdquoto the adaptive system to respond to an infectious insult Theaim of the innate response is the eradication of the DAMPand PAMP which is followed by the adaptive response withthe resolution of the immunological process The adaptiveimmune response is based on maturation and proliferationboth influenced by the ldquocytokine signaturerdquo of the innateresponse In other words every host has its own ldquocytokinesignaturerdquo for a certain insult Under normal circumstancesthese processes are well regulated maintaining an evenbalance between counteracting forces hence keeping theinflammatory response localized

Journal of Immunology Research 3

Insult

(i) Infection SIRS surgery trauma burnsI-R injury and so forth

Host response

(i) PAMP DAMP(ii) Innate adaptive

immunitytriangle

Severity and outcome

(ii) DO2VO2 imbalance ldquoSepsisrdquo

(a)

Source control(antibiotics surgery invasive radiology)

Organ support(IPPV hemodynamic renal nutrition and so forth)

Adjuvanttherapy

Resuscitation(Oxygen and fluid therapy cathecholamines transfusion and so forth)

(Immunoglobulinssteroids EC-treatment and so forth)

(b)

Figure 1 The ldquosepsis-trianglesrdquo pathomechanism and treatment SIRS systemic inflammatory response syndrome I-R ischemia-reperfusion DO2 oxygen delivery VO2 oxygen consumption PAMP pathogen-associated molecular patterns DAMP damage-associatedmolecular patterns EC extra corporeal and IPPV intermittent positive pressure ventilation

However in the case of an unbalanced (proinflammatoryand anti-inflammatory) dysregulated (maturation and pro-liferation) response the localized process goes out of controland becomes systemic in otherwords the disease of thewholebody hence it gives way for impairing the function of distantvital organs This makes the clinical manifestation of criticalillness so similar regardless of the insult To give an examplethe same gravity of acute respiratory distress syndrome(ARDS) shock or deterioration inmental function can occurin pancreatitis just aswell as aftermajor surgery or due to anytype of infection (Figure 2) The adaptive immune system asthe third level of defense is based on itsmemories It can adaptand protect us against almost any invader

In brief the ldquocytokine signaturerdquo of neutrophils andmacrophages will give signals to the T and B lymphocytesvia the dendritic cells which after proliferation bymaturationwill express different cell surface receptors in soluble ormembrane bound forms The adaptive immune response is asoluble matrix which consists of the cascade-type activationof cytokines coagulation factors the release of acute phaseproteins stress hormones and different chemokines andhormokines forming a complex network The key factor of

immune resolution is the balance between proinflammatoryand anti-inflammatory forces which ismainly determined bythe balance between the relationship of Th1 Th2 Th17 and120574ΔT to each other namely the maturation magnitude andthe duration of their activity [19]

42 Systemic Inflammatory Response Syndrome (SIRS) andImmunoparalysis Based on the Bone-criteria systemicinflammatory response syndrome invented on the Con-sensus Conference in 1991 [4] initially meant the classicalldquosepsis syndromerdquo criteria without proven infection TheSIRS-criteria have also been criticized for similar reasons asthe ldquosepsis syndromerdquo definition but nevertheless this ldquoSIRS-conceptrdquo assumed that systemic inflammatory response canoccur for an insult without infection

In the past SIRS was mainly thought to be relatedto the imbalance between the proinflammatory and anti-inflammatory responses However it is more complex In thecontext of the innate and adaptive immune responses bothproinflammatory and anti-inflammatory processes take placein a parallel fashion When the proinflammatory and anti-inflammatory forces swing into action the proinflammatory


Anti-inflammatoryProinflammatoryImmunoregulation

CoagulationCytokines and

chemokinesAcute phase

proteinsStress

hormones Hormokines Cytoplasmaticfactors

IFN-120574Il-2IL-4IL-5IL-7IL-11

IL-1RAIL-4IL-6IL-10IL-11IL-13IL-16IL-18RATGF-1205733LeptinNOTNF

1205721-glycoprotFerritinFibronectinHaptoglobinLPS protSAACRP

ACTHAVPGHCortisolProlactinHistamineNoradrenalineAdrenalinEndorphin

ADMCGRPPCTIL-6LeptinMIF

HS proteinHMG-1NO

Inflammatory respones

Leucocyte lymphocyte endothelial cells parenchymal cellsMBL NOD protein P substance

IL-1120573 endothelinIL-6 adhesion moleculesIL-8 chemokinesIL-11 elastaseIL-12 growth factorsIL-18 LTsIL-23 NOTNF120572 proteaseIFN120574 PGs

ROIMIFTBs

Complementsystem

Dysregulated generalized immune response

Pathogen 997888rarr PAMPs

Tissue injury 997888rarr DAMPs

Figure 2 The main pillars of systemic inflammatory response PAMPs pathogen-associated molecular pattern DAMPs damage-associatedmolecular pattern molecules MBL mannose-binding lectin NOD protein nucleotide-binding oligomerization domain protein and NALPa type a NOD like receptors For explanation see text

forces overwhelm the anti-inflammatory process at the begin-ning In general we can say that there is a short delay ofthe anti-inflammatory response as compared to the proin-flammatory This proinflammatory ldquodominancerdquo lasts for 2to 4 days but an oversized response which means thatthe localized insult becomes systemic will lead to differentdegree of tissue damage shock and eventually organ failureDuring the course of disease the adaptive response is initiatedby Th1 reaction In the next phase the proinflammatoryprocess slowly ldquoturns itself offrdquo while the adaptive responsewill switch to a Th2 response In other words this laterphase helps to survive the proinflammatory process afterthe eradication of the insult with ldquorestitutio ad integrumrdquo[21] However a dysregulated systemic form of the adaptiveresponse could later induce immunoparalysis jeopardizingthe bodyrsquos defense hence leaving it prone to further evenopportunistic infections There are many unanswered ques-tions in this process but discussing these issues in details goeswell beyond the scope of this paper [22]

43 The Altered Immune Response and Leukocyte Reprogram-ming In the later phase in septic patients and in patientswith severe noninfectious SIRS (such as burns traumamajor

surgery hemorrhage or ischemia-reperfusion after cardiacarrest) the anti-inflammatory process may overwhelm theproinflammatory forces This is often referred to as ldquoanergyrdquoldquoendotoxin intolerancerdquo ldquoimmunoparalysisrdquo or ldquoimmun-odepressionrdquo but these are very general and simplifieddescriptions of what is really happening The term cellularreprogramming may be more accurate indicating the cellularchanges during this process In brief cellular reprogrammingmeans two contradictory parallel cellular processes cellsderived from hematopoietic compartments such as bonemarrow spleen lymph nodes and blood become hypore-active In contrast cells derived from other tissues and solidorgans (like liver kidney lung brain or gastrointestinal tract)can often be hyperreactive causing hyperinflammation inthe particular organs especially in the infected organ Theinhibition of some signaling pathways parallel with otherswhich are maintained or enhanced results in large variety ofimmune response Immunosuppression itself does not causeharm but leaves the patient prone to infection Unfortunatelytests able to measure the degree of immunosuppression arenot available all around the clock hence the clinician hasnothing else to rely on at the bedside than the etiologyclinical picture and biomarkers in order to detect the onset


of a potentially devastating new infection as soon as possible[21 22]

5 Diagnostic Challenges

One of the most commonmisconceptions in sepsis diagnosisis that we have been searching for specific ldquomarker(s) ofsepsisrdquo However there is not and there will never be onesingle marker which is able to diagnose sepsis mainly dueto the very colorful manifestation of sepsis and due to theheterogeneity of patients

Recognizing the septic patient has two main elementsOn the one hand we have to evaluate vital organ functionand the degree of organ dysfunction via objective signssuch as hypotension hypoperfusion altered mental statusacid-base imbalance hypoxemia lactate levels renal andliver dysfunction and thrombocytopenia Based on thesefindings we should start supportive therapy without anyfurther delay and if there is any suspicion of the possibilityof an infection empirical antibiotic therapy should also bestarted immediately (Figure 1) [16]

In the meantime we have to diagnose the etiology ofcritical illness In other words we have to decide whethercritical illness is due to infection or not Because if it is due toinfection antibiotics should be started as soon as possible butif it is not related to a bacterial infection antibiotics are notjust a waste of time and money but they may also do harm inshort and long term Unfortunately diagnosing infection incritically ill patients is not easy

51 Conventional Markers of Infection Clinical signs arethe most important in recognizing critical illness butthey cannot prove infection on their own Conventional(feverhypothermia leukocytosisleukopenia tachypnoetachycardia and hypotension) indicators also listed in theclassical ldquosepsis-syndromerdquo criteria are very nonspecificin fact poor indicators of infection For microbiologicalproof of infection although very important unfortunatelyresults become available 24ndash48 hours at the earliest aftersending the specimen to the laboratory According to ourcurrent concept it is of utmost importance to start adequateantibiotic therapy as soon as possible but at least withinan hour after the onset of infection caused hypotensionotherwise chances for survival are reducing by the hour [23]

New molecular biology techniques are now availableto define the presence of bacterial or fungal DNA withinthe bloodstream of patients [24 25] Highly sophisticatedmolecular biology based tests such as polymerase chainreaction (PCR) matrix assisted laser desorptionionization(MaldiTof) and peptide nucleic acid fluorescence in situhybridization (PNAFISH) based pathogen detection can the-oretically shorten the recognition of the underlying pathogento about 8 hours [26] However these cannot differentiatebetween colonization and clinically significant infectionTherefore we need laboratory tests which are sensitive andspecific enough to show the onset andmagnitude of bacterialinvasion caused inflammatory response as soon as possibleand may also be able to follow the progress of the disease

within hours These biologically active substances are calledbiomarkers

52 The Role of Biomarkers at the Bedside There have beenseveral biomarkers developed so far [1] but neither is suitablefor all purposes Every marker has its own merit and limita-tions They inevitably can support decision making but theywill never be able to differentiate ldquosepsisrdquo from ldquoSIRSrdquo with a100 sensitivity and specificity mainly due to the problemswe discussed earlier in details regarding the problems ofdefining sepsis and also due to the complex overlappingpathomechanism of PAMP and DAMP Nevertheless thereis still an ongoing search for better new markers of inflam-matory response and infection with promising preliminaryresults [40]

There are almost 200 so-called sepsis markers thereforediscussing the features of those cannot be integrated intothe current review We will mainly focus on the two mostcommonly usedmarkers procalcitonin (PCT) andC-reactiveprotein (CRP) However briefly mentioning the main fea-tures of a few other newmarkers already applied in daily prac-tice such as soluble CD14 subtype (presepsin) and solubleurokinase-type plasminogen activator receptor (suPAR)maybe worthwhile Higher presepsin concentrations in septicpatients were associated with ICU mortality in a recent largemulticenter trial [41] It was also suggested that changes inplasma concentrations may reflect the appropriateness ofantibiotic therapy but this have to be confirmed by futurestudies [41] Regarding the suPARmolecule it has been shownto be a very good indicator of severity of the acute disease andshows good correlation with the degree of organ dysfunctionin the critically ill but cannot be regarded as a ldquosepsis markerrdquodue to its low specificity [42]

Any condition inducingDAMP [43] or PAMP could shedthe endothelial glycocalyx layer It has been confirmed inseveral experimental studies in different septic models thatdamage of the endothelial glycocalyx layer is reflected inelevated serum syndecan-1 and syndecan-4 levels [44ndash47]which may be potentially a very interesting marker in thefuture but again it may be nonspecific for bacterial infectiononly

Finally neutrophil-lymphocyte count ratio is a cheapfast and easily available tool to diagnose bacteremia andwas found to improve bloodstream infection diagnostics ina recent study on the emergency ward [48] This simple testmay also have a potential in the future

Nevertheless the two most commonly used markersin infectionsepsis diagnostics and for guiding therapeuticinterventions are PCTandCRP [49]Despite their popularitythere are still many pros and cons without clear answersregarding their usefulness and interpretation in guidingpatient management

Procalcitonin is detectable in the serum within a few (4ndash6) hours after the onset of bacterial infection During theldquonormalrdquo course of an infection it reaches its peak within24 hours and then starts its decline in the case of adequatetreatment with levels reducing by roughly 50 daily accord-ing to its half-life [27] In contrast CRP moves ldquoslowlyrdquoand under similar circumstances it reaches its maximum


Table 1 Comparison of CRP versus PCT (advantages and disadvantages)

CRP PCTDifferentiating bacterial infection from SIRS minus [27] Specific for bacteria [28 29]Response to infection Slower (days) [27] 2ndash6 hours [30]Peak response after infection 2-3 days [27] 12ndash48 hours [27]Half-life Several days [27] 20ndash35 hours [31]Plasma kinetic Slow [27] Rapid [27]Price + ++++Correlating disease severity and progression Slightly [27] +++ [32]Correlating effective therapy + +++ [33 34]Prognostic factor for mortality Weak or nonexistent [27] Good predictor [31 32]Differentiating G+ from Gminus minus [35] ++ [35]

Response to other factorsVirus autoimmune diseaseslocal infections surgery trauma[27]

Surgery trauma burncardiogenic shock liver cirrhosis[36ndash38]

Fungal infection same as bacterial [35] Slightly elevated [35]Immunosuppression Formation can be changed [27] The induction is reduced [27]Biological effect Opsonin for phagocytosis [27] Chemokine [27]Sensitivityspecificity Sensitive but nonspecific [27] Sensitive and specific [27 39]General use Outpatient care [27] In intensive care [27]

value usually within 48 hours However levels are generallyelevated in most ICU patients making interpretation of CRPvery difficult [50] The other major problem with CRP onthe ICU is that it is lagging way behind the actual events ofthe inflammatory process The most important differencesbetween the two markers are summarized in Table 1

Procalcitonin differentiates bacterial infections from sys-temic inflammatory response of other etiologies with highersensitivity and specificity compared to CRP [39] There isconsiderable evidence that PCT supported decision makingduring antibiotic treatment has several beneficial effects Itconsiderably reduced antibiotic use in lower respiratory tractinfections without compromising survival [51] and it mayalso shorten the duration of antibiotic treatment on the ICU[52]

Although in the coming paragraphs we will mainly referto studies investigating PCT the concept how to interpretthese data is potentially applicable for any inflammatorymarker and should be taken into account when evaluatingbiomarker levels at the bedside

6 Interpreting PCT

61 Sepsis Is Different in Surgical and Medical PatientsAlthough sepsis is often referred to as a ldquodefinitive diseaserdquo(see above) in a clinical trial published more than 10 yearsago PCT levels were found to be several folds higher insurgical as compared to medical patients in septic shockdespite the similar clinical manifestation and severity ofthe clinical picture [53] This indicates different degree ofinflammatory response depending on etiology Indeed thereis increasing evidence that in the case of massive cell injurysuch as in severe trauma [54] after major surgery [55] and

any ischemia-reperfusion type injury including cardiogenicshock [37] due to the mechanism of DAMP [56] unspecificelevations of PCT levels can typically be seen even in theabsence of a bacterial infection [57 58] Theoretically insurgical patients with sepsis DAMP and PAMP take placeat the same time leading to an overwhelming inflammatoryresponse whilst in medical patients it is primarily the activa-tion of the PAMP resulting in a less extensive inflammatoryresponse hence lower biomarker levels [53] In the study byClecrsquoh et al the median PCT value in SIRS in medical versussurgical patients was 03 (01ndash10) versus 57 (27ndash83) andin septic shock 84 (36ndash760) versus 340 (71ndash760) ngmlrespectively

Another very important addition to these findings wasprovided by a study by Charles et al in which they founddifferent degree of inflammatory response in patients withthe first as compared to those with the second septic insult[59] They investigated patients with primary and secondaryblood stream infections and found that the same gravity ofinfection was accompanied by a severalfold lower maximumPCT level in patients during the second event of infectionas compared to those with a primary event The receiveroperating characteristic curve of serumPCT for the diagnosisof blood stream infection in critically ill patientswith primarysepsis with a cutoff value of 556 ngmL was 0934 95 CI0881ndash0970 and in patients with secondary sepsis with aPCT cutoff 64 ngmL it was 0805 95 CI 0699ndash0879Thisobservation is in accord with what we have already discussedabout immunoparalysis and cellular reprogramming in theprevious paragraphs put into context with PCT in Figure 3This shows that lower levels of PCT should be taken seriouslyin the case of a leter (secon or third) onset of infection and thisconcept has been further supported by several recent reports[60 61]


PCT

Homeostasisbalance

New balance

New balance

Proi

nflam

mat

ory

1st infection 2nd infection 3rd infection

Ant

i-infl

amm

ator

yIm

mun

e res

pons

eM1

M1

M1M2

M2

M2

M2 = M1 = uarrM2M1 = uarruarrM2M1 = uarruarruarrM2M1

Figure 3 Procalcitonin response to consequent infectious insults During regulated inflammatory response the two phenotypes ofmacrophages (M) the proinflammatory (M1) and anti-inflammatory (M2) are balanced As time goes by due to a dysregulated responsepatients become immunoparalyzed in other words M2 overwhelms M1 hence forces are shifted towards ldquonew balancerdquo This is reflected bylower PCT peak levels after each new infectious insult which can be of the same gravity clinically For further explanation see text

These studies clearly show that a given PCT value shouldbe interpreted differently based on etiology and the timecourse of the critically ill condition It is obvious that ldquoonesize [of biomarker] does not fit allrdquo hence careful evaluationof the given clinical scenario cannot be neglected wheninterpreting a given laboratory result Before we discuss theimportance of kinetics of biomarkers let us put the results ofrecently published clinical trials into this context first

Recent large clinical trials tested the effectiveness of PCT-guided antibiotic strategies applying the ldquoone size does fitallrdquo in other words predetermined absolute values (eggt1 ngmL) as a concept and the results were either nonsignif-icant or patients required mechanical ventilation longer andthe prolonged use of antibiotics in the PCT-arm [62 63]However the percentage of surgical patients was around 40in both studies and the PCT value indicating the need for anintervention was chosen to be ge1 ngmL Based on the resultsof previous studies investigating PCT levels in surgical andmedical patients as we discussed before this 1 ngmL cutoffvalue for intervention is a very low PCT value in a specificmainly high risk surgical population Indeed in the studyby Layios et al in patients with a PCT ge1 ngmL antibioticswere withheld only in 11 Although data were not providedfor this subgroup of surgical patients one may assumethat these patients received antibiotics unnecessarily in largeproportion The same may hold true for the PASS studythat unnecessary antibiotic use and antibiotic escalation wasinevitable in the PCT-group due to the generally low ldquoalert-PCTrdquo levels (ge1 ngmL) in the study protocol [63] Howeverif a biomarkerrsquos half-life is short enough taking kinetics intoaccount instead or in addition to their absolute values mayprovide several theoretical benefits

62 Kinetics over Absolute Values Although the absolute val-ues of PCT show substantial differences in different etiologiesand the course of the disease but the kinetics may be similar

andmore useful Tsangaris et al studied 50 patients whowerein the ICU for more than 10 days free of infection and whopresented with a new onset of fever Procalcitonin showed aminimumof 2-fold increase in 27 patients from the day beforeto the day of fever onset and in these patients infection waseventually proven On the contrary infection was not provenin 23 patients in whom PCT remained persistently low andunchanged as compared to previous days Their conclusionwas that a twofold increase of PCT between fever onsetand the previous day was associated with proven infectionFurthermore a normal PCT value on the third day after thefever onset was associated with better survival It is importantto note that the observed maximum PCT values in patientswith proven infection remained relatively low (lt15 ngmL)but it was not the absolute value but the severalfold increasewhich indicated acute onset of infection [64]

This takes us to the importance of PCT kinetics In moststudies PCT kinetics were mainly tested to predict severityand outcome rather than to guide therapy [32 65] In arecent pilot study in patients treated on the ICU we foundsignificant differences in the change of PCT from the daybefore (Day

minus1

) to the day when new infection was suspectedaccording to the clinical picture (Day

0

) OnDayminus1

PCT levelswere similar in patients in whom infection was eventuallyproven as compared to patients in whom we could notprove infection Although on Day

0

absolute values of PCTlevels were elevated in both groups levels were significantlyhigher in patients in whom infection was later proven Mostimportantly while there was no significant change in thelevels of PCT fromDay

minus1

to Day0

in the noninfectious groupthe rate of increase was significant in the infection group [34]It has also been shown that PCT kinetics (gt80 drop fromits maximum value) can be very useful in stopping antibiotictherapy early hence reducing antibiotic consumption andlength of treatment significantly which is also recommendedin the recent Surviving Sepsis Guideline [6 52] These results


suggest that therapy based on PCT kinetics may be superioras compared to predefined absolute values a hypothesis to betested in the future

63 Fungal and Viral Infections Recent studies show thatfungal infections have an increasing tendency in critically illpatients [66 67] Candida spp are the third or fourth mostcommonly isolated microorganism in the bloodstream ofICU patients and its associated mortality is reported to be ashigh as 40ndash60 [67 68] Candidemia or invasive candidiasisis defined by positive blood cultures and presence of clinicalsigns of systemic infection Fungal infections are difficult todiagnose from blood cultures because it takes a considerableamount of time to grow these organisms and it often remainsnegative [69 70] Unfortunately clinical features are verynonspecific to separate bacteria-related sepsis from Candidasepsis A number of clinical trials have proposed the potentialdiagnostic value of PCT in this context Martini et alinvestigated PCT levels for the diagnosis of candidemia orbacteremia in septic patientsThey have found that a low PCTvalue (071 [05ndash11] ngmL 119901 = 0001) in a critically ill septicpatient is more likely to be related to candidemia than tobacteremia [71] Another trial by Cortegiani et al reportedthat PCT could be a useful diagnostic tool to separateCandida spp blood stream infection (099 ngmL 086ndash134)from blood stream infection caused by bacteria (167 ngmL765ndash502) or in mixed infections (476 ngmL 298ndash608)Therewas no difference in PCT levels to exclude the detectionof Candida spp by blood culture (alive Candida) and real-time PCR (killed Candida) in septic patients In this studysignificantly lower values of PCT were observed in [72]

Markova et al determined the role of PCT testingin patients with high risk for invasive fungal infectionThey included immunocompromised hematological patientsundergoing chemotherapy or allogeneic hematopoietic stemcell transplantation and had bacterial or fungal infectiouscomplications C-reactive protein and PCT were prospec-tively assessed from the day following fever onset for fourconsecutive days They found increased CRP combined withmildly or not elevated PCT in immunocompromised patientsprobably due to fungal infection Therefore the complemen-tary use of these biomarkers may help the diagnostic method[35]

A recent systemic review and meta-analysis summarizedcurrent evidence on the role of PCT in differentiating fungalinfections from other infectious diseases They identified 8eligible studies and summarized 474 episodes of suspectedfungal infections The most frequently isolated causativeorganisms were Candida albicans Candida parapsilosis Can-dida glabrataCandida tropicalisAspergillus spp and Penicil-lium zygomycota They found that PCT has a good diagnosticpower to separate invasive fungal and bacterial infection fromnoninfectious disease conditions [73]

Another clinical trial investigated the differences betweenGram-negative (Gminus) Gram-positive (G+) and fungal blood-stream infections They observed significantly higher PCTlevels in patients with Gminus as compared to G+ infections andeven lower levels in fungemia [74]

Regarding viral infections most of the published resultsagree that PCT can differentiate between viral and bacterialinfections as levels will remain low in the latter case [75ndash77] However it is important to acknowledge that any con-dition including sever viral infection nonbacterial systemicinflammatory condition such as sterile acute pancreatitis orany ischemia-reperfusion injury which is accompanied withsignificant hypotensionhypoperfusion of the tissues cancause a DAMP-induced PCT increase whichmay complicatedifferential diagnosis [56 78 79]

7 Treatment What the Future Holds

71 Extracorporeal Removal of Mediators and Toxins Extra-corporeal clearance of the plasma via hemofiltration andplasma pheresis has received major interest over the lastdecades in sepsis research As the results were contradictorynowadays the focus of interest has turned towards newalternatives such as the targeted removal of toxins andmediators via specific adsorption

711 Polymyxin-B Polymyxin-B (PMX-B) is a cyclic cationicpolypeptide antibiotic originated from Bacillus polymyxaThis antibiotic has the facility to bind and neutralize endo-toxins [80] Studies have shown that PMX-B blunts the TNF-120572 response to endotoxin [81] which is due to the high bindingaffinity of PMXndashB for the LPS molecules UnfortunatelyPMX-B infusion causes nephrotoxicity and neurotoxicityin humans [82] However when polymyxin B is linkedcovalently to a polystyrene-derived fiber in a hemoperfusioncartridge it can be used to remove circulating endotoxinswithout exerting its undesired effects systematically Thesurface area of the column is extremely large so it can clear upa large amount of circulating endotoxins in a relatively shortperiod of time [83] Another potentially beneficial effect ofPMX-B hemoperfusion is the removal of certain inflamma-tory cells [84] This device has been used and tested in manypatients with a very low incidence of adverse events (lt1)such as thrombocytopenia allergic reactions and transienthypotension [82] As PMX-B hemofiltration has been avail-able for several years it cannot be regarded as a ldquonewrdquo treat-ment alternative per se nevertheless it is far from routine usein the everyday practice hence future studies are warranted

712 CytoSorb CytoSorb is a hemadsorption device Itremoves both proinflammatory and anti-inflammatorycytokines The cartridge contains biocompatible greatlyporous polymer beads capable of absorbing molecules in thesim10ndash50 kDa range [85ndash87]

Cytokine overproduction is a common feature in manylife-threatening conditions in addition to sepsis such astrauma major surgery in high risk patients viral infectionsacute respiratory distress syndrome (ARDS) serious burninjury and acute pancreatitis liver failure just to name afew Several case reports have been published about theuse of CytoSorb treatment over the last couple of yearsThese include 120573-hemolytic streptococcus-induced necrotiz-ing fasciitis [88] septic shock with multiorgan dysfunction[89] and rhabdomyolysis [90] Elevated cytokine levels


have been reported during donor conditioning for organtransplantation which were associated with dysfunction ofdonor organs before and after transplantation [91 92] In arecent clinical trial it was found that in addition to conven-tional treatment attenuating the inflammatory response bycytokine absorption graft survival can be prolonged [91]

72 Anti-PD-1 Immunotherapy in Sepsis and Tumor DiseasesThe late phase of sepsis and the late phase of cancer by-and-large share similar immune suppression mechanismOne of the similarities is based on the presence of negativecostimulatory molecules such as PD-1 (programmed celldeath-1) Its expression is induced primarily on T cellsrsquoCD4 and CD8 surface proteins the signaling via whichPD-1 inhibits T cell proliferation cytokine production andcytotoxic ability Persistent antigen exposure (DAMP-PAMP)causes increased levels of PD-1 consequently T-cell depletion[93 94]Theoretically blocking the PD-1 receptor or its ligandby antibodies could reverse T cell dysfunction and inhibitthe pathogen or tumor cells initiated immunosuppression[94] Inhibition of the PD-1 pathway in animal modelsresulted in clinically significant survival benefit in bacterialand fungal sepsis [95 96] In a recent clinical trial patientswith lung cancer melanoma and small-cell renal cancerpatients responded to anti-PD-1 antibody treatment in 20 to25 [97] Based on the similar immune-pathomechanism ofcancer and sepsis testing the effect of anti-PD-1 or anti-PD-L1in the future certainly makes sense Furthermore since septicpatients do not require long-term anti-PD-1 or anti-PD-L1therapy the potential adverse effects of certain autoimmunereactions or other serious complications should be very rareTherefore future studies are warranted to confirm safetyand efficacy issues of anti-PD-1 anti-PD-1L treatment inimmunoparalysed septic patients [98] furthermore evaluat-ing PD-1 or PD-L1 expression in immune cellsmay be a usefulbiomarker for immunomodulatory therapy

73 Stem Cells and Genetic Treatment Bone marrow-derivedmultipotent mesenchymal stem cells (MSCs) are alreadyin the clinical use in multiple clinical disorders includingmyocardial infarction [99] diabetes [100] hematologicalmalignancies [101] hepatic [102] and renal failure [103]Recent animal experiments suggested that bone marrow-derived MSCs may also have a potential role in the treatmentof acute renal failure ARDS and sepsis [104ndash106]

In several recent animal models in mice investigatingdrug- and ischemia-reperfusion-induced acute kidney injuryMCSs therapy was found to enhance recovery and prolongsurvival [104 107 108] In other animal models circulatingMSCs were able to help to regenerate new renal tubular cellsin acute kidney injury [109 110]

MSCs can also be potentially used in ARDS by atten-uating proinflammatory response by regulating both theinnate and adaptive immune systems and modulation ofmacrophages [111] They can influence activated CD4 andCD8 T cells via the inhibition of the inflammatory cytokineproduction and stimulate the regulatory T cells MSCscan directly affect sepsis one of the most common causes

of ARDS by enhancing macrophage phagocytosis andincreasing antimicrobial peptide secretion thereby increas-ing bacterial clearance [106 111] Another animal experimentshowed that MSCs can also help to repair the injuredlung following ventilation-induced lung injury [112] Thereis increasing evidence about the potential mechanisms viawhich MSCs act in the injured lung [113] There is one ongo-ingmulticenter clinical trial on the effects of allogeneicMSCstherapy in patients with moderate to severe ARDS in whichpatient recruitment has already started [ClinicalTrialsgovNCT01775774]

As patients respond differently for seemingly same infec-tious insults genetic variants are likely to explain the differen-tial susceptibility in the risk of severe sepsis It is obvious thathost genetics can influence sepsis outcomes but no specificloci have yet been confirmedThis year the first genome-widestudy reported significant correlation between certain singlenucleotide polymorphisms and 28-day mortality in intensivecare patients with sepsis severe sepsis or septic shock [114]After the exact clarification of some responsible loci and itsrole in the background mechanism and course of sepsisgenetic manipulation may be another potential therapeuticapproach of sepsis therapy in the future

8 Conclusion

Understanding the underlying pathology in sepsis and criti-cal illness in general is inevitable in order to evaluate clinicalsigns and biomarkers in the right context at the bedsideIn-depth analysis of recent research shed light on severalimportant issues including the immunological background ofhost response for different insults summarized in the DAMPandPAMP concept which also explains why biomarker levelsshould be interpreted differently based on etiology and whytheir kinetics may carry more appropriate information thanthe absolute values Furthermore this understanding maylead us to a completely different strategy in treatment wherethe major role will be played by adsorption techniques andcellular reprograming

However this knowledge also revealed that in the com-plex condition of sepsis nothing will ever replace the welltrained experienced thinking physician who takes all ofthe available information into consideration at the bedsideand then makes a decision Finally even if this decisionwill be proved to be wrong retrospectively it should not beinterpreted as a failure but rather as an important sourceof our experience This experience which contradicted ourexpectations and disappointed us at the time leads to thedesign of several research projects and more importantlyit already helped us to understand more about sepsis andchanged the waywe thought about it 30 years ago completely

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper


References

[1] J-L Vincent ldquoWe should abandon randomized controlled trialsin the intensive care unitrdquoCritical CareMedicine vol 38 no 10supplement pp S534ndashS538 2010

[2] R C Bone C J Fisher Jr T P Clemmer G J Slotman C AMetz and R A Balk ldquoA controlled clinical trial of high-dosemethylprednisolone in the treatment of severe sepsis and septicshockrdquoTheNew England Journal of Medicine vol 317 no 11 pp653ndash658 1987

[3] R C Bone C J Fisher Jr T P Clemmer G J Slotman G AMetz and R A Balk ldquoSepsis syndrome a valid clinical entityMethylprednisolone Severe Sepsis Study Grouprdquo Critical CareMedicine vol 17 no 5 pp 389ndash393 1989

[4] ldquoAmerican College of Chest PhysiciansSociety of Critical CareMedicine Consensus Conference definitions for sepsis andorgan failure and guidelines for the use of innovative therapiesin sepsisrdquo Critical Care Medicine vol 20 no 6 pp 864ndash8741992

[5] J-L Vincent S M Opal J C Marshall and K J Tracey ldquoSepsisdefinitions time for changerdquoThe Lancet vol 381 no 9868 pp774ndash775 2013

[6] R P Dellinger M M Levy A Rhodes et al ldquoSurviving sepsiscampaign international guidelines for management of severesepsis and septic shock 2012rdquo Intensive Care Medicine vol 39no 2 pp 165ndash228 2013

[7] K-M Kaukonen M Bailey S Suzuki D Pilcher and RBellomo ldquoMortality related to severe sepsis and septic shockamong critically ill patients in Australia and New Zealand2000ndash2012rdquo Journal of the American Medical Association vol311 no 13 pp 1308ndash1316 2014

[8] D F Gaieski J M Edwards M J Kallan and B G CarrldquoBenchmarking the incidence and mortality of severe sepsis inthe united statesrdquo Critical Care Medicine vol 41 no 5 pp 1167ndash1174 2013

[9] C M Torio and R M Andrews National Inpatient HospitalCosts The Most Expensive Conditions by Payer 2011 StatisticalBrief 160 Healthcare Cost and Utilization Project (HCUP)Statistical Briefs Agency for Health Care Policy and ResearchRockville Md USA 2006ndash2013

[10] ProCESS Investigators D M Yealy J A Kellum et al ldquoArandomized trial of protocol-based care for early septic shockrdquoTheNew England Journal of Medicine vol 370 no 18 pp 1683ndash1693 2014

[11] S Heublein M Hartmann S Hagel R Hutagalung and FM Brunkhorst ldquoEpidemiology of sepsis in German hospitalsderived from administrative databasesrdquo Infection vol 17 articleS71 2013

[12] C Engel F M Brunkhorst H-G Bone et al ldquoEpidemiologyof sepsis in Germany results from a national prospectivemulticenter studyrdquo Intensive Care Medicine vol 33 no 4 pp606ndash618 2007

[13] J Harder J-M Schroder and R Glaser ldquoThe skin surface asantimicrobial barrier present concepts and future outlooksrdquoExperimental Dermatology vol 22 no 1 pp 1ndash5 2013

[14] A Baroni E Buommino V De Gregorio E Ruocco V Ruoccoand R Wolf ldquoStructure and function of the epidermis relatedto barrier propertiesrdquo Clinics in Dermatology vol 30 no 3 pp257ndash262 2012

[15] T Pelaseyed J H Bergstrom J K Gustafsson et al ldquoThemucusand mucins of the goblet cells and enterocytes provide the firstdefense line of the gastrointestinal tract and interact with the

immune systemrdquo Immunological Reviews vol 260 no 1 pp 8ndash20 2014

[16] R Rudraraju B G Jones S L Surman R E Sealy P GThomas and J L Hurwitz ldquoRespiratory tract epithelial cellsexpress retinaldehyde dehydrogenase ALDH1A and enhanceIgA production by stimulated B cells in the presence of vitaminArdquo PLoS ONE vol 9 no 1 Article ID e86554 2014

[17] M Ghosh ldquoSecreted mucosal antimicrobials in the femalereproductive tract that are important to consider for HIVpreventionrdquoTheAmerican Journal of Reproductive Immunologyvol 71 no 6 pp 575ndash588 2014

[18] M Kompoti A Michopoulos M Michalia P M Clouva-Molyvdas A E Germenis and M Speletas ldquoGenetic poly-morphisms of innate and adaptive immunity as predictors ofoutcome in critically ill patientsrdquo Immunobiology vol 220 no3 pp 414ndash421 2015

[19] W Strober and I J Fuss ldquoProinflammatory cytokines in thepathogenesis of inflammatory bowel diseasesrdquo Gastroenterol-ogy vol 140 no 6 pp 1756ndash1767 2011

[20] Q Zhang M Raoof Y Chen et al ldquoCirculating mitochondrialDAMPs cause inflammatory responses to injuryrdquo Nature vol464 no 7285 pp 104ndash107 2010

[21] J-M Cavaillon C Adrie C Fitting and M Adib-ConquyldquoReprogramming of circulatory cells in sepsis and SIRSrdquo Journalof Endotoxin Research vol 11 no 5 pp 311ndash320 2005

[22] J-M Cavaillon and M Adib-Conquy ldquoBench-to-bedsidereview endotoxin tolerance as amodel of leukocyte reprogram-ming in sepsisrdquo Critical Care vol 10 no 5 article 233 2006

[23] A Kumar D Roberts K E Wood et al ldquoDuration of hypoten-sion before initiation of effective antimicrobial therapy is thecritical determinant of survival in human septic shockrdquo CriticalCare Medicine vol 34 no 6 pp 1589ndash1596 2006

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[25] C Leli A Cardaccia M Ferranti et al ldquoProcalcitonin betterthan C-reactive protein erythrocyte sedimentation rate andwhite blood cell count in predicting DNAemia in patients withsepsisrdquo Scandinavian Journal of Infectious Diseases vol 46 no11 pp 745ndash752 2014

[26] M W Pletz N Wellinghausen and T Welte ldquoWill polymerasechain reaction (PCR)-based diagnostics improve outcome inseptic patients A clinical viewrdquo Intensive Care Medicine vol 37no 7 pp 1069ndash1076 2011

[27] M Michael ProcalcitoninmdashBiochemistry and Clinical Diagno-sis UNI-MED Science 1st edition 2010

[28] L Simon F Gauvin D K Amre P Saint-Louis and J LacroixldquoSerum procalcitonin and C-reactive protein levels as markersof bacterial infection a systematic review and meta-analysisrdquoClinical Infectious Diseases vol 39 no 2 pp 206ndash217 2004

[29] B M Tang G D Eslick J C Craig and A S McLeanldquoAccuracy of procalcitonin for sepsis diagnosis in criticallyill patients systematic review and meta-analysisrdquo The LancetInfectious Diseases vol 7 no 3 pp 210ndash217 2007

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[32] J U Jensen L Heslet T H Jensen K Espersen P Steffensenand M Tvede ldquoProcalcitonin increase in early identificationof critically ill patients at high risk of mortalityrdquo Critical CareMedicine vol 34 no 10 pp 2596ndash2602 2006

[33] D J Philpott M T Sorbara S J Robertson K Croitoru andS E Girardin ldquoNOD proteins regulators of inflammation inhealth and diseaserdquo Nature Reviews Immunology vol 14 no 1pp 9ndash23 2014

[34] N Oveges D Trasy M F Nemeth et al ldquoIncreasing procalci-tonin kinetics may be a good indicator of infection in criticallyill patientsrdquo Intensive Care Medicine vol 40 supplement 1article 0982 2014

[35] M Markova H Brodska K Malıckova et al ldquoSubstantiallyelevated C-reactive protein (CRP) together with low levelsof procalcitonin (PCT) contributes to diagnosis of fungalinfection in immunocompromised patientsrdquo Supportive Care inCancer vol 21 no 10 pp 2733ndash2742 2013

[36] C Sachse H G Machens G Felmerer A Berger and EHenkel ldquoProcalcitonin as a marker for the early diagnosis ofsevere infection after thermal injuryrdquo Journal of Burn Care andRehabilitation vol 20 no 5 pp 354ndash360 1999

[37] F M Brunkhorst A L Clark Z F Forycki and S DAnker ldquoPyrexia procalcitonin immune activation and survivalin cardiogenic shock the potential importance of bacterialtranslocationrdquo International Journal of Cardiology vol 72 no1 pp 3ndash10 1999

[38] S ConnertW Stremmel andC Elsing ldquoProcalcitonin is a validmarker of infection in decompensated cirrhosisrdquo Zeitschrift furGastroenterologie vol 41 no 2 pp 165ndash170 2003

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[40] Z Cao and R A S Robinson ldquoThe role of proteomics inunderstanding biological mechanisms of sepsisrdquo ProteomicsmdashClinical Applications vol 8 no 1-2 pp 35ndash52 2014

[41] S Masson P Caironi C Fanizza et al ldquoCirculating presepsin(soluble CD14 subtype) as a marker of host response in patientswith severe sepsis or septic shock data from the multicenterrandomized ALBIOS trialrdquo Intensive Care Medicine vol 41 no1 pp 12ndash20 2014

[42] K Donadello S Scolletta F S Taccone et al ldquoSolubleurokinase-type plasminogen activator receptor as a prognosticbiomarker in critically ill patientsrdquo Journal of Critical Care vol29 no 1 pp 144ndash149 2014

[43] P I Johansson J Stensballe L S Rasmussen and S ROstrowski ldquoHigh circulating adrenaline levels at admissionpredict increased mortality after traumardquo Journal of Traumaand Acute Care Surgery vol 72 no 2 pp 428ndash436 2012

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[45] D De Backer D O Cortes K Donadello and J-L VincentldquoPathophysiology of microcirculatory dysfunction and thepathogenesis of septic shockrdquo Virulence vol 5 no 1 pp 73ndash792014

[46] X Marechal R Favory O Joulin et al ldquoEndothelial glycocalyxdamage during endotoxemia coincides with microcirculatory

dysfunction and vascular oxidative stressrdquo Shock vol 29 no 5pp 572ndash576 2008

[47] T Nikaido Y Tanino X Wang et al ldquoSerum syndecan-4 as apossible biomarker in patients with acute pneumoniardquo Journalof Infectious Diseases 2015

[48] A J M Loonen C P C de Jager J Tosserams et al ldquoBiomark-ers and molecular analysis to improve bloodstream infectiondiagnostics in an emergency care unitrdquo PLoS ONE vol 9 no1 Article ID e87315 2014

[49] C Pierrakos and J-L Vincent ldquoSepsis biomarkers a reviewrdquoCritical Care vol 14 no 1 article R15 2010

[50] P Dandona D Nix M F Wilson et al ldquoProcalcitonin increaseafter endotoxin injection in normal subjectsrdquo Journal of ClinicalEndocrinology and Metabolism vol 79 no 6 pp 1605ndash16081994

[51] M Christ-Crain D Jaccard-Stolz R Bingisser et al ldquoEffectof procalcitonin-guided treatment on antibiotic use and out-come in lower respiratory tract infections cluster-randomisedsingle-blinded intervention trialrdquoTheLancet vol 363 no 9409pp 600ndash607 2004

[52] L Bouadma C-E Luyt F Tubach et al ldquoUse of procalcitoninto reduce patientsrsquo exposure to antibiotics in intensive care units(PRORATA trial) a multicentre randomised controlled trialrdquoThe Lancet vol 375 no 9713 pp 463ndash474 2010

[53] C Clecrsquoh J-P Fosse P Karoubi et al ldquoDifferential diagnosticvalue of procalcitonin in surgical and medical patients withseptic shockrdquo Critical Care Medicine vol 34 no 1 pp 102ndash1072006

[54] O Mimoz J F Benoist A R Edouard M Assicot C Bohuonand K Samii ldquoProcalcitonin and C-reactive protein duringthe early posttraumatic systemic inflammatory response syn-dromerdquo Intensive CareMedicine vol 24 no 2 pp 185ndash188 1998

[55] C Sponholz Y Sakr K Reinhart and F Brunkhorst ldquoDiagnos-tic value and prognostic implications of serum procalcitoninafter cardiac surgery a systematic review of the literaturerdquoCritical Care vol 10 no 5 article R145 2006

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[57] B Uzzan R Cohen P Nicolas M Cucherat and G-Y PerretldquoProcalcitonin as a diagnostic test for sepsis in critically ill adultsand after surgery or trauma a systematic review and meta-analysisrdquo Critical Care Medicine vol 34 no 7 pp 1996ndash20032006

[58] M Meisner K Tschaikowsky A Hutzler C Schick and JSchuttler ldquoPostoperative plasma concentrations of procalci-tonin after different types of surgeryrdquo Intensive Care Medicinevol 24 no 7 pp 680ndash684 1998

[59] P E Charles C Tinel S Barbar et al ldquoProcalcitonin kineticswithin the first days of sepsis relationship with the appropriate-ness of antibiotic therapy and the outcomerdquo Critical Care vol13 no 2 article R38 2009

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[61] B M Rau I Frigerio M W Buchler et al ldquoEvaluation of pro-calcitonin for predicting septic multiorgan failure and overallprognosis in secondary peritonitis a prospective international


multicenter studyrdquo Archives of Surgery vol 142 no 2 pp 134ndash142 2007

[62] N Layios B Lambermont J-L Canivet et al ldquoProcalcitoninusefulness for the initiation of antibiotic treatment in intensivecare unit patientsrdquo Critical Care Medicine vol 40 no 8 pp2304ndash2309 2012

[63] J-U Jensen B Lundgren L Hein et al ldquoThe Procalci-tonin And Survival Study (PASS)mdasha randomised multi-centerinvestigator-initiated trial to investigate whether daily mea-surements biomarker Procalcitonin and pro-active diagnosticand therapeutic responses to abnormal Procalcitonin levelscan improve survival in intensive care unit patients Calculatedsample size (target population) 1000 patientsrdquo BMC InfectiousDiseases vol 8 article 91 2008

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[66] A M Tortorano G Dho A Prigitano et al ldquoInvasive fungalinfections in the intensive care unit a multicentre prospectiveobservational study in Italy (2006ndash2008)rdquoMycoses vol 55 no1 pp 73ndash79 2012

[67] M T Montagna G Caggiano G Lovero et al ldquoEpidemiologyof invasive fungal infections in the intensive care unit Results ofa multicenter Italian survey (AURORA Project)rdquo Infection vol41 no 3 pp 645ndash653 2013

[68] HWisplinghoff T Bischoff S M Tallent H Seifert R PWen-zel and M B Edmond ldquoNosocomial bloodstream infectionsin US hospitals analysis of 24179 cases from a prospectivenationwide surveillance studyrdquo Clinical Infectious Diseases vol39 no 3 pp 309ndash317 2004

[69] B Gloor C A Muller M Worni et al ldquoPancreatic infectionin severe pancreatitis the role of fungus and multiresistantorganismsrdquo Archives of Surgery vol 136 no 5 pp 592ndash5962001

[70] J J De Waele D Vogelaers S Blot and F Colardyn ldquoFungalinfections in patients with severe acute pancreatitis and the useof prophylactic therapyrdquo Clinical Infectious Diseases vol 37 no2 pp 208ndash213 2003

[71] A Martini L Gottin N Menestrina V Schweiger D Simionand J-L Vincent ldquoProcalcitonin levels in surgical patients atrisk of candidemiardquo Journal of Infection vol 60 no 6 pp 425ndash430 2010

[72] A Cortegiani V Russotto F Montalto et al ldquoProcalcitonin as amarker ofCandida species detection by blood culture and poly-merase chain reaction in septic patientsrdquo BMC Anesthesiologyvol 14 article 9 2014

[73] Y-H Dou J-K Du H-L Liu and X-D Shong ldquoThe role ofprocalcitonin in the identification of invasive fungal infection-a systemic review and meta-analysisrdquo Diagnostic Microbiologyand Infectious Disease vol 76 no 4 pp 464ndash469 2013

[74] H Brodska K Malıckova V Adamkova H Benakova M MStrsquoastna and T Zima ldquoSignificantly higher procalcitonin levelscould differentiate Gram-negative sepsis from Gram-positiveand fungal sepsisrdquo Clinical and Experimental Medicine vol 13no 3 pp 165ndash170 2013

[75] P Schuetz D N Amin and J L Greenwald ldquoRole of pro-calcitonin in managing adult patients with respiratory tractinfectionsrdquo Chest vol 141 no 4 pp 1063ndash1073 2012

[76] E Cuquemelle F Soulis D Villers et al ldquoCan procalcitoninhelp identify associated bacterial infection in patients withsevere influenza pneumonia A multicentre studyrdquo IntensiveCare Medicine vol 37 no 5 pp 796ndash800 2011

[77] E Piacentini B Sanchez V Arauzo E Calbo E Cuchi and JM Nava ldquoProcalcitonin levels are lower in intensive care unitpatients with H1N1 influenza A virus pneumonia than in thosewith community-acquired bacterial pneumonia A pilot studyrdquoJournal of Critical Care vol 26 no 2 pp 201ndash205 2011

[78] M Annborn J Dankiewicz D Erlinge et al ldquoProcalcitoninafter cardiac arrestmdashan indicator of severity of illness ischemia-reperfusion injury and outcomerdquo Resuscitation vol 84 no 6pp 782ndash787 2013

[79] N Yonetci U Sungurtekin N Oruc et al ldquoIs procalcitonina reliable marker for the diagnosis of infected pancreaticnecrosisrdquo ANZ Journal of Surgery vol 74 no 7 pp 591ndash5952004

[80] A P Zavascki L Z Goldani J Li and R L Nation ldquoPolymyxinB for the treatment of multidrug-resistant pathogens a criticalreviewrdquo Journal of Antimicrobial Chemotherapy vol 60 no 6pp 1206ndash1215 2007

[81] C R Sharp A E DeClue C E Haak A R Honaker and C RReinero ldquoEvaluation of the anti-endotoxin effects of polymyxinB in a feline model of endotoxemiardquo Journal of Feline Medicineand Surgery vol 12 no 4 pp 278ndash285 2010

[82] E Esteban R Ferrer L Alsina and A Artigas ldquoImmunomod-ulation in sepsis the role of endotoxin removal by polymyxinB-immobilized cartridgerdquoMediators of Inflammation vol 2013Article ID 507539 12 pages 2013

[83] H Shoji T Tani K Hanasawa and M Kodama ldquoExtracor-poreal endotoxin removal by polymyxin B immobilized fibercartridge designing and antiendotoxin efficacy in the clinicalapplicationrdquoTherapeutic Apheresis vol 2 no 1 pp 3ndash12 1998

[84] M Nishibori H K Takahashi H Katayama et al ldquoSpecificremoval of monocytes from peripheral blood of septic patientsby polymyxin B-immobilized filter columnrdquo Acta MedicaOkayama vol 63 no 1 pp 65ndash69 2009

[85] T Taniguchi ldquoCytokine adsorbing columnsrdquo Contributions toNephrology vol 166 pp 134ndash141 2010

[86] A Spittler M Razenberger H Kupper et al ldquoRelationshipbetween interleukin-6 plasma concentration in patients withsepsis monocyte phenotype monocyte phagocytic propertiesand cytokine productionrdquo Clinical Infectious Diseases vol 31no 6 pp 1338ndash1342 2000

[87] R de Pablo J Monserrat E Reyes et al ldquoMortality in patientswith septic shock correlates with anti-inflammatory but notproinflammatory immunomodulatory moleculesrdquo Journal ofIntensive Care Medicine vol 26 no 2 pp 125ndash132 2011

[88] H Hetz R Berger P Recknagel and H Steltzer ldquoSeptic shocksecondary to 120573-hemolytic streptococcus-induced necrotizingfasciitis treated with a novel cytokine adsorption therapyrdquoInternational Journal of Artificial Organs vol 37 no 5 pp 422ndash426 2014

[89] R Basu S Pathak J Goyal R Chaudhry R B Goel and ABarwal ldquoUse of a novel hemoadsorption device for cytokineremoval as adjuvant therapy in a patient with septic shock withmulti-organ dysfunction a case studyrdquo Indian Journal of CriticalCare Medicine vol 18 no 12 pp 822ndash824 2014

[90] M Wiegele and C G Krenn ldquoCytosorb in a patient withlegionella-pneumonia associated rhabdomyolysisrdquo ASAIOJournal vol 61 no 3 pp e14ndashe16 2015


[91] J A Kellum R Venkataraman D Powner M Elder GHergenroeder and M Carter ldquoFeasibility study of cytokineremoval by hemoadsorption in brain-dead humansrdquo CriticalCare Medicine vol 36 no 1 pp 268ndash272 2008

[92] M J Wilhelm J Pratschke F Beato et al ldquoActivation of theheart by donor brain death accelerates acute rejection aftertransplantationrdquo Circulation vol 102 no 19 pp 2426ndash24332000

[93] C L Day D E Kaufmann P Kiepiela et al ldquoPD-1 expressionon HIV-specific T cells is associated with T-cell exhaustion anddisease progressionrdquo Nature vol 443 no 7109 pp 350ndash3542006

[94] A H Sharpe E J Wherry R Ahmed and G J FreemanldquoThe function of programmed cell death 1 and its ligands inregulating autoimmunity and infectionrdquo Nature Immunologyvol 8 no 3 pp 239ndash245 2007

[95] X Huang F Venet Y L Wang et al ldquoPD-1 expression bymacrophages plays a pathologic role in altering microbialclearance and the innate inflammatory response to sepsisrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 106 no 15 pp 6303ndash6308 2009

[96] P Brahmamdam S Inoue J Unsinger K C Chang J EMcDunn and R S Hotchkiss ldquoDelayed administration of anti-PD-1 antibody reverses immune dysfunction and improvessurvival during sepsisrdquo Journal of Leukocyte Biology vol 88 no2 pp 233ndash240 2010

[97] S L Topalian F S Hodi J R Brahmer et al ldquoSafety activityand immune correlates of anti-PD-1 antibody in cancerrdquo TheNew England Journal of Medicine vol 366 no 26 pp 2443ndash2454 2012

[98] R S Hotchkiss G Monneret and D Payen ldquoImmunosuppres-sion in sepsis a novel understanding of the disorder and a newtherapeutic approachrdquoTheLancet InfectiousDiseases vol 13 no3 pp 260ndash268 2013

[99] A Bronckaers P Hilkens W Martens et al ldquoMesenchy-mal stemstromal cells as a pharmacological and therapeuticapproach to accelerate angiogenesisrdquo Pharmacology and Ther-apeutics vol 143 no 2 pp 181ndash196 2014

[100] S Dave ldquoMesenchymal stem cells derived in vitro transdiffer-entiated insulin-producing cells a new approach to treat type1 diabetesrdquo Advanced Biomedical Research vol 3 no 1 article266 2014

[101] F Casiraghi G Remuzzi M Abbate and N Perico ldquoMultipo-tent mesenchymal stromal cell therapy and risk of malignan-ciesrdquo StemCell Reviews and Reports vol 9 no 1 pp 65ndash79 2013

[102] J-S Ye X-S Su J-F Stoltz N de Isla and L Zhang ldquoSignallingpathways involved in the process of mesenchymal stem cellsdifferentiating into hepatocytesrdquo Cell Proliferation vol 48 no2 pp 157ndash165 2015

[103] A FWise and S D Ricardo ldquoMesenchymal stem cells in kidneyinflammation and repairrdquo Nephrology vol 17 no 1 pp 1ndash102012

[104] X Han L Zhao G Lu et al ldquoImproving outcomes of acutekidney injury using mouse renal progenitor cells alone orin combination with erythropoietin or suraminrdquo Stem CellResearch andTherapy vol 4 no 3 article 74 2013

[105] F Xu Y Hu J Zhou and X Wang ldquoMesenchymal stem cells inacute lung injury are they ready for translational medicinerdquoJournal of Cellular and Molecular Medicine vol 17 no 8 pp927ndash935 2013

[106] K Nemeth A Leelahavanichkul P S T Yuen et al ldquoBonemarrow stromal cells attenuate sepsis via prostaglandin E 2-dependent reprogramming of host macrophages to increasetheir interleukin-10 productionrdquo Nature Medicine vol 15 no1 pp 42ndash49 2009

[107] M Morigi M Introna B Imberti et al ldquoHuman bone marrowmesenchymal stem cells accelerate recovery of acute renalinjury and prolong survival in micerdquo Stem Cells vol 26 no 8pp 2075ndash2082 2008

[108] F Togel KWeiss Y Yang ZHu P Zhang andCWestenfelderldquoVasculotropic paracrine actions of infusedmesenchymal stemcells are important to the recovery from acute kidney injuryrdquoTheAmerican Journal of PhysiologymdashRenal Physiology vol 292no 5 pp F1626ndashF1635 2007

[109] F Anglani M Forino D Del Prete E Tosetto R Torregrossaand A DrsquoAngelo ldquoIn search of adult renal stem cellsrdquo Journalof Cellular and Molecular Medicine vol 8 no 4 pp 474ndash4872004

[110] J V Bonventre and A Zuk ldquoIschemic acute renal failure aninflammatory diseaserdquo Kidney International vol 66 no 2 pp480ndash485 2004

[111] G F Curley J A Scott and J G Laffey ldquoTherapeutic poten-tial and mechanisms of action of mesenchymal stromal cellsfor Acute Respiratory Distress Syndromerdquo Current Stem CellResearch andTherapy vol 9 no 4 pp 319ndash329 2014

[112] G F CurleyMHayes B Ansari et al ldquoMesenchymal stem cellsenhance recovery and repair following ventilator-induced lunginjury in the ratrdquoThorax vol 67 no 6 pp 496ndash501 2012

[113] J W Lee X Fang N Gupta V Serikov and M A MatthayldquoAllogeneic human mesenchymal stem cells for treatment of Ecoli endotoxin-induced acute lung injury in the ex vivo perfusedhuman lungrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 106 no 38 pp 16357ndash163622009

[114] A Rautanen T C Mills A C Gordon et al ldquoGenome-wideassociation study of survival from sepsis due to pneumonia anobservational cohort studyrdquo The Lancet Respiratory Medicinevol 3 no 1 pp 53ndash60 2015

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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myocardial infarction) This holds true for most diseases inclassical medicine and surgery However defining sepsis isnot that simple The term we call ldquosepsis syndromerdquo wasconceived in a hotel room in Las Vegas in 1980 during theprotocol writing of one of the first prospective randomizedtrials in sepsis performed by a group of scientists led bythe late Roger Bone [2 3] Based on the inclusion criteria ofthis study a statement paper was later published by the sameauthors titled ldquoSepsis Syndrome A Valid Clinical Entityrdquo[3] However these classical signs of the ldquosepsis syndromerdquosuch as feverhypothermia leukocytosisleukopenia tachy-cardia and hypotension meant a very large and nonspe-cificnoninfectious cohort of patients For this reason a fewyears later a consensus conference was brought together anddefined the so called ldquoconsensus criteriardquo of sepsis [4] whichhas also been recently questioned and criticized by Vincentet al [5] In the most current Surviving Sepsis CampaignGuideline a more robust more detailed definition has beencreated in order to ldquosaverdquo the previous concept of the Bone-criteria [6]

These efforts clearly show that finding the appropriatedefinition of sepsis has been a continuous challenge for morethan 30 years The difficulty in defining sepsis originatesfrom its pathophysiology to be discussed in Section 4 Thishas been recognized by international societies and currentlyan international Task Force has been working on a newpathophysiology based sepsis definition Nevertheless inmost specialties the disease itself is easily diagnosed bya laboratory or radiological test However in the case ofsepsis it is different which makes not just the diagnosis butthe interpretation of the results of clinical trials and alsoepidemiological data very difficult

3 Epidemiology

According to recent surveys we treat several folds morecritically ill patients on the intensive care units (ICU)worldwide these days as compared to the figures from morethan 10 years ago [7] There seems to be an increase inthe incidence of sepsis with mortality rates of 20ndash50and according to recent data from the United States sepsisis the single most expensive reason for hospitalization atpresent [8 9] However it is important to note that reportedmortality shows considerable variation across the globe Arecent retrospective analysis fromAustralia andNewZealandshowed an increase in the number of critically ill and septicpatients over the last 12 years with a mortality reductionfrom more than 30 to less than 20 [7] In the PROCESStrial from the United States mortality was around 20 [10]According to these data outcome has improved dramaticallyover the years However results from Europe both retro-spective and prospective indicate greater mortality of 45ndash55 which was also accompanied by a 2- to 3-fold longerICU and hospital stay [11 12] as compared to that reportedby the two previously mentioned studies This raises thequestion ofwhether the care is better in those countrieswhichreported lower mortality rate or is it the patient selectionthat causes this difference Although it is difficult to give adefinitive answer referring to our previous chapter due to

the difficulties in defining sepsis severe sepsis and septicshock one cannot exclude that this difference can be theresult of the uncertainties in patient selection and in thosecountries reporting higher mortality rates sicker patientswere included in the ldquoseptic shockrdquo cohort

Indeed patients with the same diagnosis of ldquoseptic shockrdquocould have completely different severity and prognosis Thesame holds true for every potential ldquoinsultrdquo in critical caresuch as trauma sterile inflammation (acute pancreatitis)ischemia-reperfusion injury major surgery burns and infec-tion These conditions share the same feature in their patho-physiology namely that it is not the insult per se but the hostrsquosresponse especially the immune response which determinesseverity and outcome (Figure 1)

4 Pathophysiology

41 From Localized Insult to ldquoCytokine Stormrdquo The immunesystem is a ldquoteam effortrdquo that involves many different playersinteracting with each other as an orchestra The immuneresponse to pathogens relies on both innate and adaptivecomponentsThefirst line of defense against invaders consistsof physical barriers such as the skin [13 14] the mucousmembranes of our gastrointestinal [15] and respiratory [16]and genitourinary [17] tracts The second line is the rapiddefense by the innate immune system (including complementproteins sentinel phagocyte cells and natural killer cells)which plays an activator and a controller role of the adaptiveimmune system [18] The innate system acts by broad recog-nition of antigens mainly by sensing pathogen-associatedmolecular patterns (PAMP) of carbohydrates and fatty acidslocated on the surfaces of common pathogens By-and-largewhen a local response spread systemically the activation ofseveral classes of pattern recognition receptors will generatea ldquocytokine-chemokine stormrdquo [19] However very similarmolecules are released due to cell injury after trauma burnsischemia-reperfusion pancreatitis major surgery and soforth derived fromnecrotic cells mainly from themitochon-dria These are called ldquodamage-associated molecular pat-ternsrdquo (DAMP) It was a very important recognition that aftercellular injury similar proteins will be released during bacte-rial infection because the genetic background of the bacteriaand the mitochondria is very similar [20]This highlights thefact that the Bone-concept inevitablymixed patients who suf-fered insults due to PAMP DAMP or the mixture of the two

Activation of neutrophils macrophages and monocytesby costimulatory molecules at the site of infection will turnthe local adaptive immune system on and give ldquopermissionrdquoto the adaptive system to respond to an infectious insult Theaim of the innate response is the eradication of the DAMPand PAMP which is followed by the adaptive response withthe resolution of the immunological process The adaptiveimmune response is based on maturation and proliferationboth influenced by the ldquocytokine signaturerdquo of the innateresponse In other words every host has its own ldquocytokinesignaturerdquo for a certain insult Under normal circumstancesthese processes are well regulated maintaining an evenbalance between counteracting forces hence keeping theinflammatory response localized


Insult


Host response


immunitytriangle



(a)



Adjuvanttherapy



(b)











proteinsStress







HS proteinHMG-1NO




ROIMIFTBs

Complementsystem
































6 Interpreting PCT





PCT

Homeostasisbalance

New balance

New balance

Proi

nflam

mat

ory


Ant

i-infl

amm

ator

yIm

mun

e res

pons

eM1

M1

M1M2

M2

M2








minus1


0

) OnDayminus1


0


minus1

to Day0






















8 Conclusion






References































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Insult


Host response


immunitytriangle



(a)



Adjuvanttherapy



(b)











proteinsStress







HS proteinHMG-1NO




ROIMIFTBs

Complementsystem
































6 Interpreting PCT





PCT

Homeostasisbalance

New balance

New balance

Proi

nflam

mat

ory


Ant

i-infl

amm

ator

yIm

mun

e res

pons

eM1

M1

M1M2

M2

M2








minus1


0

) OnDayminus1


0


minus1

to Day0






















8 Conclusion






References































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















proteinsStress







HS proteinHMG-1NO




ROIMIFTBs

Complementsystem
































6 Interpreting PCT





PCT

Homeostasisbalance

New balance

New balance

Proi

nflam

mat

ory


Ant

i-infl

amm

ator

yIm

mun

e res

pons

eM1

M1

M1M2

M2

M2








minus1


0

) OnDayminus1


0


minus1

to Day0






















8 Conclusion






References































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of








































6 Interpreting PCT





PCT

Homeostasisbalance

New balance

New balance

Proi

nflam

mat

ory


Ant

i-infl

amm

ator

yIm

mun

e res

pons

eM1

M1

M1M2

M2

M2








minus1


0

) OnDayminus1


0


minus1

to Day0






















8 Conclusion






References































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















PCT

Homeostasisbalance

New balance

New balance

Proi

nflam

mat

ory


Ant

i-infl

amm

ator

yIm

mun

e res

pons

eM1

M1

M1M2

M2

M2








minus1


0

) OnDayminus1


0


minus1

to Day0






















8 Conclusion






References































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































8 Conclusion






References































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















References































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article sepsis: from pathophysiology to...

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