review article a pathophysiological insight into sepsis...

Review ArticleA Pathophysiological Insight into Sepsis and Its Correlationwith Postmortem Diagnosis

C Pomara I Riezzo S Bello D De Carlo M Neri and E Turillazzi

Department of Clinical and Experimental Medicine Section of Forensic Pathology Ospedale Colonnello DrsquoAvanzoUniversity of Foggia Viale degli Aviatori 1 71100 Foggia Italy

Correspondence should be addressed to E Turillazzi emanuela turillazziinwindit

Received 23 December 2015 Revised 21 March 2016 Accepted 10 April 2016

Academic Editor Dianne Cooper

Copyright copy 2016 C Pomara 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

Background Sepsis is among the leading causes of death worldwide and is the focus of a great deal of attention from policymakersand caregivers However sepsis poses significant challenges from a clinical point of view regarding its early detection and thebest organization of sepsis care Furthermore we do not yet have reliable tools for measuring the incidence of sepsis Methodsbased on analyses of insurance claims are unreliable and postmortem diagnosis is still challenging since autopsy findings are oftennonspecific Aim The objective of this review is to assess the state of our knowledge of the molecular and biohumoral mechanismsof sepsis and to correlate them with our postmortem diagnosis ability Conclusion The diagnosis of sepsis-related deaths is anillustrative example of the reciprocal value of autopsy both for clinicians and for pathologists A completemethodological approachintegrating clinical data by means of autopsy and histological and laboratory findings aiming to identify and demonstrate the hostresponse to infectious insults is mandatory to illuminate the exact cause of death This would help clinicians to compare pre- andpostmortem findings and to reliably measure the incidence of sepsis

1 Introduction

Sepsis can be defined as a syndrome of dysregulated inflam-mation caused by the failure of infection control and con-tainmentmechanisms It should be considered amajor publichealth problem since it affects millions of people worldwideeach year with an incidence which is dramatically increasing[1] It accounts for most deaths in critically ill patients [2ndash4]Thehospitalmortality of patients with sepsis ranges from283to 411 in North America and Europe [5 6]

Consequently considerable attention is dedicated to sep-sis by policymakers and caregivers However these effortsare tempered by several limitations First of all difficultyin defining sepsis still exists due to the emerging biologicalinsights and reported variation in epidemiology Recentlythe Third International Consensus Definitions Task Forcedefined sepsis as ldquolife-threatening organ dysfunction due toa dysregulated host response to infectionrdquo [7 8] howeverthe performance of clinical criteria for this sepsis definitionis unknown [7] Furthermore sepsis poses heavy challengesfrom a clinical point of view regarding its early detection and

the best organization of sepsis care [6 9] Finally we do notyet have reliable tools for measuring the incidence of sepsisMethods based on analyses of insurance claim data usingsepsis-specific codes or separate codes for infection andorgandysfunction are unreliable in informing or measuring theeffects of policy changes [1] and the postmortem diagnosisof sepsis is still challenging as the results of postmorteminvestigations often show a relative paucity of significantmacroscopic and histopathological findings [10 11] Apartfrom the possibility of demonstrating infected sites in theinternal organs (ie septicopyaemic abscess) the inflamma-tory organ changes observed at autopsy are mediated bythe endogenous inflammatory mediators that are neitherspecific nor sensitive with regard to sepsis [11] These canalso be demonstrated in different clinical conditions goingalong with systemic inflammatory response syndrome (SIRS)or prolonged ischemia [11] Furthermore the presence of apathogen in the blood or tissues does not necessarily indicatethat the complex syndrome of sepsis has occurred [12]Theseissues are further demonstrated by the discrepancies existingbetween clinical and postmortem diagnosis of sepsis [13ndash15]

Hindawi Publishing CorporationMediators of InflammationVolume 2016 Article ID 4062829 11 pageshttpdxdoiorg10115520164062829

2 Mediators of Inflammation

Despite the fact that the latter is still a diagnosis of exclusionsepsis is an intriguing field of interest in autopsy practiceand the diagnosis of sepsis-related deaths is an illustrativeexample of the reciprocal value of autopsy both for cliniciansand for pathologists Upon studying these deaths the pathol-ogist needs to approach the complex pathophysiologicalmechanisms underlying sepsis This may lead in turn to anincreased understanding of the pathogenic hypotheses andto the accuracy of existing diagnostic tools to be checked [16]Autopsies should still serve as a very important part of qualitycontrol in clinical diagnosis and treatment of sepsis [17 18]Last but not least the issue of the diagnostic reliability of fatalsepsis is even more pivotal One important area which hasseen a rising number of clinical negligence claims compriseshealthcare-associated infections and sepsis [19]

The objective of this review is to assess the state of ourknowledge of the molecular and biohumoral mechanisms ofsepsis and to correlate them with our postmortem diagnosisability

2 The Inflammatory Response

The septic response is an extremely complex chain of eventsinvolving inflammatory and anti-inflammatory processeshumoral and cellular reactions and circulatory changesWhen an infectious insult occurs it initiates a series of eventsresulting in the release of inflammation mediators whichinvolves both a local reaction and a systemic response andwhich finally could impact on organs function [20]

Sepsis triggers the production of a diverse array ofcytokines that are proinflammatory and anti-inflammatory[21 22] Cytokines are low molecular weight compoundswhich are considered potent positive and negative regula-tors of inflammation Some cytokines possess proinflamma-tory effects such as tumour necrosis factor- (TNF-) alphainterleukin- (IL-) 1 and interleukin-8 while others haveanti-inflammatory effects including IL-10 and IL-1 receptorantagonist and some are supposed to act as pro- and anti-inflammatory IL-6 as an example [23]

Proinflammatory cytokines trigger a beneficial responsesuch as increased local coagulation limited tissue damageand elimination of the pathogen Overwhelming productionof these proinflammatory cytokines however can be verydangerous in that excessive cytokines destroy the normalregulation of the immune response and induce pathologicalinflammatory disorders such as capillary leakage tissueinjury and organ failure Similarly the anti-inflammatorycytokines play a critical role in regulating overall immuneresponse in establishing homeostasis and in checking theeffects of the proinflammatory ones in order to solve inflam-mation and heal tissue Therefore their dysregulation canalso trigger pathogenesis [24] since it has been shown thatan intense anti-inflammatory response may induce a stateof immunosuppression in patients with sepsis [25] When astate of anti-inflammatory predominance occurs monocytesare deactivated This results in reduced antigen presentationand decreased production of proinflammatory cytokinesleading to pathogen persistence and further fuelling theinflammatory process [21 22 25] A tightly regulated balance

in the cytokine network which comprises pro- and anti-inflammatory cytokines is crucial for eliminating invadingpathogens on the one hand and restricting excessive tissue-damaging inflammation on the other [26]

In brief when an infectious insult occurs pattern recog-nition receptors (PRRs) which are expressed on epithelialbarriers as well as on resident immune cells such as den-dritic cells and macrophages detect invading microorgan-isms A specific family of PRRs named toll-like receptors(TLRs) recognizes conserved macromolecular motifs frommicroorganisms called pathogen-associated molecular pat-terns (PAMPs) The stimulation of TLRs or the nucleotideoligomerization domain NOD-like receptor (NLR) family ofintracellular PRRs results in the triggering of downstreamsignalling cascades Depending on the particular receptorengaged this process leads to the activation of a tran-scriptional response programme that includes nuclear factor120581B (NF-120581B) followed by the production and secretion ofcytokines chemokines and nitric oxide [21 22] Cytokinesusually bind their specific receptors induce signalling path-ways and thus regulate immune responses and other cellfunctions [24]

Therefore different types of cells tissuesorgans orproteinother molecules may function as effectors mod-ulating the immune response through various pro- oranti-inflammatory mediators Resident macrophages andpolymorphonuclear cells (PMCs) initiate the primary hostresponse to the invading microorganisms They are respon-sible for the primary phagocytosis and subsequent activationand recruitment of granulocytes and monocytes Leukostasisof neutrophils (the so-called leucocyte sticking) in the liversinusoids in the pulmonary vessels and so forth is thecommon histological counterpart of this phenomenon [11]Proliferation of astrocytes and microglial cells is a commonpostmortem histological finding in septic patients Howeverit is highly nonspecific as itmay reflect several kinds of insultsincluding ischemia [11]

Endothelial cells (ECs) activation occurs during sepsisThe interaction between ECs and leukocytes a hallmark ofthe inflammatory process comprises adhesive and migra-tory molecular events including low-affinity transient andreversible rolling adhesions integrin-dependent firm adhe-sive interactions and migratory events of the leukocytesthrough the endothelium and finally in the interstitialspace [27 28] A variety of chemical mediators secretedfrom inflamed tissue and the entire process of leukocyte-endothelial cell adhesion are regulated by the sequentialactivation of different families of adhesion molecules that areexpressed on the surface of leukocytes and ECs Lectin-likeadhesion glycoproteins selectins mediate leukocyte rollingThe firm adhesion and subsequent transendothelial migra-tion of leukocytes aremediated by the interaction of integrinsexpressed by leukocytes with immunoglobulin-like adhesionmolecules on ECs for example intercellular cell adhesionmolecules (ICAM) 1ndash5 vascular cell adhesion molecule-1(VCAM-1) and the junctional adhesion molecules (JAMs)which are expressed on endothelial and other cells [2930] Recently EC-active molecules (ie the angiopoietinpathway Ang-2 soluble fms-like tyrosine kinase-1) have been

Mediators of Inflammation 3

proposed to correlate significantly with organ dysfunctionand mortality in patients with sepsis [31 32]

Sepsis is also associated with robust activation of thecomplement system as demonstrated by the presence ofcomplement activation products (C3a C5a andC5b-9) in theplasma [33] C3a and C5a anaphylatoxins are small cleavageproducts of C3 and C5 and possess proinflammatory activ-ities C5a especially reacts with its receptors on phagocytes(neutrophils macrophages) and on a variety of organs totrigger numerous biological effects These include increasingvascular permeability and inducing smooth muscle con-traction inducing chemotaxis of PMCs monocytes andother cell types [34 35] In experimental studies on animalmodels (rats or mice with cecal ligation and puncture CLP)both rabbit polyclonal neutralizing antibodies and mousemonoclonal antibodies that neutralized C5a were highlyeffective in attenuating the parameters of sepsis (clinicalsymptoms evidence of multiorgan failure MOF consump-tive coagulopathy innate immune functions apoptosis etc)resulting in greatly improved survival [36 37] The effectsof C5a contribute to immunoparalysis MOF the apoptosisof thymocytes and adrenal medullary cells and imbalancesin the coagulation system [38] In addition C5a is involvedin the development of septic cardiomyopathy and severe leftventricular dysfunction [39] At autopsy the left ventricleis often dilated and the ventricular walls have a flaccidappearance [11]

Other products derived from activation of the comple-ment system play an important role in sepsis such as C3b(from C3) which is a key opsonisation factor that reacts withphagocytes receptors to favour internalization of bacteria andtheir subsequent eliminationThe membrane attack complex(C5b-9) causes lysis of Gram-negative bacteria [38]

Finally sepsis also affects other biological systems suchas the coagulation system and the autonomic nervous system[39] In the clinical setting of sepsis dysregulation of thecoagulation cascade results in major complications Theextent of activation of the coagulation cascade during sepsiscan range from an insignificant level to the occurrence ofdisseminated intravascular coagulation (DIC) When DICoccurs at autopsy various degree of haemorrhage can beobserved on the skin on mucocutaneous surfaces and serousmembranes and finally in parenchymal organs [10 11]Increasing evidence points to an extensive cross talk betweeninflammation and coagulation in which the protease acti-vated cell receptors play an important role (Figure 1)

3 The Concept of (Compartmentalization) ofthe Inflammatory Response in Sepsis

A fundamental step in the comprehension of sepsis patho-physiology is to appreciate that the inflammatory responsevaries from one compartment to another and not all com-partments behave similarly [40] Chinnaiyan et al supportedthis concept by studying gene expression in different tissuesin CLP model of sepsis in rats They showed that the sepsisresponse elicited gene expression profiles that were eitherorgan specific common tomore than one organ or distinctlyopposite in some organs [41]

Each organ has a distinctive molecular response tosystemic inflammation Several experimental pieces of dataconfirm this observation For example neutrophil seques-tration in lung and liver resulted differently regulated bychemokines in a murine experimental model of peritonitis[42] After injection of LPS (lipopolysaccharide) in a micemodel NF-120581B activation in liver was mediated through TNFand IL-1 receptor-dependent pathways but in the lung LPSinduced NF-120581B activation was largely independent of thesereceptors [43] Although data are still missing in humansmouse alveolar macrophages do not produce IL-10 [44] donot express TLR9 and are thus insensitive to bacterial DNA[45] and fail to produce IFN-120573 in response to TLR4 and TLR3agonists [46] thus demonstrating that in this animal modelalveolar macrophages behave differently to other types ofmacrophages

Through the bloodstream a strict cross talk exists betweenthe different organs and compartments Both pro- and anti-inflammatory mediators are present concomitantly in thebloodstream evoking different responses in the variousorgans The latter in turn respond through the local pro-duction of different mediators and the activation of differentcellular types [40] Most tissues contribute to the releaseof inflammatory mediators and there is local activation ofintracellular signalling pathways [40]

This concept is of paramount clinical importance asthe various organs may respond differently to therapeuticstrategies On the other hand upon approaching sepsis-related deaths pathologists must keep in mind that tissueinjury can be initiated remotely from an insult in a farawaysite and that all organs and compartments may be involved(Figure 2)

Different organs and systems are interconnected viahumoral and biochemical interactions and are clustered intofunctional modules sharing many common pathophysiolog-ical mechanisms Diagnostic postmortem strategies basedon the measurement of compartmentalized mediators mayprove useful as a diagnostic strategy [47 48]

4 Microcirculation and Microvesicles

Sepsis is a disease of microcirculation [49] Nuclear vac-uolization cytoplasmic swelling and protrusion cytoplasmicfragmentation and various degrees of endothelial detach-ment from its basement membrane have been demonstratedduring sepsis [50 51] Endothelial physical disruption leads toan extravascular leak of protein-rich oedema and polymor-phonuclear cells (PMNs) influx into organs Furthermoreendothelial damage may induce leukocyte and platelet aggre-gation as well as aggravation of coagulopathy thus favouringimpaired perfusion tissue hypoxia and subsequent organdysfunction [51 52]

Deleterious effects on the vascular function are medi-ated by increased synthesis of inflammatory cytokines andchemokines and increased expression of endothelial adhe-sion molecules [49ndash51] Microvascular endothelial cells(MVECs) that are critical modulators of blood flow andmicrovascular function are principal targets of the systemicinflammation of sepsis [52]


Inflammatory insult

PAMPs (LPS bacterial DNA)

PRRs

DAMPs (heat-shock protein uric acid etc)

TLRs

VEGF

Ang-12s-ICAM-1

s-VCAM-1sE-selectin-1

Regulators of endothelial activation

Mediators of permeability and vasomotor tone

Epithelial cells Adipocytes

s-Flt Endothelin-1

Mediators of coagulation

vWF

Inflammatory mediators

TNF-120572

Chemokines

CRPLBP

PCT

IL-1IL-10

IL-8 IL-6

Complement activated products

C5aC3a

Complement system

C5b-9

Endothelial cells Granulocytes

Eosinophil

Neutrophil

Basophil

B lymphocyteT lymphocyte

Naturalkiller cell

White blood cells

Figure 1 Schematic of events associated with major mediators of cytokine cascade on initiation of sepsis The release of a large amountof pathogen and damage associated molecular patterns (PAMPs and DAMPs) from invading microorganisms andor damaged host tissuerespectively results in the overstimulation of pattern-recognition receptors (PRRs) of immune cells This process activates an inflammatorycascade in which large amounts of cytokines are released into the body Macrophages and endothelial cells are then hyperactivated by theunusually large quantity of circulating cytokinesThe activation of macrophages and endothelial cells results in the release of more cytokinesexacerbating the inflammatory response The profound proinflammatory response is counteracted by certain anti-inflammatory cytokinesincluding IL-10 transforming growth factor-120573 (TGF-120573) and IL-4 which attempt to restore immunological equilibrium

Microvasculature dysfunction in sepsis is almost ubiq-uitous Pulmonary MVECs injury and barrier dysfunctionresult in the leak of protein-rich fluid and circulatingneutrophils into the pulmonary interstitium and alveolarspaces [52ndash54] Recently it has been demonstrated that septicpulmonary microvascular barrier dysfunction is associatedwith significant pulmonary MVECs death which is largelyapoptotic [52] Experimental observations provide proof thatseptic acute kidney injury (AKI) can occur in the setting ofrenal hyperaemia and that ischemia is not necessarily presentNonhemodynamic mechanisms of cell injury are likely to beat work due to a combination of immunologic toxic andinflammatory factors that may affect the microvasculatureand the tubular cells [55ndash58]There is evidence that adhesionmolecule activation both on the renal endothelium andon epithelial cells leads to enhanced leukocyte adhesionfollowed by the influx of activated leukocytes into the renalinterstitium [57] Finally renal mitochondrial dysfunction

has been demonstrated in CLP murine model of sepsisleading to a decrease in renal complexes I and IIIII respi-ration MnSOD (manganese superoxide dismutase) activityand ATP levels This was associated with increased mito-chondrial superoxide levels impaired renalmicrocirculationand impaired renal function [59] Oxidant generation bythe renal tubules and renal microvascular failure are earlyevents which lead toAKI [60ndash62] Cerebralmicrocirculatorydysfunction has been demonstrated in various experimentalmodels of sepsis [63] and it is thought to be one of the mainpathophysiological mechanisms leading to brain damage alsoin humans [64] Both endotoxin or more accurately termedbacterial lipopolysaccharide (LPS) and proinflammatorycytokines induce the expression ofCD40VCAM-1 or ICAM-1 andE-selectin onhumanbrainmicrovessel endothelial cells[65ndash69]

Finally in recent years a growing body of evidence hasbeen established regarding the role of microvesicles (MVs)


Cerebral microcirculatory dysfunction

Neuronal degeneration

Impaired astrocyte function

Sepsis

Pulmonary infiltration

Acute lung injury

Cytokines ICAM-1VCAM-1

E-selectin

NO

Endothelial activation

Neutrophilic infiltration to cardiomyocytes

Myocardial depression

MIF

Contractile dysfunction

Direct tubular cell injury

ROSRNS

Liver injury

Chemokines

Figure 2 A schematic representing the involvement of different organs in sepsis During sepsis large amounts of inflammatory mediatorsare found within the bloodstream They can act on different organs and induce tissue injury that in turn will favour further production ofinflammatory mediators Cross talk between the different organs and tissues is further mediated by the local delivery of mediators that canamplify or limit the inflammatory response (MIF macrophage migration inhibitory factor NO nitric oxide ROS reactive oxygen speciesRNS reactive nitrogen species VCAM-1 vascular adhesion molecule-1 and ICAM-1 intercellular adhesion molecule-1)

in sepsis [70] These extracellular vesicles are released inthe extracellular environment through a membrane reorga-nization and blebbing process following cell activation orapoptosisThey constitute a storage pool of bioactive effectorswith varied cellular origins and are able to act as intercel-lular messengers or effectors through multiple amplificationand regulatory loops affecting vascular cells functions [71]Thus MVs contribute to the spread of inflammatory andprothrombotic vascular status They may also affect smoothmuscle tissue through adhesion molecules activation of NF-120581B and the expression of inducible nitric oxide synthaseand cyclooxygenase-2 with an increase in nitric oxide andvasodilator prostanoids leading to arterial hyporeactivity[72ndash74]

In recent years the analysis of circulating-cell-derivedMVs has become more defined and clinically more usefuland several groups suggest that it may enter mainstreamclinical testing [75 76] Endothelial-derivedmicrovesicles areconsidered relevant biomarkers of septic shock-induced DICand have been proposed as a significant diagnostic tool toevaluate early vascular injury [74] An increase of platelet

derived microvesicles has been demonstrated in the develop-ment of sepsis-related renal impairment [77] and in severefungal sepsis [78] Finally MVs released from peripheralblood PMNs have a similar size and orientation but differ inprotein composition and functional properties These affectendothelial cells platelets monocytes and macrophagesThey also show antibacterial properties since they are capableof a significant reduction in bacterial growth (Figure 3) [79ndash81]

5 The Blood Compartment

Blood compartment plays a key role in the inflammatoryresponse Waves of mediators with both anti- and proin-flammatory properties are detectable in the plasma of septicpatients Many of these are considered reliable markers forin vita diagnosis of sepsis and some have been proposedalso as biological markers of the severity of sepsis but nonealone is entirely specific for infection because they can bealso detected in the absence of infection [82] The futuredirection of research is most likely to focus on the use of


MVs

Apoptosis

Platelet aggregation

Monocytes

Endothelial physical disruption

Abnormal coagulation

Leukocyte extravasation

ICAM-1

E-selectin


ICAM-1

NF-120581B

NO

Arterial hyporeactivity

Increased microvascular permeability

Vasoplegia

Activated cell

Cell

Granulocytes

Eosinophil

Neutrophil

Basophil

VCAM-1

Figure 3 A schematic representing microvesicles (MVs) functions MVs are released in the extracellular environment through a membranereorganization and blebbing process following cell activation or apoptosisThey contribute to the spread of inflammatory and prothromboticvascular status and they may affect smooth muscle tissue through adhesion molecules (E-selectin ICAM and VCAM) activation of nuclearfactor 120581B and the expression of inducible nitric oxide synthase and cyclooxygenase-2 with an increase in nitric oxide (NO) and vasodilatorprostanoids leading to arterial hyporeactivity

panels or combinations of markers with clinical signs Somebiomarkers may also be useful for prognosis and guidingtherapy [83ndash86] However nowadays the ideal biomarkerwith high sensitivity and specificity and cost effectiveness andwith definite cut-off ranges and time of blood sampling is yetto be found [87]

As molecular and humoral mechanisms are thought toplay a key part in the pathophysiology of sepsis postmortemdiagnostic strategies based on the concentration of suchmediators have been investigated

Many authors propose the detection of procalcitonin(PCT) as a useful and reliable marker of sepsis in routineautopsy investigations [88ndash91] PCT a prohormone com-posed of 116 amino acids is the precursor of the calciumhomoeostasis hormone calcitonin which is found in thyroidC cells and pulmonary endocrine cells Clinically relevantlevels of PCT influence the immunologic responses thatcontribute to systemic inflammatory responses and septicshock Many studies have indicated that PCT is an excellentmarker of bacterial infection in patients with sepsis and itsrelated conditions Bode-Janisch et al outline that at PCT

levels lt2 ngmL bacterial sepsis or septic shock can almostcertainly be excluded as cause of death [89] PCT levelsge10 ngmL can be detected occasionally in conditions otherthan sepsis A final assessment should therefore take intoaccount the PCT levels autopsy results and the histopatho-logical andmicrobiological findings [91] Other authors indi-cate high diagnostic accuracy for both lipopolysaccharide-binding protein (LBP) and PCT considered individuallyand combined in detecting sepsis-related outcomes in post-mortem [92]

However due to the detectability of high levels of PCTalso in aseptic inflammation (ie chronic inflammatory andautoimmune conditions myocardial infarction etc) [93ndash103] a pressing need to identify additional biomarkers isevident [91]

As demonstrated by the studies mentioned above muchattention has been focused on cytokines and other mediatorsas diagnostic tools in many diseases and they certainlyhold promise also for the discovery of reliable postmortembiomarkers of sepsis


Soluble interleukin-2 receptor (sIL-2R) and LBP seem torepresent appropriate diagnostic tools for the postmortemdiagnosis of sepsis [104] Postmortem IL-6 and C-reactiveprotein (CRP) serum levels were investigated by Tsokoset al in sepsis and nonseptic fatalities and both IL-6 andCRP serum concentrations seem to be suitable biochemicalmarkers of sepsis [105] However since pathological condi-tions other than sepsis (trauma burn injury etc) may beassociated with elevated IL-6 andor CRP levels the authorsthemselves warn about the need to rule out such conditionsupon interpreting postmortem values of IL-6 and CRP [105]

Other biomarkers of potential relevance to sepsissepticshock diagnostics have been proposed more recently

Triggering receptor expressed onmyeloid cells-1 (TREM-1) is a recently discovered member of the immunoglobulinsuperfamily of receptors that is specifically expressed on thesurfaces of neutrophils and monocytes and upregulated inbacterial sepsis This is associated with a marked plasmaelevation in the soluble form of this molecule (sTREM-1)Studies have indicated that sTREM-1 could be a valuable diag-nostic biomarker for sepsis [106] Palmiere et al investigatedsTREM-1 concentration in the serum of patients who diedfrom sepsis and found that when individually considered itdid not provide better sensitivity and specificity than PCTin detecting sepsis However simultaneous assessment ofPCT and sTREM-1 in postmortem serum could improvediagnostic accuracy [87] Results from septic patients inintensive care units found that sTREM-1 PCT and CRPlevels indicate infection while sTREM-1 and PCT levelspredict prognosis Moreover sTREM-1 appears to be thebest indicator for the diagnosis of sepsis and assessment ofprognosis of blood culture-positive bacteremia [107]

Presepsin (sCD14-ST) is a solubleN-terminal fragment ofproteinCD14which is released into circulation duringmono-cyte activation on the recognition of LPS from infectiousagents [108] it shows promise for diagnostic and prognosticpurposes in septic patients [109] It has been investigatedin sepsis-related death The results show that even thoughincreases in both PCT and sCD14-ST concentrations wereobserved in the control cases coherent PCT and sCD14-STresults in cases with suspected sepsis allowed the diagnosisto be confirmed Conversely no relevant correlation wasidentified between postmortem serum and pericardial fluidsCD14-ST levels in either the septic or control groups [110]

Endocan (endothelial cell-specific molecule-1) a 50-kDadermatan sulphate proteoglycan expressed by endothelialcells in lung and kidney can be detected at low levelsin the serum of healthy subjects Increased concentrationswere described in patients with sepsis severe sepsis andseptic shock compared to healthy individuals with serumconcentrations related to the severity of illness [111] Palmiereand Augsburger found that postmortem serum endocanconcentrations were significantly higher in sepsis fatal caseswith values ranging from 0519 ngmL to 6756 ngmL whilein most patients of the control group endocan was unde-tectableThe authors argue that endocan could be considered

a suitable biological parameter for the detection of sepsis-related deaths in forensic pathology routine [112]

Neopterin (D-erytro-110158402101584031015840-trihydroxypropylterin) abiochemical product of guanosine triphosphate pathwayhas been proposed to aid in the diagnosis of bacterial [113]and viral infections [114] Also in the forensic literatureneopterin has been proposed as a marker of inflammatorydiseases [115ndash117] Postmortem serum neopterin levels over500 nmolL were observed in bacterial and viral infectioncases as well as in delayed deaths due to trauma [118] Forthis reason the specificity of neopterin as a clinical markerof bacterial sepsis is limited [119]

Conclusively there is a strong body of evidence thatpostmortem concentration of serum cytokines and othermediators of inflammation may be an area of great interestwith exciting diagnostic possibilities for sepsisseptic shock-related deaths [118 119] However at present an ideal clinicaland postmortem marker of sepsis does not exist [118]

In a previous review Pierrakos and Vincent identifiednearly 180 distinct molecules that have been proposed aspotential biological markers of sepsis [83] However only20 of these biomarkers have been assessed specifically inappropriate studies for use in the diagnosis of sepsis [84]

6 Conclusion

The difficulties of the postmortem diagnosis of death dueto sepsis are well known The major limitation is the poorspecificity of macroscopic and routine histological findingsencountered in such cases Due to the complexmolecular andcellular mechanisms underlying sepsis proof of the presenceof germs alone cannot be of evidential value in establishinga causal relationship between infection and outcome Thusthe old saying byWilliam Osler (1849 to 1919) ldquoexcept on fewoccasions the patient appears to die from the bodyrsquos responseto infection rather than from the infectionrdquo is still true[84]

A completemethodological approach integrating clinicaldata by means of autopsy and histological and labora-tory findings aiming to identify and demonstrate the hostresponse to infectious insult is mandatory Such an approachwould be likely to produce an accurate objective surveillanceof deaths due to sepsis and improve our knowledge of theclinical-pathological correlation in sepsis thus contributingto the evaluation of the effectiveness of therapies Finallyautopsy is a critical tool for protection from false liabilityclaims and settling valid claims quickly and fairly

Disclosure

Readers can refer to Sepulchretum Sive Anatomia Practicaex Cadaveribus Morbo Denatis (Burial vaultcemetery oranatomical studies on bodies affected by disease) Bonet T(1679) Leonardus Chouet Geneva

Competing Interests

The authors declare that they have no competing interests


References

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[2] S L Murphy J Xu and K D Kochanek ldquoDeaths preliminarydata for 2010rdquoNational Vital Statistics Reports vol 60 no 4 pp1ndash51 2012

[3] 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 Research2006ndash2013 Rockville Md USA 2011

[4] G Clemente A TuttolomondoDColomba et al ldquoWhen sepsisaffects the heart a case report and literature reviewrdquo WorldJournal of Clinical Cases vol 3 no 8 pp 743ndash750 2015

[5] M M Levy A Artigas G S Phillips et al ldquoOutcomes of theSurviving Sepsis Campaign in intensive care units in the USAand Europe a prospective cohort studyrdquo The Lancet InfectiousDiseases vol 12 no 12 pp 919ndash924 2012

[6] F B Mayr S Yende and D C Angus ldquoEpidemiology of severesepsisrdquo Virulence vol 5 no 1 pp 4ndash11 2014

[7] C W Seymour V X Liu T J Iwashyna et al ldquoAssessment ofclinical criteria for sepsis for the third international consensusdefinitions for sepsis and septic shock (Sepsis-3)rdquoThe Journal ofthe American Medical Association vol 315 no 8 pp 762ndash7742016

[8] M Shankar-Hari G S Phillips M L Levy et al ldquoDevelopinga new definition and assessing new clinical criteria for septicshockrdquoThe Journal of theAmericanMedical Association vol 315no 8 pp 775ndash787 2016

[9] S Lucas ldquoSepsis definitionsrdquo The Lancet vol 381 no 9885article 2249 2013

[10] S Lucas ldquoThe autopsy pathology of sepsis-related deathrdquoCurrent Diagnostic Pathology vol 13 no 5 pp 375ndash388 2007

[11] M Tsokos ldquoPostmortem diagnosis of sepsisrdquo Forensic ScienceInternational vol 165 no 2-3 pp 155ndash164 2007

[12] J A Morris L M Harrison and S M Partridge ldquoPostmortembacteriology a re-evaluationrdquo Journal of Clinical Pathology vol59 no 1 pp 1ndash9 2006

[13] S A Blosser H E Zimmerman and J L Stauffer ldquoDo autopsiesof critically ill patients reveal important findings that wereclinically undetectedrdquo Critical Care Medicine vol 26 no 8 pp1332ndash1336 1998

[14] G D Perkins D F McAuley S Davies and F Gao ldquoDiscrepan-cies between clinical and postmortem diagnoses in critically illpatients an observational studyrdquo Critical Care vol 7 no 6 ppR129ndashR132 2003

[15] J Roulson E W Benbow and P S Hasleton ldquoDiscrepanciesbetween clinical and autopsy diagnosis and the value of postmortem histology a meta-analysis and reviewrdquoHistopathologyvol 47 no 6 pp 551ndash559 2005

[16] G Y A De Vlieger E M J L Mahieu and W MeerssemanldquoClinical review what is the role for autopsy in the ICUrdquoCritical Care vol 14 no 2 article 221 2010

[17] C C H J Kuijpers J Fronczek F R W Van De Goot H WM Niessen P J van Diest and M Jiwa ldquoThe value of autopsiesin the era of high-tech medicine discrepant findings persistrdquoJournal of Clinical Pathology vol 67 no 6 pp 512ndash519 2014

[18] J G van den Tweel and C Wittekind ldquoThe medical autopsyas quality assurance tool in clinical medicine dreams andrealitiesrdquo Virchows Archiv vol 465 no 1 pp 75ndash81 2016

[19] S D Goldenberg H Volpe and G L French ldquoClinical negli-gence litigation and healthcare-associated infectionsrdquo Journalof Hospital Infection vol 81 no 3 pp 156ndash162 2012

[20] J C Marshall and K Reinhart ldquoInternational sepsis forumBiomarkers of sepsisrdquoCritical Care vol 37 pp 2290ndash2298 2009

[21] W Schulte J Bernhagen and R Bucala ldquoCytokines in sepsispotent immunoregulators and potential therapeutic targetsmdashanupdated viewrdquoMediators of Inflammation vol 2013 Article ID165974 16 pages 2013

[22] M Aziz A Jacob W-L Yang A Matsuda and P Wang ldquoCur-rent trends in inflammatory and immunomodulatory media-tors in sepsisrdquo Journal of Leukocyte Biology vol 93 no 3 pp329ndash342 2013

[23] J Scheller A Chalaris D Schmidt-Arras and S Rose-JohnldquoThe pro- and anti-inflammatory properties of the cytokineinterleukin-6rdquo Biochimica et Biophysica Acta (BBA)mdashMolecularCell Research vol 1813 no 5 pp 878ndash888 2011

[24] H Chaudhry J Zhou Y Zhong et al ldquoRole of cytokines as adouble-edged sword in sepsisrdquo In Vivo vol 27 no 6 pp 669ndash684 2013

[25] A Ashare L S Powers N S Butler K C Doerschug M MMonick andGWHunninghake ldquoAnti-inflammatory responseis associated with mortality and severity of infection in sepsisrdquoAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 288 no 4 pp L633ndashL640 2005

[26] J Cohen ldquoThe immunopathogenesis of sepsisrdquoNature vol 420no 6917 pp 885ndash891 2002

[27] K Ley C Laudanna M I Cybulsky and S NoursharghldquoGetting to the site of inflammation the leukocyte adhesioncascade updatedrdquo Nature Reviews Immunology vol 7 no 9 pp678ndash689 2007

[28] T A Springer ldquoTraffic signals for lymphocyte recirculation andleukocyte emigration the multistep paradigmrdquo Cell vol 76 no2 pp 301ndash314 1994

[29] H F Langer and T Chavakis ldquoLeukocytemdashendothelial inter-actions in inflammationrdquo Journal of Cellular and MolecularMedicine vol 13 no 7 pp 1211ndash1220 2009

[30] A K Kakkar and D J Lefer ldquoLeukocyte and endothelialadhesion molecule studies in knockout micerdquo Current Opinionin Pharmacology vol 4 no 2 pp 154ndash158 2004

[31] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[32] S Skibsted A E Jones M A Puskarich et al ldquoBiomarkers ofendothelial cell activation in early sepsisrdquo Shock vol 39 no 5pp 427ndash432 2013

[33] P A Ward ldquoRole of the complement in experimental sepsisrdquoJournal of Leukocyte Biology vol 83 no 3 pp 467ndash470 2008

[34] M-J Rabiet E Huet and F Boulay ldquoThe N-formyl peptidereceptors and the anaphylatoxin C5a receptors an overviewrdquoBiochimie vol 89 no 9 pp 1089ndash1106 2007

[35] P A Ward ldquoThe harmful Role of C5a on innate immunity insepsisrdquo Journal of Innate Immunity vol 2 no 5 pp 439ndash4452010

[36] D Rittirsch M A Flierl B A Nadeau et al ldquoFunctional rolesfor C5a receptors in sepsisrdquo Nature Medicine vol 14 no 5 pp551ndash557 2008

[37] B J Czermak V Sarma C L Pierson et al ldquoProtective effects ofC5a blockade in sepsisrdquo Nature Medicine vol 5 no 7 pp 788ndash792 1999


[38] P A Ward R-F Guo and N C Riedemann ldquoManipulationof the complement system for benefit in sepsisrdquo Critical CareResearch and Practice vol 2012 Article ID 427607 8 pages 2012

[39] D Rittirsch M A Flierl and P A Ward ldquoHarmful molecularmechanisms in sepsisrdquo Nature Reviews Immunology vol 8 no10 pp 776ndash787 2008

[40] J-M Cavaillon and D Annane ldquoCompartmentalization of theinflammatory response in sepsis and SIRSrdquo Journal of EndotoxinResearch vol 12 no 3 pp 151ndash170 2006

[41] A M Chinnaiyan M Huber-Lang C Kumar-Sinha et alldquoMolecular signatures of sepsis multiorgan gene expressionprofiles of systemic inflammationrdquo American Journal of Pathol-ogy vol 159 no 4 pp 1199ndash1209 2001

[42] M A Mercer-Jones M S Shrotri J C Peyton D G Remickand W G Cheadle ldquoNeutrophil sequestration in liver andlung is differentially regulated by CndashXndashC chemokines duringexperimental peritonitisrdquo Inflammation vol 23 no 4 pp 305ndash319 1999

[43] M A Koay J W Christman L J Wudel et al ldquoModulationof endotoxin-induced NF-120581B activation in lung and liverthrough TNF type 1 and IL-1 receptorsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 6 pp L1247ndashL1254 2002

[44] L Salez M Singer V Balloy C Creminon and M ChignardldquoLack of IL-10 synthesis by murine alveolar macrophagesupon lipopolysaccharide exposure Comparison with peri-toneal macrophagesrdquo Journal of Leukocyte Biology vol 67 no4 pp 545ndash552 2000

[45] K Suzuki T Suda T Naito K Ide K Chida and H Naka-mura ldquoImpaired Toll-like receptor 9 expression in alveolarmacrophages with no sensitivity to CpG DNArdquo AmericanJournal of Respiratory and Critical Care Medicine vol 171 no7 pp 707ndash713 2005

[46] A Punturieri R S Alviani T Polak P Copper J Sonstein andJ L Curtis ldquoSpecific engagement of TLR4 or TLR3 does notlead to IFN-120573-mediated innate signal amplification and STAT1phosphorylation in residentmurine alveolar macrophagesrdquoTheJournal of Immunology vol 173 no 2 pp 1033ndash1042 2004

[47] B Schrag K Iglesias P Mangin and C Palmiere ldquoProcalci-tonin andC-reactive protein in pericardial fluid for postmortemdiagnosis of sepsisrdquo International Journal of Legal Medicine vol126 no 4 pp 567ndash572 2012

[48] A Vege T O Rognum A O Aasen and O D SaugstadldquoAre elevated cerebrospinal fluid levels of IL-6 in sudden unex-plained deaths infectious deaths and deaths due to heartlungdisease in infants and children due to hypoxiardquo Acta Paedi-atrica vol 87 no 8 pp 819ndash824 1998

[49] P E Spronk D F Zandstra and C Ince ldquoBench-to-bedsidereview sepsis is a disease of themicrocirculationrdquoCritical Carevol 8 no 6 pp 462ndash468 2004

[50] AMMuller andM Tsokos ldquoPathology of human endotheliumin septic organ failurerdquo in Forensic Pathology Reviews MTsokos Ed vol 4 pp 161ndash192 Humana Press New Jersey NJUSA 2006

[51] B Vallet ldquoBench-to-bedside review endothelial cell dysfunc-tion in severe sepsis a role in organ dysfunctionrdquoCritical Carevol 7 no 2 pp 130ndash138 2003

[52] K Reinhart O Bayer F Brunkhorst andMMeisner ldquoMarkersof endothelial damage in organ dysfunction and sepsisrdquoCriticalCare Medicine vol 30 no 5 pp S302ndashS312 2002

[53] S E Gill R Taneja M Rohan L Wang and S MehtaldquoPulmonary microvascular albumin leak is associated with

endothelial cell death in murine sepsis-induced lung injury invivordquo PLoS ONE vol 9 no 2 Article ID e88501 2014

[54] LWang R TanejaHMRazavi C LawCGillis and SMehtaldquoSpecific role of neutrophil inducible nitric oxide synthase inmurine sepsis-induced lung injury in vivordquo Shock vol 37 no 5pp 539ndash547 2012

[55] L Wan S M Bagshaw C Langenberg T Saotome C Mayand R Bellomo ldquoPathophysiology of septic acute kidney injurywhat do we really knowrdquo Critical Care Medicine vol 36 no 4pp S198ndashS203 2008

[56] R Bellomo L Wan C Langenberg et al ldquoSeptic acute kidneyinjury new conceptsrdquo Nephron Experimental Nephrology vol109 no 4 pp e95ndashe100 2008

[57] K Ishikawa C N May G Gobe C Langenberg and RBellomo ldquoPathophysiology of septic acute kidney injury adifferent view of tubular injuryrdquo Contributions to Nephrologyvol 165 pp 18ndash27 2010

[58] X Wu R Guo Y Wang and P N Cunningham ldquoThe role ofICAM-1 in endotoxin-induced acute renal failurerdquo AmericanJournal of PhysiologymdashRenal Physiology vol 293 no 4 ppF1262ndashF1271 2007

[59] NK Patil N Parajuli L AMacMillan-Crow andP RMayeuxldquoInactivation of renal mitochondrial respiratory complexes andmanganese superoxide dismutase during sepsis mitochondria-targeted antioxidant mitigates injuryrdquo American Journal ofPhysiologymdashRenal Physiology vol 306 no 7 pp F734ndashF7432014

[60] J H Holthoff Z Wang K A Seely N Gokden and P RMayeux ldquoResveratrol improves renalmicrocirculation protectsthe tubular epithelium and prolongs survival in amousemodelof sepsis-induced acute kidney injuryrdquo Kidney Internationalvol 81 no 4 pp 370ndash378 2012

[61] Z Wang J H Holthoff K A Seely et al ldquoDevelopment ofoxidative stress in the peritubular capillary microenvironmentmediates sepsis-induced renal microcirculatory failure andacute kidney injuryrdquoAmerican Journal of Pathology vol 180 no2 pp 505ndash516 2012

[62] L Wu N Gokden and P R Mayeux ldquoEvidence for the role ofreactive nitrogen species in polymicrobial sepsis-induced renalperitubular capillary dysfunction and tubular injuryrdquo Journal ofthe American Society of Nephrology vol 18 no 6 pp 1807ndash18152007

[63] F S Taccone F Su C Pierrakos et al ldquoCerebral microcircula-tion is impaired during sepsis an experimental studyrdquo CriticalCare vol 14 article R140 2010

[64] F S Taccone S Scolletta F Franchi K Donadello and MOddo ldquoBrain perfusion in sepsisrdquo Current Vascular Pharmacol-ogy vol 11 no 2 pp 170ndash186 2013

[65] K M Omari and K Dorovini-Zis ldquoCD40 expressed by humanbrain endothelial cells regulates CD4+ T cell adhesion toendotheliumrdquo Journal of Neuroimmunology vol 134 no 1-2 pp166ndash178 2003

[66] D Wong and K Dorovini-Zis ldquoExpression of vascular celladhesion molecule-1 (VCAM-1) by human brain microvesselendothelial cells in primary culturerdquo Microvascular Researchvol 49 no 3 pp 325ndash339 1995

[67] D C Hess Y Thompson A Sprinkle J Carroll and J SmithldquoE-selectin expression on human brain microvascular endo-thelial cellsrdquoNeuroscience Letters vol 213 no 1 pp 37ndash40 1996

[68] P RieckmannaUMichelMAlbrechtW Buck LWockel andK Felgenhauer ldquoCerebral endothelial cells are a major source


for soluble intercellular adhesion molecule-1 in the humancentral nervous systemrdquoNeuroscience Letters vol 186 no 1 pp61ndash64 1995

[69] D C Hess T Bhutwala J C Sheppard W Zhao and J SmithldquoICAM-1 expression on human brainmicrovascular endothelialcellsrdquo Neuroscience Letters vol 168 no 1-2 pp 201ndash204 1994

[70] F Meziani X Delabranche P Asfar and F Toti ldquoBench-to-bedside review circulating microparticlesmdasha new player insepsisrdquo Critical Care vol 14 article 236 2010

[71] O Morel F Toti B Hugel and J-M Freyssinet ldquoCellularmicroparticles a disseminated storage pool of bioactive vascu-lar effectorsrdquo Current Opinion in Hematology vol 11 no 3 pp156ndash164 2004

[72] T N Pitanga L de Aragao V C Franca et al ldquoNeutrophil-derived microparticles induce myeloperoxidase-mediateddamage of vascular endothelial cellsrdquo BMC Cell Biology vol 15article 15 2014

[73] X Delabranche J Boisrame-Helms P Asfar et al ldquoMicroparti-cles are new biomarkers of septic shock-induced disseminatedintravascular coagulopathyrdquo Intensive CareMedicine vol 39 no10 pp 1695ndash1703 2013

[74] V L Reid and N R Webster ldquoRole of microparticles in sepsisrdquoBritish Journal of Anaesthesia vol 109 no 4 pp 503ndash513 2012

[75] W Jy L L Horstman J J Jimenez et al ldquoMeasuring circu-lating cell-derived microparticlesrdquo Journal of Thrombosis andHaemostasis vol 2 no 10 pp 1842ndash1851 2004

[76] J-M Freyssinet and F Dignat-George ldquoMore on measuringcirculating cell-derived microparticlesrdquo Journal of Thrombosisand Haemostasis vol 3 no 3 pp 613ndash614 2005

[77] M Tokes-Fuzesi G Woth B Ernyey et al ldquoMicroparticles andacute renal dysfunction in septic patientsrdquo Journal of CriticalCare vol 28 no 2 pp 141ndash147 2013

[78] G Woth M Tokes-Fuzesi T Magyarlaki G L Kovacs IVermes and D Muhl ldquoActivated platelet-derived microparticlenumbers are elevated in patients with severe fungal (Candidaalbicans) sepsisrdquo Annals of Clinical Biochemistry vol 49 no 6pp 554ndash560 2012

[79] P S Prakash C C Caldwell A B Lentsch T A Pritts andB R H Robinson ldquoHuman microparticles generated duringsepsis in patients with critical illness are neutrophil-derived andmodulate the immune responserdquo The Journal of Trauma andAcute Care Surgery vol 73 no 2 pp 401ndash407 2012

[80] C I Timar A M Lorincz R Csepanyi-Komi et al ldquoAntibac-terial effect of microvesicles released from human neutrophilicgranulocytesrdquo Blood vol 121 no 3 pp 510ndash518 2013

[81] P Lacy ldquoA new way of trapping bugs neutrophil microvesiclesrdquoBlood vol 121 no 3 pp 420ndash421 2013

[82] J-L Vincent and L Teixeira ldquoSepsis biomarkers Value andlimitationsrdquo American Journal of Respiratory and Critical CareMedicine vol 190 no 10 pp 1081ndash1082 2014

[83] C Pierrakos and J-L Vincent ldquoSepsis biomarkers a reviewrdquoCritical Care vol 14 article R15 2010

[84] K Reinhart M Bauer N C Riedemann and C S HartogldquoNew approaches to sepsis molecular diagnostics and biomark-ersrdquo Clinical Microbiology Reviews vol 25 no 4 pp 609ndash6342012

[85] B Cai E A Deitch and L Ulloa ldquoNovel insights for systemicinflammation in sepsis and hemorrhagerdquo Mediators of Inflam-mation vol 2010 Article ID 642462 10 pages 2010

[86] R A Claus G P Otto H-P Deigner andM Bauer ldquoApproach-ing clinical reality markers for monitoring systemic inflamma-tion and sepsisrdquo Current Molecular Medicine vol 10 no 2 pp227ndash235 2010

[87] N Tziolos A Kotanidou and S E Orfanos ldquoBiomarkers ininfection and sepsis can they really indicate final outcomerdquoInternational Journal of Antimicrobial Agents vol 46 pp S29ndashS32 2015

[88] C Palmiere D Bardy P Mangin andM Augsburger ldquoValue ofsTREM-1 procalcitonin and CRP as laboratory parameters forpostmortem diagnosis of sepsisrdquo Journal of Infection vol 67 no6 pp 545ndash555 2013

[89] S Bode-Janisch S Schutz A Schmidt et al ldquoSerum procal-citonin levels in the postmortem diagnosis of sepsisrdquo ForensicScience International vol 226 no 1ndash3 pp 266ndash272 2013

[90] F Ramsthaler M Kettner G Mall and H Bratzke ldquoThe useof rapid diagnostic test of procalcitonin serum levels for thepostmortem diagnosis of sepsisrdquo Forensic Science Internationalvol 178 no 2-3 pp 139ndash145 2008

[91] M Tsokos U Reichelt A Nierhaus and K Puschel ldquoSerumprocalcitonin (PCT) a valuable biochemical parameter for thepost-mortem diagnosis of sepsisrdquo International Journal of LegalMedicine vol 114 no 4-5 pp 237ndash243 2001

[92] M Augsburger K Iglesias D Bardy P Mangin and CPalmiere ldquoDiagnostic value of lipopolysaccharide-binding pro-tein and procalcitonin for sepsis diagnosis in forensic pathol-ogyrdquo International Journal of Legal Medicine vol 127 no 2 pp427ndash435 2013

[93] H H Liu J B Guo Y Geng and L Su ldquoProcalcitonin presentand futurerdquo Irish Journal of Medical Science vol 184 no 3 pp597ndash605 2015

[94] M M Shaikh L E Hermans and J M van Laar ldquoIs serumprocalcitonin measurement a useful addition to a rheumatol-ogistrsquos repertoire A review of its diagnostic role in systemicinflammatory diseases and joint infectionsrdquo Rheumatology vol54 no 2 Article ID keu416 pp 231ndash240 2015

[95] O K Eberhard M Haubitz F M Brunkhorst V Kliem KM Koch and R Brunkhorst ldquoUsefulness of procalcitoninfor differentiation between activity of systemic autoimmunedisease (systemic lupus erythematosussystemic antineutrophilcytoplasmic antibody-associated vasculitis) and invasive bacte-rial infectionrdquo Arthritis amp Rheumatism vol 40 no 7 pp 1250ndash1256 1997

[96] B Lindahl H Toss A Siegbahn P Venge and L WallentinldquoMarkers of myocardial damage and inflammation in relationto long-termmortality in unstable coronary artery diseaserdquoTheNew England Journal of Medicine vol 343 no 16 pp 1139ndash11472000

[97] S N Murat A Kurtul I E Celik et al ldquoThe associationof serum procalcitonin level with the no-reflow phenomenonafter a primary percutaneous coronary intervention in patientswith ST-elevation myocardial infarctionrdquo Coronary and ArteryDisease vol 27 pp 116ndash121 2016

[98] C Picariello C Lazzeri P Attana M Chiostri G F Gensiniand S Valente ldquoProcalcitonin as a reliable biomarker in acutecoronary syndromes what is its rolerdquo Journal of EmergencyMedicine vol 45 no 6 pp 921ndash922 2013

[99] A Canbay O O Celebi S Celebi S Aydogdu and E DikerldquoProcalcitonin amarker of heart failurerdquoActa Cardiologica vol70 no 4 pp 473ndash478 2015

[100] H-S Tong Y-S Liu Q Wen Y-Q Tang F-F Yuan and LSu ldquoSerum procalcitonin predicting mortality in exertional


heatstrokerdquo Emergency Medicine Journal vol 29 no 2 pp 113ndash117 2012

[101] D Tian S Zhang X He and H Liu ldquoSerum procalcitonin as adiagnostic marker in acute ischemic strokerdquo NeuroReport vol26 no 1 pp 33ndash37 2015

[102] C Balci R Sivaci G Akbulut and H S Karabekir ldquoProcalci-tonin levels as an early marker in patients with multiple traumaunder intensive carerdquo Journal of International Medical Researchvol 37 no 6 pp 1709ndash1717 2009

[103] M Maier S Wutzler M Lehnert et al ldquoSerum procalcitoninlevels in patients with multiple injuries including visceraltraumardquo Journal of TraumamdashInjury Infection and Critical Carevol 66 no 1 pp 243ndash249 2009

[104] U Reichelt R Jung A Nierhaus and M Tsokos ldquoSerialmonitoring of interleukin-1120573 soluble interleukin-2 receptorand lipopolysaccharide binding protein levels after death acomparative evaluation of potential postmortem markers ofsepsisrdquo International Journal of Legal Medicine vol 119 no 2pp 80ndash87 2005

[105] M Tsokos U Reichelt R Jung A Nierhaus and K PuschelldquoInterleukin-6 and C-reactive protein serum levels in sepsis-related fatalities during the early postmortem periodrdquo ForensicScience International vol 119 no 1 pp 47ndash56 2001

[106] S GibotM-N Kolopp-SardaM C Bene et al ldquoPlasma level ofa triggering receptor expressed onmyeloid cells-1 its diagnosticaccuracy in patients with suspected sepsisrdquo Annals of InternalMedicine vol 141 no 1 pp 9ndash15 2004

[107] L Su B Han C Liu et al ldquoValue of soluble TREM-1 procal-citonin and C-reactive protein serum levels as biomarkers fordetecting bacteremia among sepsis patients with new fever inintensive care units a prospective cohort studyrdquo BMC InfectiousDiseases vol 12 article 157 2012

[108] T Shozushima G Takahashi N Matsumoto M Kojika YOkamura and S Endo ldquoUsefulness of presepsin (sCD14-ST)measurements as a marker for the diagnosis and severity ofsepsis that satisfied diagnostic criteria of systemic inflammatoryresponse syndromerdquo Journal of Infection andChemotherapy vol17 no 6 pp 764ndash769 2011

[109] S Masson P Caironi E Spanuth et al ldquoPresepsin (solubleCD14 subtype) and procalcitonin levels formortality predictionin sepsis data from the Albumin Italian Outcome Sepsis trialrdquoCritical Care vol 18 no 1 article R6 2014

[110] C Palmiere M Mussap D Bardy F Cibecchini and PMangin ldquoDiagnostic value of soluble CD14 subtype (sCD14-ST) presepsin for the postmortem diagnosis of sepsis-relatedfatalitiesrdquo International Journal of Legal Medicine vol 127 no4 pp 799ndash808 2013

[111] A Scherpereel F Depontieu B Grigoriu et al ldquoEndocan a newendothelial marker in human sepsisrdquo Critical Care Medicinevol 34 no 2 pp 532ndash537 2006

[112] C Palmiere andMAugsburger ldquoEndocanmeasurement for thepostmortem diagnosis of sepsisrdquo Legal Medicine vol 16 no 1pp 1ndash7 2014

[113] B Pourakbari S Mamishi J Zafari et al ldquoEvaluation of pro-calcitonin and neopterin level in serum of patients with acutebacterial infectionrdquoThe Brazilian Journal of Infectious Diseasesvol 14 no 3 pp 252ndash255 2010

[114] C Mitaka ldquoClinical laboratory differentiation of infectious ver-sus non-infectious systemic inflammatory response syndromerdquoClinica Chimica Acta vol 351 no 1-2 pp 17ndash29 2005

[115] T Ishikawa M Hamel B-L Zhu et al ldquoComparative evalua-tion of postmortem serum concentrations of neopterin and C-reactive proteinrdquo Forensic Science International vol 179 no 2-3pp 135ndash143 2008

[116] E Ambach W Tributsch D Fuchs G Reibnegger R Hennand H Wachter ldquoPostmortem evaluation of serum and urineneopterin concentrationsrdquo Journal of Forensic Sciences vol 36no 4 pp 1089ndash1093 1991

[117] E AmbachW TributschW Rabl et al ldquoPostmortemneopterinconcentrations comparison of diagnoses with and withoutcellular immunological backgroundrdquo International Journal ofLegal Medicine vol 104 no 5 pp 259ndash262 1991

[118] C Palmiere and M Augsburger ldquoMarkers for sepsis diagnosisin the forensic setting state of the artrdquoCroatianMedical Journalvol 55 no 2 pp 103ndash114 2014

[119] S De Rosa P Cirillo M Pacileo et al ldquoNeopterin from for-gotten biomarker to leading actor in cardiovascular pathophys-iologyrdquo Current Vascular Pharmacology vol 9 no 2 pp 188ndash199 2011

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Despite the fact that the latter is still a diagnosis of exclusionsepsis is an intriguing field of interest in autopsy practiceand the diagnosis of sepsis-related deaths is an illustrativeexample of the reciprocal value of autopsy both for cliniciansand for pathologists Upon studying these deaths the pathol-ogist needs to approach the complex pathophysiologicalmechanisms underlying sepsis This may lead in turn to anincreased understanding of the pathogenic hypotheses andto the accuracy of existing diagnostic tools to be checked [16]Autopsies should still serve as a very important part of qualitycontrol in clinical diagnosis and treatment of sepsis [17 18]Last but not least the issue of the diagnostic reliability of fatalsepsis is even more pivotal One important area which hasseen a rising number of clinical negligence claims compriseshealthcare-associated infections and sepsis [19]

The objective of this review is to assess the state of ourknowledge of the molecular and biohumoral mechanisms ofsepsis and to correlate them with our postmortem diagnosisability

2 The Inflammatory Response

The septic response is an extremely complex chain of eventsinvolving inflammatory and anti-inflammatory processeshumoral and cellular reactions and circulatory changesWhen an infectious insult occurs it initiates a series of eventsresulting in the release of inflammation mediators whichinvolves both a local reaction and a systemic response andwhich finally could impact on organs function [20]

Sepsis triggers the production of a diverse array ofcytokines that are proinflammatory and anti-inflammatory[21 22] Cytokines are low molecular weight compoundswhich are considered potent positive and negative regula-tors of inflammation Some cytokines possess proinflamma-tory effects such as tumour necrosis factor- (TNF-) alphainterleukin- (IL-) 1 and interleukin-8 while others haveanti-inflammatory effects including IL-10 and IL-1 receptorantagonist and some are supposed to act as pro- and anti-inflammatory IL-6 as an example [23]

Proinflammatory cytokines trigger a beneficial responsesuch as increased local coagulation limited tissue damageand elimination of the pathogen Overwhelming productionof these proinflammatory cytokines however can be verydangerous in that excessive cytokines destroy the normalregulation of the immune response and induce pathologicalinflammatory disorders such as capillary leakage tissueinjury and organ failure Similarly the anti-inflammatorycytokines play a critical role in regulating overall immuneresponse in establishing homeostasis and in checking theeffects of the proinflammatory ones in order to solve inflam-mation and heal tissue Therefore their dysregulation canalso trigger pathogenesis [24] since it has been shown thatan intense anti-inflammatory response may induce a stateof immunosuppression in patients with sepsis [25] When astate of anti-inflammatory predominance occurs monocytesare deactivated This results in reduced antigen presentationand decreased production of proinflammatory cytokinesleading to pathogen persistence and further fuelling theinflammatory process [21 22 25] A tightly regulated balance

in the cytokine network which comprises pro- and anti-inflammatory cytokines is crucial for eliminating invadingpathogens on the one hand and restricting excessive tissue-damaging inflammation on the other [26]

In brief when an infectious insult occurs pattern recog-nition receptors (PRRs) which are expressed on epithelialbarriers as well as on resident immune cells such as den-dritic cells and macrophages detect invading microorgan-isms A specific family of PRRs named toll-like receptors(TLRs) recognizes conserved macromolecular motifs frommicroorganisms called pathogen-associated molecular pat-terns (PAMPs) The stimulation of TLRs or the nucleotideoligomerization domain NOD-like receptor (NLR) family ofintracellular PRRs results in the triggering of downstreamsignalling cascades Depending on the particular receptorengaged this process leads to the activation of a tran-scriptional response programme that includes nuclear factor120581B (NF-120581B) followed by the production and secretion ofcytokines chemokines and nitric oxide [21 22] Cytokinesusually bind their specific receptors induce signalling path-ways and thus regulate immune responses and other cellfunctions [24]

Therefore different types of cells tissuesorgans orproteinother molecules may function as effectors mod-ulating the immune response through various pro- oranti-inflammatory mediators Resident macrophages andpolymorphonuclear cells (PMCs) initiate the primary hostresponse to the invading microorganisms They are respon-sible for the primary phagocytosis and subsequent activationand recruitment of granulocytes and monocytes Leukostasisof neutrophils (the so-called leucocyte sticking) in the liversinusoids in the pulmonary vessels and so forth is thecommon histological counterpart of this phenomenon [11]Proliferation of astrocytes and microglial cells is a commonpostmortem histological finding in septic patients Howeverit is highly nonspecific as itmay reflect several kinds of insultsincluding ischemia [11]

Endothelial cells (ECs) activation occurs during sepsisThe interaction between ECs and leukocytes a hallmark ofthe inflammatory process comprises adhesive and migra-tory molecular events including low-affinity transient andreversible rolling adhesions integrin-dependent firm adhe-sive interactions and migratory events of the leukocytesthrough the endothelium and finally in the interstitialspace [27 28] A variety of chemical mediators secretedfrom inflamed tissue and the entire process of leukocyte-endothelial cell adhesion are regulated by the sequentialactivation of different families of adhesion molecules that areexpressed on the surface of leukocytes and ECs Lectin-likeadhesion glycoproteins selectins mediate leukocyte rollingThe firm adhesion and subsequent transendothelial migra-tion of leukocytes aremediated by the interaction of integrinsexpressed by leukocytes with immunoglobulin-like adhesionmolecules on ECs for example intercellular cell adhesionmolecules (ICAM) 1ndash5 vascular cell adhesion molecule-1(VCAM-1) and the junctional adhesion molecules (JAMs)which are expressed on endothelial and other cells [2930] Recently EC-active molecules (ie the angiopoietinpathway Ang-2 soluble fms-like tyrosine kinase-1) have been
















Inflammatory insult


PRRs


TLRs

VEGF

Ang-12s-ICAM-1





s-Flt Endothelin-1


vWF


TNF-120572

Chemokines

CRPLBP

PCT

IL-1IL-10

IL-8 IL-6


C5aC3a

Complement system

C5b-9


Eosinophil

Neutrophil

Basophil


Naturalkiller cell

White blood cells









Sepsis


Acute lung injury


E-selectin

NO




MIF



ROSRNS

Liver injury

Chemokines








MVs

Apoptosis


Monocytes




ICAM-1

E-selectin


ICAM-1

NF-120581B

NO



Vasoplegia

Activated cell

Cell

Granulocytes

Eosinophil

Neutrophil

Basophil

VCAM-1


















6 Conclusion



Disclosure


Competing Interests



References



































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of































Inflammatory insult


PRRs


TLRs

VEGF

Ang-12s-ICAM-1





s-Flt Endothelin-1


vWF


TNF-120572

Chemokines

CRPLBP

PCT

IL-1IL-10

IL-8 IL-6


C5aC3a

Complement system

C5b-9


Eosinophil

Neutrophil

Basophil


Naturalkiller cell

White blood cells









Sepsis


Acute lung injury


E-selectin

NO




MIF



ROSRNS

Liver injury

Chemokines








MVs

Apoptosis


Monocytes




ICAM-1

E-selectin


ICAM-1

NF-120581B

NO



Vasoplegia

Activated cell

Cell

Granulocytes

Eosinophil

Neutrophil

Basophil

VCAM-1


















6 Conclusion



Disclosure


Competing Interests



References



































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















Sepsis


Acute lung injury


E-selectin

NO




MIF



ROSRNS

Liver injury

Chemokines








MVs

Apoptosis


Monocytes




ICAM-1

E-selectin


ICAM-1

NF-120581B

NO



Vasoplegia

Activated cell

Cell

Granulocytes

Eosinophil

Neutrophil

Basophil

VCAM-1


















6 Conclusion



Disclosure


Competing Interests



References



































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















MVs

Apoptosis


Monocytes




ICAM-1

E-selectin


ICAM-1

NF-120581B

NO



Vasoplegia

Activated cell

Cell

Granulocytes

Eosinophil

Neutrophil

Basophil

VCAM-1


















6 Conclusion



Disclosure


Competing Interests



References



































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























6 Conclusion



Disclosure


Competing Interests



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 a pathophysiological insight into sepsis...

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