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Whether innate immune cells may be adapted into potential memory states has becoming an important question in the field of immunity. Although previous conceptual paradigm failed to acknowledge this important question, emerging clinical and basic observations have started to shed intriguing clues to shake the previous dogma regarding innate immunity of being "simple", "raw", "first-line defense with no memory". We have aimed to further address this fundamental issue in this dissertation work, under the close guidance of Dr. Liwu Li. We have chosen to use the model system of Toll-Like-Receptor (TLR) signaling networks within primary monocytes. TLRs play fundamental roles in sensing pathogen-associated molecular patterns (PAMPs) and modulation of innate immunity. Lipopolysaccharide (LPS), an endotoxin found on the cell membrane of gram-negative bacteria, is the ligand of TLR4 and induces a range of inflammatory as well as anti-inflammatory responses. Higher dosages of LPS were known to cause robust yet transient expression of pro-inflammatory mediators. On the other hand, the effects of super-low dose LPS, commonly manifested in humans with adverse health conditions, have been largely ignored in the basic research field. Super-low dose LPS may skew host immune environment into a mild non-resolving pro-inflammatory state, which is a risk factor for inflammatory diseases such as atherosclerosis, compromised wound healing, and elevated risks for sepsis. Our central hypothesize is that monocytes may be adapted by super-low dose LPS into a non-resolving low-grade inflammatory state conducive for the pathogenesis of inflammatory diseases. We have employed both in vitro cell culture system as well as in vivo disease models to test this hypothesis. For the in vitro system, we have cultured primary murine monocytes with increasing signal strength of LPS. Monocyte phenotypes such as the expression of key inflammatory mediators including cytokines, chemokines, and cellular surface markers were studied. Potential molecular and cellular mechanisms were examined. We revealed a novel low-grade inflammatory monocyte phenotype termed ML adapted by super-low dose LPS, mediated through IRF5. For the in vivo system, we have employed both acute and chronic models of inflammation. For the chronic model, we have tested the effects of super-low dose LPS on monocyte polarization in vivo, as well as its contribution to the pathogenesis of atherosclerosis. Furthermore, we have tested the effects of programmed monocytes on wound healing. For the acute model, we have tested the effects of pre-conditioning with super-low dose LPS on the subsequence risks of sepsis elicited by cecal ligation and puncture. We have demonstrated aggravated atherosclerosis, compromised wound healing, and increased sepsis mortality in mice pre-conditioned with super-low dose LPS. Taken together, our findings reveal that monocytes can be differentially programmed into distinct states, depending on the signal strength of LPS. The differential programming and adaptation of monocytes can occur both in vitro and in vivo, and may bear profound pathological consequences. / Ph. D.

No / Expecting ambulance clinicians to dependably differentiate the life-threatening organ dysfunction caused by sepsis from an inflammatory response to a non-infectious aetiology, relying upon vital signs and a physical examination of the patient alone, must be considered unrealistic. Although lactate measurement has been integrated into numerous prehospital sepsis screening tools, it is not yet measured routinely within UK ambulance services. Research has generally focused on whether handheld point-of-care lactate measurement devices are as accurate as laboratory analysis of venous or arterial samples. The weight of literature has concluded negatively in relation to this. However, there is potential for handheld devices to be used independently to monitor trends in lactate elimination or accumulation to inform decisions on the efficacy of prehospital interventions, or simply to report categorical data in terms of whether lactate levels are elevated or not. This offers UK paramedics the opportunity to improve sepsis care through the enhanced assessment of risk and acuity, the identification of patients with cryptic shock, more aggressive fluid resuscitation and advanced notification to receiving units.

No / The aim of this review was to examine whether the measurement of lactate in capillary blood samples using point-of-care handheld analysers corresponds sufficiently closely with arterial and venous whole-blood samples analysed by hospital central laboratory or blood gas analyser to be used interchangeably. A systematic search, informed by focused inclusion/exclusion criteria, was performed using multiple databases up to October 2015. A total of 65 articles were considered to have potential relevance and were evaluated in full text, of which ultimately five articles met all inclusion/exclusion criteria, and a final four were selected after data extraction and quality appraisal. All four studies found a predominantly upward bias in the measurement of lactate in capillary samples tested using a handheld point-of-care device over arterial or venous samples tested by laboratory methods or blood gas analyser. In terms of correlation, there was consensus between the studies that the strength of association between the two methods of measurement was statistically significant. Three studies directly examined the extent of agreement between point-of-care capillary lactate measurements and those of laboratory or blood gas analyser reference determined to ±2 standard deviations; 95% confidence intervals, and report contextually broad limits of agreement, identifying a potential for both over triage and, to a lesser extent, under triage. The findings of the review do not support interchangeable use of handheld fingertip point-of-care lactate measurement with laboratory or blood gas analyser methods in the identification of sepsis.

Bakgrund: Sepsis drabbar årligen 49 miljoner människor världen över varav 11 miljoner insjuknade leder till dödsfall. För att skapa förutsättningarna att bota och minska dödligheten av patienter med sepsis krävs tidig diagnos och behandling av sjukdomen. Sjuksköterskan har oftast första kontakten med patienten och har centrala ansvaret att bedöma, planera, genomföra och utvärdera omvårdnaden. Sjuksköterskan har stor betydelse vid identifiering och behandling av sepsis. Syfte: Beskriva sjuksköterskors upplevelser att vårda patienter med sepsis. Metod: Litteraturstudien utformades från Polit och Becks (2021) nio steg. Sökningarna utfördes i Cinahl, PubMed och PsycInfo vilket genererade i åtta artiklar, fem kvalitativa och tre kvantitativa. Artiklarna kvalitetsgranskades utifrån Forsberg och Wengströms (2023) granskningsmallar.   Resultatet: Databearbetningen genererade tre huvudteman Sjuksköterskans oro: identifiering och prioritering av sepsis, Teamarbetets betydelse för sepsisvården, Betydelsen av en fungerande organisation. Resultatet belyser att patientens status, teamarbete och organisatoriska faktorer påverkade det vårdande förloppet. Oro upplevdes relaterat till identifiering och prioritering. För ett förbättrat vårdförlopp var trygghet och stöd från teamet runt patienten viktiga aspekter. Tidsbrist och underbemanning skapade upplevelse av stress vilket påverkade sepsisvården negativt. Slutsats: Litteraturstudien visar att sjuksköterskor har olika upplevelser av att vårda patienter med sepsis. Upplevda svårigheter bör ses över för utveckling av sepsisvården till det bättre.

Sepsis ist ein häufiges und akut lebensbedrohliches Syndrom, das eine Organfunktionsstörung in Folge einer dysregulierten Immunantwort auf eine Infektion beschreibt. Eine frühzeitige Diagnosestellung und Therapieeinleitung sind von zentraler Bedeutung für das Überleben der Patient:innen. In einer Pilotstudie konnte unsere Forschungsgruppe mittels Durchflusszytometrie eine ausgeprägte Hyporeaktivität der Thrombozyten bei Sepsis nachweisen, die einen potenziell neuen Biomarker zur Sepsis-Früherkennung darstellt. Zur Evaluation des Ausmaßes und Entstehungszeitpunktes der detektierten Thrombozytenfunktionsstörung wurden im Rahmen der vorliegenden Arbeit zusätzlich zu Patient:innen mit Sepsis (SOFA-Score ≥ 2; n=13) auch hospitalisierte Patient:innen mit einer Infektion ohne Sepsis (SOFA-Score < 2; n=12) rekrutiert. Beide Kohorten wurden zu zwei Zeitpunkten (t1: <24h; t2: Tag 5-7) im Krankheitsverlauf mittels Durchflusszytometrie und PFA-200 untersucht und mit einer gesunden Kontrollgruppe (n=28) verglichen. Phänotypische Auffälligkeiten der Thrombozyten bei Sepsis umfassten: (i) eine veränderte Expression verschiedener Untereinheiten des GPIb-IX-V-Rezeptorkomplexes, die auf ein verstärktes Rezeptor-Shedding hindeutet; (ii) ein ausgeprägtes Mepacrin-Beladungsdefizit, das auf eine zunehmend reduzierte Anzahl von δ-Granula entlang des Infektion-Sepsis Kontinuums hinweist; (iii) eine Reduktion endständig gebundener Sialinsäure im Sinne einer verstärkten Desialylierung. Die funktionelle Analyse der Thrombozyten bei Sepsis ergab bei durchflusszytometrischer Messung der Integrin αIIbβ3-Aktivierung (PAC-1-Bindung) eine ausgeprägte generalisierte Hyporeaktivität gegenüber multiplen Agonisten, die abgeschwächt bereits bei Infektion nachweisbar war und gemäß ROC-Analysen gut zwischen Infektion und Sepsis diskriminierte (AUC >0.80 für alle Agonisten). Im Gegensatz dazu zeigten Thrombozyten bei Sepsis und Analyse mittels PFA-200 unter Einfluss physiologischer Scherkräfte eine normale bis gar beschleunigte Aggregation. Die Reaktivitätsmessung von Thrombozyten mittels Durchflusszytometrie stellt weiterhin einen vielversprechenden Biomarker für die Sepsis-Früherkennung dar. Für weitere Schlussfolgerungen ist jedoch eine größere Kohorte erforderlich. In nachfolgenden Untersuchungen sollten zudem mechanistische Ursachen der beschriebenen phänotypischen und funktionellen Auffälligkeiten von Thrombozyten bei Infektion und Sepsis z.B. mittels Koinkubationsexperimenten untersucht werden. / Sepsis is a frequent and life-threatening condition that describes organ dysfunction resulting from a dysregulated host immune response to infection. Early diagnosis and treatment are essential to improve patient survival. In a previous pilot study with sepsis patients, our research identified a severe platelet hyporeactivity using flow cytometry which could become a potential new biomarker for early sepsis diagnosis. To evaluate onset and extend of the detected platelet dysfunction in this study, we extended our patient cohort in addition to sepsis (SOFA-score ≥2; n=13) also to hospitalized patients with infection without sepsis (SOFA-score <2; n=12). Both cohorts were assessed at two time points during the disease (t1: <24h; t2: day 5-7) by flow cytometry and PFA-200 and compared with a healthy control group (n=28). Platelet phenotypic abnormalities during sepsis included: (i) altered expression of subunits of the GPIb-IX-V receptor complex, pointing to increased receptor shedding; (ii) a severe mepacrine loading deficit, indicating an increasingly reduced number of δ-granules along the infection-sepsis continuum; (iii) a reduction of terminally bound sialic acid, suggesting increased desialylation. Functional analysis of platelets in sepsis revealed a marked and generalized hyporeactivity toward multiple agonists when integrin αIIbβ3 activation (PAC-1 binding) was measured by flow cytometry, which was already to a lesser extend present in patients with infection and discriminated well between infection and sepsis according to ROC analysis (AUC >0.80 for all agonists). In contrast, platelets from septic patients showed normal to even accelerated aggregation when measured under flow condition and physiological shear forces by PFA-200. Analysis of platelet reactivity by flow cytometry remains a promising biomarker for early sepsis detection, but a larger cohort is needed for further conclusions. In subsequent studies, mechanistic causes of the described alterations in platelet phenotype and function during infection and sepsis should be investigated, e.g. by means of co-incubation experiments.

<strong>Background</strong>: The rate of maternal death from sepsis has increased in several European countries, most notably the UK, where sepsis is now the leading cause of direct maternal death. An increase in maternal mortality also implies an increase in the number of women with severe, life-threatening morbidity. Key information gaps in the understanding of severe maternal sepsis in the UK are: the incidence, main causative organisms, infection sources, and risk factors for severe maternal sepsis. <strong>Methods</strong>: Four population-based observational studies were conducted to address these evidence gaps. <strong>Results</strong>: The incidence of severe maternal morbidity from sepsis is increasing in the UK, a trend also evident in the USA. The most common sources are respiratory tract, genital tract and urinary tract infection. The predominant organisms causing infection are E. coli, group A streptococcus, and strong circumstantial evidence of Streptococcus pneumonia. Sepsis progresses very rapidly particularly with group A streptococcal infection. Approximately 20% of women with severe sepsis progress to septic shock and 2% of women die. Risk factors for severe maternal sepsis in the UK with a large effect size are: febrile illness or antibiotics in the 2 weeks prior to onset of severe sepsis (aOR=12.1, 95% CI 8.1-18.0), caesarean section after the onset of labour (aOR= 8.1, 95% CI 4.7-14.0), multiple pregnancy (aOR= 5.8, 95% CI 1.5-21.5), infection with group A streptococcus (aOR=4.8 for progression to septic shock, 95% CI 2.2-10.8), pre-labour caesarean section (aOR= 3.8, 95% CI 2.2-6.6), low socioeconomic status (aOR=2.6, 95% CI 1.03-6.7), and operative vaginal delivery (aOR=2.5, 95% CI 1.3-4.7). Risk factors are significantly cumulative. <strong>Conclusions</strong>: Infection prior to or after delivery, even if the woman appears to be well, should be a marker for close clinical monitoring. Suspicion of group A streptococcus should be regarded as an obstetric emergency and treated ahead of laboratory confirmation.

Bakgrund: Sepsis är ett livshotande tillstånd med hög dödlighet som drabbar 30 miljoner människor världen över och resulterar i omkring sex miljoner dödsfall årligen. Tecken och symtom är diffusa och det finns idag ett behov av utökad kunskap om sjuksköterskans omvårdnadsåtgärder vid sepsis. Syfte: Syftet var att beskriva sjuksköterskans omvårdnadsåtgärder för att upptäcka sepsis i ett tidigt skede. Metod: Studien genomfördes som en allmän litteraturstudie med inspiration av innehållsanalys där resultatet utgörs av 15 vetenskapliga artiklar. Resultat: Resultatet presenteras i kategorierna klinisk bedömning, kunskap och övervakning. I resultatet framgår det att sjuksköterskans förmåga att kombinera klinisk observation med ett standardiserat mätinstrument möjliggör en tidig upptäckt av sepsis. Det framgår även att sjuksköterskor som har uppdaterat sin kunskap om sepsis och dess progression genom fortbildning blev mer säkra på att upptäcka och identifiera patienter med sepsis. Sjuksköterskor kan även ta hjälp av datoriserade övervakningssystem, som larmar vid misstanke om sepsis. Konklusion: Varje enskild omvårdnadsåtgärd i resultatet kan bidra till att sepsis upptäcks tidigt, framförallt när implementering av mätinstrument, kunskap och utbildning kombineras kan dödligheten och lidandet för patienten minska. Det anses att ytterligare forskning är nödvändig kring sjuksköterskans omvårdnadsåtgärder för att tidigt upptäcka sepsis. / Background:Sepsis is a life-threatening condition that affects 30 million people worldwide and results in about six million deaths annually. Signs and symptoms are diffuse and today there is a need for increased knowledge of the nurse's nursing measures in case of sepsis. Aim:The purpose was to describe the nurse's nursing measures to detect sepsis at an early stage. Method:The study was conducted as a general literature study, inspired bycontent analysisand the result is based on 15scientific articles. Results:The result is presented in the categories clinical assessment, knowledgeand monitoring.Theresult shows that the nurse's ability to combine clinical observation with a standardized measuring instrument enables an early detection of sepsis. It also appears that nurses who have updated their knowledge of sepsis and its progression through continuing education became more confident in detecting and identifying patients with sepsis. Nurses can also use computerized monitoring systemsin nursing care, which alert in case of suspicion of sepsis.Conclusion:Every single nursing measure in the resultcan help to detect sepsis early, especially when combining measuring instruments, knowledge and education. Thiscan reduce mortality and suffering for the patient,butfurther research is necessary regarding the nursing care measures to detect sepsis early.

Le récepteur TREM-1 (Triggering Receptor Expressed on Myeloid cells-1) joue un rôle crucial dans la mise en place du sepsis en amplifiant la réponse immunitaire de l'hôte. TLT-1 (TREM-Like Transcript-1) appartient à la famille des récepteurs TREMs, est exprimé exclusivement sur les plaquettes activées et est connu pour faciliter l'agrégation plaquettaire en liant le fibrinogène. Ces travaux montrent qu'une forme soluble de TLT-1 est impliquée dans la régulation de l'inflammation au cours du sepsis en modulant l'activation leucocytaire et le dialogue plaquette-neutrophile. Un peptide de 17 acides aminés issu de sa portion extracellulaire est porteur de cette activité par compétition avec le ligand de TREM-1. Alors que l'administration tant précoce que tardive de LR17 au cours du sepsis expérimental murin augmentait la survie, les animaux KO TLT-1 étaient hautement susceptibles à l'infection. Nous avons identifié ici un récepteur soluble libéré au cours de l'activation plaquettaire comme un potentiel régulateur de la réaction inflammatoire au cours du sepsis, ouvrant ainsi de nouvelles perspectives thérapeutiques / The Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) plays a crucial role during the onset of sepsis by amplifying the host immune response. The TREM-Like Transcript-1 (TLT-1) belongs to the TREM family, is selectively expressed on activated platelets, and is known to facilitate platelet aggregation through binding to fibrinogen. Here we show that a soluble form of TLT-1 is implicated in the regulation of inflammation during sepsis by dampening leukocytes activation and modulating platelet-neutrophil crosstalk. A 17-aa sequence of the TLT-1 extracellular domain (LR17) is responsible for this activity through competition with the TREM-1 ligand. While early or late LR17 treatment of septic mice improves survival, treml-1-/- animals are highly susceptible to polymicrobial infection. The present findings identify platelet derived sTLT-1 as a potent endogenous regulator of sepsis associated inflammation and open new therapeutic perspectives

Para descrever a incidência, fatores de risco e evolução clínica da sepse neonatal hospitalar por Klebsiella spp. foi realizado um estudo retrospectivo e prospectivo de 45 neonatos com sepse e Klebsiella spp. na hemocultura. A taxa geral de sepse hospitalar por Klebsiella spp foi de 3,7%, identificando K. pneumoniae (91%), K. oxytoca (9%), e 55,6% de cepas multirresistentes. Os principais fatores de risco foram uso prévio de antibióticos, prematuridade, baixo peso e catéter central. Houve complicações em 28,9% dos casos, com mortalidade de 11%. A sepse por Klebsiella spp. foi freqüente nas unidades neonatais, com taxa elevada de complicações e mortalidade, principalmente na infecção por cepas multirresistentes / In order to describe the incidence, risk factors and clinical evolution of hospital-origin sepsis by Klebsiella spp. in neonatal units, a retrospective and prospective study of 45 neonates with sepsis and Klebsiella spp. at the hemoculture was carried out.The overall hospital sepsis rate by Klebsiella spp. was 3.7%, with the identification of K. pneumoniae (91%), K. oxytoca (9%) and 55.6% of multi-resistant strains. The main risk factors were previous antibiotic use, prematurity, low weight and central catheter.There were complications in 28.9% of the cases, with a mortality rate of 11%.The sepsis by Klebsiella spp. was frequent at the neonatal units, with a high rate of complications and mortality, especially in multi-resistant strain infections