sepsis markers in blood

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importance of biomarkers in sepsis

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Presentation Transcript

Slide 4: 

The clinical definitions of sepsis used in diagnosis extend beyond systemic infection to focus on the symptoms generated by the host response in combating an infection. Despite a broad range of clinical measures, the complexity and heterogeneity of host response to infection, even within distinct populations, frequently lead to delayed diagnosis, which in turn leads to ineffective and belated antimicrobial treatment

Slide 5: 

A positive culture from blood, urine, cerebrospinal fluid, or bronchial fluid represents the most certain method of diagnosis. Unfortunately, clinical symptoms frequently manifest themselves in the absence of a positive culture; among the studies we reviewed, positive cultures ranged from 8% to 73% in neonatal diagnoses and from 8% to 88% in adult diagnoses. An additional drawback of culture-based diagnosis is the 24- to 48-h assay time.

Slide 6: 

for rapid diagnostics, the majority of current research has focused on the search for a "magic bullet" biomarker as a provision for confirmed pathogen presence

Slide 8: 

Predisposition, insult Infection, Response, and Organ dysfunction (PIRO) staging system to determine optimum treatment for individual patients by stratifying their individual symptoms and risks

Slide 11: 

Although traditional ELISAs (2–3 h), immunoluminometric PCT assays (3 h), and DNA detection by PCR (5–6 h) provide more rapid results than culture testing (24–48 h), these methods are incapable of monitoring the exponential changes in biomarkers occurring in both sepsis and experimental in vivo endotoxemia.

C-Reactive Protein : 

C-Reactive Protein

History : 

History A protein that precipitate the “C” polysaccharide derived from the pneumococcal cell wall in acute phase. (J Exp Med 1930; 52:561) Ligands: phosphocholine (1971) Chromosome 1 IL-6, IL-1ß, TNF-a Hepatocyte predominant

Protein Structure : 

Protein Structure Pentraxin 5 protomer (23kDa,206 aa) Central pore Acting as an opsonin for gram-positive bacteria to aid in their phagocytosis, CRP increases late during the onset of sepsis. JBC 2004;279(47);48487

SIRS : 

SIRS CRP is effective CRP is unspecific in critical ill patient PCT(procalcitonin) is better and more reliable to prognosis CRP: sensitivity 75% specificity 67% PCT is better

Slide 17: 

The secretion of CRP begins within 4–6 h after stimulus Doubles every 8 hours Peaks at 36–50 h Half-life of 19 h >30-35 mg% in bacterial infections. Up to 20 mg% in viral infections.

Slide 19: 

Muller et al Critical Care Medicine in Apr 2000 demonstrated that PCT was superior to CRP, IL-6, lactate levels in predicting sepsis, with Sn = 89% & Sp = 94%.

Pathophysiology : 

Pathophysiology PCT produced for a few hrs only, by monocytes adherent to tissues (not produced in circulating monocytes). Secreted PCT acts is chemotactic to other monocytic cells. Endogenous tissue cells also produce PCT but only after monocyte adhesion.

Slide 21: 

Conversely, leukopenic patients have significantly lower concentrations of PCT during sepsis, with concentrations failing to exceed 2 µg/L even during septic shock .

TNF - a : 

TNF - a Tumor necrosis factor- (TNF) is considered the likely initiating factor in the activation of host response and subsequent cytokine release during infection, with concentrations increasing to 24 times (828 ng/L) their preinfection concentrations at 2 h post-lipopolysaccharide (LPS) challenge during in vivo experimental endotoxemia. However, the diagnostic utility of TNF is insufficient for distinguishing infectious inflammation.

Slide 34: 

Difficulties in using TNF for sepsis diagnosis arise from the central role this cytokine plays in the inflammatory response, its short-term concentration in response to bacterial challenge, its short half-life of 17 min, and from excessive concentrations of soluble receptors p55 (sTNF-RI) and p75 (sTNF-RII) during sepsis. Tumor necrosis factor-á (TNF-á), mainly produced by activated monocytes and macrophages, has a broad spectrum of biological activities . TNF-á is a major mediator of immune and inflammatory responses. TNF-á promotes acute inflammatory responses, such as occurs in sepsis and septic shock

IL-1 : 

IL-1 including IL-1, IL-1ß, and IL-1 receptor antagonist (IL-1ra), which exists in substantial excess of IL-1ß during sepsis. concentrations of IL-1ra have been shown to be consistently increased in sepsis patients, with adult concentrations of 2–31 µg/L (in healthy adults, concentrations are undetectable) and neonatal concentrations of 6–30 µg/L (concentrations in uninfected neonates, 2–3 µg/L).

IL-6 : 

IL-6 Increased concentrations correlating to infection have been demonstrated by several studies. Adult values for sepsis are reported in the range of 300-2700 ng/L above the 100 ng/L range for SIRS. Although its usefulness in adult diagnosis has not be tested clinically, IL-6 is considered applicable in neonatal diagnosis.

IL-18 : 

IL-18 proinflammatory cytokine biomarker commonly associated with sepsis is IL-18, which induces IFN- and amplifies Th1 differentiation. The higher concentrations of IL-18 observed in gram-positive compared with gram-negative infections. The usefulness of this marker has been reported in several studies, including differentiation of sepsis from severe injury values ranged from 588 to 1121 ng/L for sepsis, compared with 64–188 ng/L for healthy or uninfected control individuals.

IL-10 : 

IL-10 Anti inflammatory cytokines also increase during sepsis. In reported studies, IL-10 concentrations were increased (22–383 ng/L) in septic adults, whereas it was undetectable in all control and healthy individuals, with the exception in one study. However, IL-10 concentrations are reported to increase within 2 h of blunt trauma, in correlation with injury severity, and in uninfected surgical patients.

dna fingerprinting : 

dna fingerprinting Current genetic studies indicate that detection of specific DNA sequences common to all bacteria is another possible means of diagnosis. 16S rRNA mecA gene was highly specific for the detection of methicillin-resistant strains of staphylococci. Finally, the presence of 18S rRNA indicated the presence of fungal infections caused by Candida albicans. specific targets in a 5–6 h time frame.

HLA- DR : 

HLA- DR % of HLA-DR monocytes. HLA-DR returns to normal in mild inflammation. If it is < 30% on monocytes severe sepsis.

Slide 46: 

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