الفهرس 
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Abstract
Sepsis represent a significant challenge in pediatric intensive care medicine. Despite high engagement in sepsis research, the pathophysiology of sepsis is not satisfying understood, its incidence continues to rise and sepsis associated mortality remains high. Innate immunity represents the first defense mechanism against invading microorganisms and is primarily mediated by neutrophile granulocytes and monocytes and/or macrophages which express pattern recognition receptors (PRRs). The expression of the receptor for advanced glycation end-products (RAGE) as a member of the PRR family is physiologically low but can be induced by a wide range of inflammatory stimuli. This is due to the fact that the transcription of RAGE is controlled by several pro-inflammatory transcription factors.
Sepsis is directly associated with severe systemic inflammatory responses. One of the mechanisms by which infection contributes to the presence of the persistent inflammatory response pathway is mediated by receptor-ligand binding. The receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs) belong to the group of pattern recognition receptors.
Ligands for RAGE include, the S100 family of proteins, peptides, beta amyloid, HGMB1, MAC1 and LPS. The interaction between RAGE and its ligands is promoted and mediated by the transcription factor NF-kB cascade, culminating in the increased production of inflammatory mediators. Similar to some members of the TLR family (TLR-2 and TLR-4), RAGE has a soluble isoform (sRAGE) that originates from alternative splicing of mRNA and/or proteolytic cleavage.
Currently, there is debate in the literature regarding the functions of sRAGE. Some researchers believe that sRAGE acts as a decoy receptor, hindering the increase of pro-inflammatory mediators, whereas other researchers relate sRAGE with propagation of the inflammatory response by binding to CD11b receptors on leukocytes. The differing opinions are justified in part because of the lack of published data regarding sRAGE. To help elucidate the functions of sRAGE, this study aimed to evaluate the correlation between plasma levels of sRAGE, the inflammatory response and survival in patients with varying degrees of sepsis.
The current work aimed to study the role of sRAGE as a potential diagnostic and prognostic marker in sepsis and septic shock in pediatric intensive care unit.
Methodology:
This case-control study was conducted on 40 patients (20 patients with septic shock and 20 patients with sepsis) and 40 healthy control at Pediatric ICU, Ain Shams University Hospitals
Inclusion Criteria:
• Age: 1 month – 5 years old.
Patients in this study were divided into 3 groups:
• Control group: 40 Healthy Children aged from 1 month_ 5 years.
• Cases group: which divided into two groups:
group 1: 20 patients with sepsis which is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.
Organ dysfunction can be identified as an acute change in total SOFA score > 2 points consequent to the infection.
group 2: 20 patients with septic shock which is defined as severe infection leading to cardiovascular dysfunction (including hypotension, need for treatment with a vasoactive medication, or impaired perfusion) (Scott et al., 2020).
Exclusion Criteria:
a) Older than 5 years old.
b) Patients who were disseminated malignancies or receiving chemotherapy, HIV-Positive, with advanced hepatic disease, in end-of-life conditions, andthose who refused to participate in the study were excluded.
Methods:
• Full history and examination were done for each patient.
• Routine laboratory investigations.
• Inflammatory marker on diagnosis of sepsis and septic shock:
1. C-reactive protein (CRP) assay.
2. Procalcitonin assay.
3. Soluble isoform of a receptor for advanced glycation end product (sRAGE) assay:
By using Enzyme Linked Immunsorbent Assay (ELISA) Techniques by drawing 3ml of the patients blood for testin
(sRAGE) assay kit:
Catalogue no: 201-12-0028.
Sensitivity: 14.752pg/L.
Assay range: 15pg/L-4000pg/L.
Manufacture By:
SHUNGHAI SUNRED BIOLOGICAL TECHNOLOGY CO. LTD IN CHINA.
The Importing Company BY: Biogen Company _ AL mansora city- Egypt.
Principle of the Assay:
This kit was based on sandwich enzyme-linked immune-sorbent assay technology. Capture antibody was pre-coated onto 96-well plates. And the biotin conjugated antibody was used as detection antibodies. The standards, test samples and biotin conjugated detection antibody were added to the wells subsequently, and washed with wash buffer. HRP-Streptavidin was added and unbound conjugates were washed away with wash buffer. TMB substrates were used to visualize HRP enzymatic reaction. TMB was catalyzed by HRP to produce a blue color product that changed into yellow after adding acidic stop solution. The density of yellow is proportional to the target amount of sample captured in plate. Read the O.D. absorbance at 450nm in a microplate reader, and then the concentration of target can be calculated.
The results of our present study can be summarized as follows:
• Three groups were age and sex matched with the Mean±SD in each of control group, sepsis group and septic shock group was 31.67±20.10, 29.32±18.95 and 29.94±13.48 respectively, as there is no statistically significant difference between the groups with p-value (p=0.583).
• There is a slightly higher prevalence of pneumonia in the septic shock group (60%) compared to the sepsis group (50%), but this difference is not statistically significant (p-value = 0.487). Additionally, the results revealed that bronchiolitis is absent in the septic shock group, while gastroenteritis with dehydration and viral septicemia with encephalitis are more evenly distributed between the two groups.
• The mortality rate in septic shock group was (10 patients (50 %)) and 5 patients (25%) in sepsis group which developed to septic shock. denoting that, the septic shock is the main cause of higher mortality rate in all over patients.
• There was a statistically significant higher mean value of procalcitonin in Septic shock group was 2.62±0.79 comparing to Sepsis group was 2.04±0.52, with p-value (p=0.009).
• There was highly statistically significant higher mean value of sRAGE (pg/ml) in septic shock group was 352.15±120.07, followed by Sepsis group was 279.93±92.92, then Control group 176.52±54.37, with p-value (p<0.001). While, there was no statistically significant difference between sepsis group and septic shock group, with p-value (p>0.05).
• In Sepsis Cases, there was statistically significant positive correlation between sRAGE “pg/ml” with Procalcitonin (ng/L). While there was no statistically significant correlation between sRAGE with CRP.
• In Sepsis Cases, There was no statistically significant correlation between sRAGE with Prism Score 3.
• In Sepsis Cases, there was no statistically significant correlation between sRAGE with Creatinine.
• In Septic Shock Cases, the results showed statistically significant positive correlation between sRAGE “pg/ml” with Procalcitonin (ng/L), Albumin (gm/dL), Prism Score 3 and Prism Score 4, with p-value (p<0.001; p=0.008; p<0.001 and p<0.001). While There was no statistically significant correlation between sRAGE with CRP.
• Sepsis vs. Control group: Receiver operating characteristics (ROC) curve was performed for sRAGE and demonstrated an area under the curve of 0.773 (0.647-0.871) with P value <0.05. The best cut off value for discrimination between Sepsis vs. Control group using sRAGE was >200.9 with sensitivity 60% and specificity 70%.
• Septic shock vs. Control group: Receiver operating characteristics (ROC) curve was performed for sRAGE and demonstrated an area under the curve of 0.780 (0.648-0.872) with P value <0.05. The best cut off value for discrimination between Septic shock vs. Control group using sRAGE was >269.7 with sensitivity 65% and specificity 97.5%.
• In our study, In Sepsis cases, we found statistically significant higher mean value of sRAGE “pg/ml” in Non Survivor group was 372.41±84.08 comparing to Survivor group was 259.10±92.14, with p-value (p<0.05). Also, statistically significant higher mean value of Procalcitonin (ng/L), Prism Score 3 and Prism Score 4 in Non Survivor group comparing to Survivor group, with p-value (p<0.05).
• In our study, In Septic shock cases, we found statistically significant higher mean value of sRAGE “pg/ml” in Non Survivor group was 498.32±187.00 comparing to Survivor group was 205.97±73.91, with p-value (p<0.001). Also, statistically significant higher mean value of Procalcitonin (ng/L), Prism Score 3 and Prism Score 4 in Non Survivor group comparing to Survivor group, with p-value (p<0.05).
• In Sepsis cases, ROC curve analysis proved good discriminating power of the Serum RAGE between Non Survivor group and Survivor group where Area under the ROC curve (AUC) = 0.760 with (95% Confidence interval 0.52–0.92); p<0.001. Cutoff point >270 with sensitivity= 80% and specificity=73.3%
• In Septic Shock Cases, ROC curve analysis proved good discriminating power of the Serum RAGE between Non Survivor group and Survivor group where Area under the ROC curve (AUC) = 0.955 with (95% Confidence interval 0.76–0.99); p<0.001. Cutoff point >310.9 with sensitivity= 90% and specificity=91%.