interleukin-8 and Appendicitis

We aimed to demonstrate the potential of precision medicine to describe the inflammatory landscape present in children with suspected appendicitis. Our primary objective was to determine levels of seven inflammatory protein mediators previously associated with intra-abdominal inflammation (C-reactive protein-CRP, procalcitonin-PCT, interleukin-6 (IL), IL-8, IL-10, monocyte chemoattractant protein-1-MCP-1, and serum amyloid A-SAA) in a cohort of children with suspected appendicitis. Subsequently, using a multiplex proteomics approach, we examined an expansive array of novel candidate cytokine and chemokines within this population.. We performed a secondary analysis of targeted proteomics data from Alberta Sepsis Network studies. Plasma mediator levels, analyzed by Luminex multiplex assays, were evaluated in children aged 5-17 years with nonappendicitis abdominal pain (NAAP), acute appendicitis (AA), and nonappendicitis sepsis (NAS). We used multivariate regression analysis to evaluate the seven target proteins, followed by decision tree and heat mapping analyses for all proteins evaluated.. 185 children were included: 83 with NAAP, 79 AA, and 23 NAS. Plasma levels of IL-6, CRP, MCP-1, PCT, and SAA were significantly different in children with AA compared to those with NAAP (. Multiplex proteomic analyses described the inflammatory landscape of children presenting to the ED with suspected appendicitis. We have demonstrated the feasibility of this approach to identify potential novel candidate cytokines/chemokine patterns associated with a specific illness (appendicitis) amongst those with a broad ED presentation (abdominal pain). This approach can be modelled for future research initiatives in pediatric emergency medicine.

Topics: Adolescent; Appendicitis; Chemokine CCL2; Chemokines; Child; Child, Preschool; Cytokines; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Precision Medicine; Prospective Studies; Proteomics; Sepsis; Serum Amyloid A Protein

The diagnosis of appendicitis is difficult and resource consuming. New inflammatory markers have been proposed for the diagnosis of appendicitis, but their utility in combination with traditional diagnostic variables has not been tested. Our objective is to explore the potential of new inflammatory markers for improving the diagnosis of appendicitis.. The diagnostic properties of the six most promising out of 21 new inflammatory markers (interleukin [IL]-6, chemokine ligand [CXCL]-8, chemokine C-C motif ligand [CCL]-2, serum amyloid A [SAA], matrix metalloproteinase [MMP]-9, and myeloperoxidase [MPO]) were compared with traditional diagnostic variables included in the Appendicitis Inflammatory Response (AIR) score (right iliac fossa pain, vomiting, rebound tenderness, guarding, white blood cell [WBC] count, proportion neutrophils, C-reactive protein and body temperature) in 432 patients with suspected appendicitis by uni- and multivariable regression models.. Of the new inflammatory variables, SAA, MPO, and MMP9 were the strongest discriminators for all appendicitis (receiver operating characteristics [ROC] 0.71) and SAA was the strongest discriminator for advanced appendicitis (ROC 0.80) compared with defence or rebound tenderness, which were the strongest traditional discriminators for all appendicitis (ROC 0.84) and the WBC count for advanced appendicitis (ROC 0.89). CCL2 was the strongest independent discriminator beside the AIR score variables in a multivariable model. The AIR score had an ROC area of 0.91 and could correctly classify 58.3 % of the patients, with an accuracy of 92.9 %. This was not improved by inclusion of the new inflammatory markers.. The conventional diagnostic variables for appendicitis, as combined in the AIR score, is an efficient screening instrument for classifying patients as low-, indeterminate-, or high-risk for appendicitis. The addition of the new inflammatory variables did not improve diagnostic performance further.

Topics: Acute Disease; Aged; Appendicitis; Biomarkers; C-Reactive Protein; Chemokine CCL2; Female; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Male; Matrix Metalloproteinase 9; Middle Aged; Peroxidase; ROC Curve; Serum Amyloid A Protein

The objective was to assess the accuracy of novel and traditional biomarkers in patients with suspected appendicitis as a function of duration of symptoms.. This was a prospective cohort study, conducted in a tertiary care emergency department (ED). The authors enrolled children 3 to 18 years old with acute abdominal pain of less than 96 hours and measured serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP), white blood cell (WBC) count, and absolute neutrophil count (ANC). Final diagnosis was determined by histopathology or telephone follow-up. Trends in biomarker levels were examined based on duration of abdominal pain. The accuracy of biomarkers was assessed with receiver operating characteristic (ROC) curves. Optimal cut-points and test performance characteristics were calculated for each biomarker..   Of 280 patients enrolled, the median age was 11.3 years (interquartile range [IQR] = 8.6 to 14.8), 57% were male, and 33% had appendicitis. Median IL-6, median CRP, mean WBC count, and mean ANC differed significantly (p < 0.001) between patients with nonperforated appendicitis and those without appendicitis; median IL-8 levels did not differ between groups. In nonperforated appendicitis, median IL-6, WBC, and ANC levels were maximal at less than 24 hours of pain, while CRP peaked between 24 and 48 hours. In perforated appendicitis, median IL-8 levels were highest by 24 hours, WBC count and IL-6 by 24 to 48 hours, and CRP after 48 hours of pain. The WBC count appeared to be the most useful marker to predict appendicitis in those with fewer than 24 or more than 48 hours of pain, while CRP was the most useful in those with 24 to 48 hours of pain.. In this population, the serum levels and accuracy of novel and traditional biomarkers varies in relation to duration of abdominal pain. IL-6 shows promise as a novel biomarker to identify children with appendicitis.

Topics: Abdominal Pain; Adolescent; Appendicitis; Biomarkers; C-Reactive Protein; Child; Child, Preschool; Diagnosis, Differential; Female; Humans; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Pilot Projects; ROC Curve; Sensitivity and Specificity; Young Adult

The inflammatory process in the post-appendectomy period is not well characterized. In a pilot study, we prospectively followed the kinetics of different inflammatory mediators before and after appendectomy in children, and compared the results of the groups open appendectomy (OA) and laparoscopic appendectomy (LA).. Levels of sP-selectin, tPA, MCP-1, IL-6, IL-8, sVCAM-1, and sCD40L were measured before appendectomy and on the next three consecutive days in the serum of 25 children (16 males and 9 females) aged 7 - 16 years (mean 12.6+/-2.47 years) with non-perforated acute appendicitis.. LA and OA were performed in 16 and 9 patients respectively. None of the markers of inflammation differed significantly by surgical approach at any point of observation. However, sP-selectin, MCP-1 and sVCAM-1 levels were found to have significantly different postoperative kinetics with a trend towards higher values in the laparoscopic group compared to the open appendectomy group (p=0.034, p=0.016 and p=0.025, respectively).. The cytokines sP-selectin, MCP-1 and sVCAM-1 may play a role in the possible post-appendectomy cytokine activation after non-perforated appendicitis. Since this phenomenon is more evident after LA than after OA, the contribution of the different LA procedures has to be further investigated.

Topics: Adolescent; Appendectomy; Appendicitis; Biomarkers; CD40 Ligand; Child; Cytokines; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Laparoscopy; Male; Membrane Cofactor Protein; P-Selectin; Pilot Projects; Prospective Studies; Tissue Plasminogen Activator; Vascular Cell Adhesion Molecule-1

Acute appendicitis (AA) is the most common life-threatening surgical emergency in pediatrics. To characterize the nature of the inflammatory response in AA, gene expression profiles were generated. We found remarkable uniformity in the genes that were differentially expressed between patients with appendicitis and control groups. Sixty-four probe sets were differentially expressed in samples from patients with both severe and mild appendicitis compared to control samples, and within this group we were able to identify four dominant clusters. Interestingly, expression levels of interleukin (IL)-8 significantly correlated with histologic score, and expression of IL-8 protein was observed within both neutrophils and mononuclear cells by immunohistochemistry, suggesting a possible role in the etiology of appendicitis. Although there was some overlap between genes reported to be differentially expressed in Crohn's disease (CD) and those observed in AA, differential expression of genes involved in interferon responses that characterize CD was not observed.

Topics: Acute Disease; Adolescent; Appendicitis; Child; Child, Preschool; Crohn Disease; Female; Gene Expression Profiling; Humans; Interleukin-8; Leukocytes, Mononuclear; Male; Neutrophils

Appendicitis is a very common surgical diagnosis with unclear pathology. Human cytomegalovirus (HCMV) can modulate our immune system and has been associated with inflammatory bowel disease (IBD) and various other inflammatory diseases.. We investigated the association between HCMV and acute appendicitis in 14 immunocompetent patients. Tissue sections from 10 AIDS patients with verified HCMV infection were used as positive controls, and uninflamed intestinal tissue sections from 12 patients were used as negative controls.. Cells double positive for HCMV early antigens and IL-6/IL-8 were observed in the appendices of 64.3% of appendicitis patients (9 of 14) by immunohistochemical analysis. HCMV late antigen was found in the appendices of 42.9% of the acute appendicitis patients (6 of 14). Latent HCMV appendix infection, as verified by in situ hybridization, as well as HCMV IgG, was observed in 78.6% of patients (11 of 14). The study samples from all 6 healthy appendices were negative for HCMV early and late antigens, although 50% (3 of 6) were HCMV IgG and HCMV DNA positive.. We have shown that HCMV infection of the appendix is associated with acute appendicitis (P = 0.002) and possibly with the severity of the disease. Our study identified HCMV as a pathogen to be sought for in the appendicitis patient group, possibly allowing further medical treatment of these patients.

Topics: Adult; Aged; Antigens, Viral; Appendicitis; Case-Control Studies; Cytomegalovirus Infections; Disease Progression; Female; Humans; Immunocompetence; Interleukin-6; Interleukin-8; Male; Middle Aged; Prevalence; Sweden

Appendicitis is a common surgical problem that is associated with a systemic inflammatory response. Previous studies have shown that cytokines are activated early in acute inflammation and sepsis and may serve as indicators of clinical severity. In this study we examined the role of cytokines as serum markers to distinguish nonperforated versus perforated appendicitis. Patients with the presumptive diagnosis of appendicitis had serum drawn preoperatively. Only patients (n = 59) with an intraoperative diagnosis of nonperforated (n = 34) and perforated (n = 25) appendicitis had serum drawn 12 hours postoperatively. Diagnosis was later confirmed by pathologic examination. The serum specimens were batch analyzed using enzyme-linked immunosorbent assays specific for interleukin (IL)-1beta, IL-2, IL-6, IL-8, and IL-10. Serum from normal healthy subjects served as control specimens (n = 9). Patients in the nonperforated and perforated groups were similar with regard to age, gender, race, white blood cell count, and fever. All cytokine levels including preoperative, postoperative, nonperforated, and perforated were higher in patients with appendicitis as compared with controls. IL-1beta, IL-2, and IL-10 levels were not different between groups with appendicitis. Preoperative serum levels of IL-6 (P = 0.036) and IL-8 (P = 0.047) were higher in patients with perforated versus nonperforated appendicitis. In addition postoperative serum levels of IL-6 (P = 0.0001) remained higher in the perforated group versus the nonperforated group. Serum levels of IL-6 and IL-8 may have a role in discerning the extent of disease in this condition. This initial step in systemically studying the role of cytokines in this disease may ultimately lead to the development of molecular indicators to aid in diagnosis and differentiate appendicitis from other conditions.

Topics: Adult; Aged; Appendicitis; Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-1; Interleukin-10; Interleukin-2; Interleukin-6; Interleukin-8; Interleukins; Intestinal Perforation; Male; Middle Aged; Postoperative Period; Predictive Value of Tests; Preoperative Care; Rupture, Spontaneous

Cytokines and leukocyte adhesion molecules are activated and found in increased concentrations in bacterial infection. The purpose of this study was to investigate whether some of these new serum markers could be feasible as a single on-admission test to predict acute appendicitis (AA).. In an open prospective study the diagnostic potentials of two cytokine measurements (interleukin-6 and interleukin-8), soluble leukocyte adhesion molecule (CD44), C-reactive protein (CRP) and white blood cell (WBC) count were compared in 80 consecutive patients who had undergone surgery for suspected AA. The diagnostic performance of each parameter was tested by using receiver operating characteristic (ROC) curves.. Phlegmonous AA was found in 34%, gangrenous AA in 40% and perforated AA in 5% of the patients. The proportion of negative explorations was 21%. Preoperative serum concentrations of IL-6 and CRP were elevated only in gangrenous and perforated AA. The concentrations of IL-8 and CD44 remained unchanged in AA. The sensitivity (84%), specificity (79%) and diagnostic accuracy (82%) of IL-6 were higher than the values for CRP, WBC, IL-8 and CD44 in predicting AA.. ROC analysis confirmed that IL-6 showed the best trend in the diagnosis of AA. However, the diagnosis of AA was not greatly improved by any of the new serum markers as single on-admission tests.

Topics: Acute Disease; Adult; Appendicitis; Biomarkers; C-Reactive Protein; Child; Female; Humans; Hyaluronan Receptors; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Middle Aged; Predictive Value of Tests; Sensitivity and Specificity

Secretion of chemokines by epithelial cells may represent a crucial event in the pathogenesis of inflammatory bowel disease (IBD). Expression of the chemokine epithelial neutrophil-activating peptide 78 (ENA-78) was monitored in patients with IBD and normal controls.. In situ hybridizations were performed on 41 tissue specimens from 15 patients with IBD and 10 controls to detect ENA-78 messenger RNA (mRNA). Immunofluorescence stainings were used to localize ENA-78 protein.. Intestinal epithelial cells expressing ENA-78 mRNA at detectable levels are found at comparable frequencies in patients with Crohn's disease and ulcerative colitis. Tissue specimens with mild to moderate histological signs of disease activity show slightly higher frequencies of ENA-78 mRNA-expressing epithelial cells than areas with signs of severe disease activity (P = 0.14). Immunofluorescence stainings showed presence of the ENA-78 protein in > 90% of preserved epithelial cells in IBD, in control tissues, ENA-78 mRNA was not detectable, and ENA-78 protein was detectable in 0%-30% of epithelial cells.. The observations are in agreement with a role of the C-X-C chemokine ENA-78 in the pathogenesis of IBD.

Topics: Acute Disease; Adult; Amino Acid Sequence; Appendicitis; Chemokine CXCL5; Chemokines; Chemokines, CXC; Female; Fluorescent Antibody Technique; Humans; Inflammation Mediators; Inflammatory Bowel Diseases; Interleukin-8; Intestinal Mucosa; Male; Middle Aged; Reference Values; RNA, Messenger; Tissue Distribution

Interleukin-8 (IL-8) is a chemoattractant that is highly selective for neutrophils. This study was designed to investigate the presence of IL-8 in peritoneal fluid of patients with acute appendicitis. The clinical circumstances underlying the secretion of IL-8 by mesothelium and its mechanism of activation have not been defined. In an in vitro model for bacterial peritonitis the role of bacteria in activating human mesothelial cells to secrete IL-8 was studied. Cultured human mesothelium was incubated with various species of pathogenic bacteria, isolated from peritoneal exudate fluids of patients with appendicitis. The amount of IL-8 secreted by the cultured mesothelial cells was determined in an IL-8 ELISA, as IL-8 was present in the original peritoneal fluid of these patients. Peritoneal fluids from patients with a perforated appendix were found to contain a significantly higher concentration of IL-8 compared to peritoneal fluids from patients with nonperforating appendicitis (121.6 (57.8) ng/ml versus 0.2 (0.07) ng/ml, respectively; mean (SEM), P < or = 0.01). Species of Bacteroïdes and Fusobacterium necrophorum induced IL-8 secretion from cultured mesothelial monolayers to levels comparable to those found in peritoneal fluids in vivo. Heat-killed bacteria and bacterial supernatant were also able to stimulate mesothelium to secrete IL-8. The results suggest that in the early phase of bacterial peritonitis the influx of PMN is regulated by bacteria-induced IL-8 secretion by the mesothelium lining the peritoneal cavity.

Topics: Acute Disease; Appendicitis; Ascitic Fluid; Bacterial Adhesion; Bacterial Infections; Cells, Cultured; Epithelium; Humans; Interleukin-8; Lipopolysaccharides; Peritonitis