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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 3  |  Page : 1083-1089

Stromal-derived-factor-1 (CXCL12) and its receptor (CXCR4) in pediatric sepsis


1 Department of Pediatrics, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
3 Department of Pediatrics, El-Bagour General Hospital, Menoufia, El-Bagour, Egypt

Date of Submission26-Mar-2018
Date of Acceptance07-May-2018
Date of Web Publication17-Oct-2019

Correspondence Address:
Eslam G. M. Mosa
El-Bagour, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_127_18

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  Abstract 

Objective
To assess the role of serum levels of stromal-derived-factor 1 and its receptor α-chemokine receptor type 4 (CXCR4) as reliable markers for diagnosis of sepsis in the emergency department.
Background
Pediatric sepsis is a major cause of morbidity and mortality in children admitted to the pediatric ICU. The chemokine CXCL12 and its receptor CXCR4 are now known to play an important role in inflammatory states and mediate lymphocyte migration.
Patients and methods
In a prospective cohort study, we randomly enrolled 23 critically ill children admitted into pediatric ICU, and 15 healthy children served as controls. Serum levels of CXCL12 and lymphocyte expression of CXCR4 were measured for patients as well as control by enzyme-linked immunosorbent assay technique and flow cytometry, respectively.
Results
Serum levels of CXCL12 and lymphocytes expression levels of CXCR4 were significantly higher among the all patients with sepsis compared with controls (P < 0.001). The diagnostic accuracy of CXCL12 in diagnosis of pediatric sepsis was 92.1%, with a sensitivity 100% and a specificity 80% at a cutoff point 89.3 pg/ml, whereas the diagnostic accuracy of mean fluorescent intensity of lymphocyte expression of CXCR4 was 92.1%, with sensitivity 95.6%, specificity 86.7%, at cutoff point of 120.2%. Furthermore, serum level of CXCL12 and CXCR4 expression were significantly elevated in nonsurvived compared with survived patients (P < 0.001).
Conclusion
Overall, the data support the view that measurements of serum CXCL12 and CXCR4 expression result in substantial added value for early diagnosis and prognosis of pediatric sepsis.

Keywords: biomarkers, chemokines, critically ill, CXCL12, CXCR4, sepsis


How to cite this article:
El-Gendy FM, Badr HS, Abd-Elbaki HS, Soliman MA, Mosa EG. Stromal-derived-factor-1 (CXCL12) and its receptor (CXCR4) in pediatric sepsis. Menoufia Med J 2019;32:1083-9

How to cite this URL:
El-Gendy FM, Badr HS, Abd-Elbaki HS, Soliman MA, Mosa EG. Stromal-derived-factor-1 (CXCL12) and its receptor (CXCR4) in pediatric sepsis. Menoufia Med J [serial online] 2019 [cited 2019 Nov 12];32:1083-9. Available from: http://www.mmj.eg.net/text.asp?2019/32/3/1083/268803




  Introduction Top


Pediatric sepsis is a major cause of morbidity and mortality in children and a leading reason for medical admissions to the pediatric ICU (PICU), as it can occur secondary to pneumonia, diarrhea, and other invasive bacterial diseases. All over the world, infections account for more than 30% of total deaths in children. In Egypt, infection accounts for 33% of deaths under 5 years of age, and a complication of the infection by septic shock raises the mortality rate to 50% [1].

Sepsis is as life-threatening organ dysfunction caused by a dysregulated host response to infection. Severe sepsis is defined as sepsis plus one of the following: cardiovascular organ dysfunction or acute respiratory distress syndrome or two or more other organ dysfunctions. Septic shock is defined as sepsis-induced hypotension persisting despite adequate fluid resuscitation [2].

The knowledge of factors that affect the outcome in severe sepsis and septic shock will help in the early recognition of children who are at the highest risk of death and help in time-sensitive management, which may improve the outcome [3].

The early diagnosis and management of pediatric infection are mandatory for effective outcome. Clinical difficulties in identifying the early infection in children and also in discriminating between bacterial and viral etiology have led to the evaluation of several biomarkers including hematologic parameters, acute-phase proteins, chemokines, cytokines, and cell-surface antigens [4]. The high mortality and severe outcome of pediatric sepsis are mainly related to the combination of the derangements in the innate immune system and the complex interactions between the microorganism and the host defense [5].

Chemokines are chemotactic cytokines that give directional guidance for leukocyte migration. They are classified to some subgroups by the position of the first two conserved cysteine residues near the amino terminus. Cytokines, leukotriene, proteases, integrins and bacterial products are implicated in bone marrow neutrophil release; however, attention has centered on cysteine-X-cysteine (CXC) chemokine and Toll-like receptor signaling during leucocyte release [6].

α-Chemokine receptor type 4 (CXCR4), also called CD184, is specific for stromal-derived-factor-1, also called CXCL12, a potent molecule involved in a chemotactic activity for lymphocytes [7]. CXCL12 belongs to the CXC group of chemokines. It is a potent chemoattractant involved in angiogenesis, leukocyte trafficking, and other disorders [8]. The CXCR4 expression on the surface of circulating blood lymphocytes was demonstrated to be upregulated during sepsis or after lipopolysaccharide stimulation [6].

Previous studies have suggested that CXCL12 and its receptor CXCR4 play an important role in HIV infection, neurodegenerative diseases, cancer development, and progression [9].

Moreover, CXCR4 is intensively studied in different autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosis, and autoimmune disorders of the central nervous system such as multiple sclerosis, for its involvement in leukocyte chemotaxis in specific inflammatory conditions [10].

Furthermore, the CXCL12/CXCR4 axis plays a crucial role in the homing of stem and progenitor cells in the bone marrow and controls their mobilization into peripheral blood and tissues in homeostatic conditions as well as after tissue injury or stress [10].

This study aimed to determine the diagnostic characteristics of serum CXCL12 and expression levels of CXCR4 in pediatric sepsis.


  Patients and Methods Top


This study was conducted on 38 infants and children of matched age and sex who attended the PICU of Menoufia University Hospitals. The study was carried out from February 2016 to June 2016. This study was carried out in Pediatrics and Clinical Pathology Departments, Faculty of Medicine, Menoufia University. The study was approved by the Ethics Committee of Faculty of Medicine, Menoufia University. An informed written consent was obtained from parents. The studied children were divided into two groups: group I, the cases group, included 23 infants and children with diagnostic criteria of sepsis by applying the criteria of 2013 guidelines of surviving sepsis campaign to diagnose sepsis, severe sepsis, and septic shock in pediatric age group [11]. They included nine male and 14 female patients. Group II, the control group, included 15 healthy children, with eight males and seven females, without any symptoms or signs of sepsis.

The exclusions criteria were children 18 years or older, neonates, length of stay in unit less than 4 h, admission in a state of continuous cardiopulmonary resuscitation without achieving stable vital signs for at least 2 h, patients with oncological diseases or admitted to PICU after surgery, traumatic patients, known cases of metabolic diseases, and known cases of chronic hepatic or kidney diseases.

Blood cultures were done for cases suspicious of sepsis using bottles with daily subculture on blood and MacConkey agar plates, both in aerobic and anaerobic conditions. If no growth occurred after 10 days of incubation, blood culture was considered negative.

Other investigations included complete blood count, Leishman-stained blood smears, C-reactive protein (CRP) quantitative assay, serum levels of CXCL12, and expression levels of CXCR4 on lymphocytes.

Samples of venous blood were obtained from a peripheral or central vein under aseptic conditions from all septic and nonseptic children at the time of initial laboratory evaluation. Two milliliter of blood draw was collected into a plain vacutainer tube and then centrifuged, and then the serum was separated for quantitative assay of CRP on the Beckman Coulter AU480 fully automated autoanalyzer (Beckman Coulter, Brea, California, USA). The remaining portion of serum was stored at − 80°C till the time of assay of CXCL12 by ELISA provided by Sun Red Biological Technology (Shanghai, China) according to manufacturer's instructions.

Another 1 ml was delivered to an EDTA vacutainer tube for assay of complete blood count (CBC) by automated cell counter Sysmex XN-1000 (Sysmex Corporation, Kobe, Japan) and for blood smear, and the remaining portion was used for studying the expression of CXCR4 by flow cytometry (BD FACSCaliber; BD Immune Cytometry Systems, San Jose, California, USA) using the anti-human CXCR4 PE monoclonal Ab (MoAb), provided by affymetrix ebioscience, catalogue number 12-9999-41 (Thermo Fisher Scientific, Waltham, Massachusetts, USA), where 100 μl of peripheral blood was added to a tube (after adjusting the total leucocyte count to 10 000/μl), and then 5 μl of CXCR4 (CD184) PE MoAb. An isotopic control and an autocontrol tubes were involved.

The tubes were well and gently mixed and incubated for 15 min in a dark at room temperature (18–25°C). Cells were subjected to red-blood-cell lysis by 2 ml of lysing solution for 3 min; then tubes were washed three times in PBS and finally the cells were suspended in 200 μl of PBS for final flow cytometric analysis. Mean fluorescence intensity (MFI) of CXCR4 expression on lymphocyte population was measured and used for statistical analysis.

Statistical analysis

The data collected were tabulated and analyzed by statistical package for the social sciences software (SPSS) (SPSS Inc., Chicago, Illinois, USA) version 16 on IBM compatible computer. Quantitative data were expressed as the mean ± SD and analyzed by applying t-test for comparison between two groups of normally distributed variables, whereas for comparison between two groups of not normally distributed variables, Mann–Whitney U-test was applied. Qualitative data were expressed as number and percentage and analyzed by applying χ2-test, and for a 2 × 2 table and if one cell has expected number less than 5, Fisher's exact test was applied. Spearman correlation was used for non-normally distributed quantitative variables or when one of the variables is qualitative. Receiver operating characteristic (ROC) curve was used to determine cutoff points, sensitivity, and specificity for quantitative variables.


  Results Top


There were no significant differences between group I (cases) and group II (controls) regarding age and sex (P > 0.05), but there was a significant difference regarding weight, being lower in group I than in group II (P < 0.05) [Table 1].
Table 1: Demographic data and weight of the studied groups

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A highly significant difference was present between the two groups about the presence of SIRS and sepsis (P < 0.001) [Table 2].
Table 2: Comparing the studied groups regarding sepsis

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The commonest organism in our study in 11 patient was Gram-negative bacilli, who represent 47.8% of all patients, followed by Gram-positive cocci in six patients, who represent 26.1% of all patients, and only one (4.3%) patient had Gram-negative bacilli + candida in the blood culture results; however, five patients did not have any growth in their cultures, who represent 21.7% of all patients in our study.

There was a highly significant difference between group I and group II regarding the serum levels of CXCL12 [Table 3] and MFI of CXCR4 expression, being higher in the septic children as compared with the nonseptic ones. Moreover, the level of CRP was higher in septic children than in normal controls (P < 0.001) [Table 3].
Table 3: Comparison between cases and controls regarding mean fluorescent intensity of CXCR4 expression on lymphocytes, serum CXCL12 levels, and C-reactive protein

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There was a highly significant difference between nonsurvived and survived cases regarding the levels of CXCR4 and CXCL12 (P < 0.001). Moreover, there was a highly significant difference between nonsurvived and survived cohort patients as regards to the length of PICU stay (P < 0.001) with range 8–15 and mean ± SD 11.3 ± 2.3 among the survived group. And with range 25–34 and mean ± SD 29.6 ± 3.3 among the nonsurvived group [Table 4].
Table 4: CXCR4, CXCL12 levels, and the length of pediatric ICU stay among nonsurvived and survived cases

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The performance of CXCL12 and CXCR4, as a diagnostic marker, relative to classic inflammation and sepsis biomarkers was tested through ROC curve analysis, which showed that the diagnostic accuracy of CXCL12 in the diagnosis of pediatric sepsis was 92.1%, with sensitivity of 100%, specificity of 80%, positive predictive value of 88.5%, and negative predictive values of 100%, at a cutoff value of 89.3 pg/ml. The diagnostic accuracy of MFI of CXCR4 expression on lymphocytes in diagnosis of pediatric sepsis was 92.1%, with a sensitivity of 95.6%, a specificity of 86.7%, a positive predictive value of 91.7%, and a negative predictive value of 92.8%, at a cutoff value of 120.2 [Table 5].
Table 5: Diagnostic validity of CXCL12 and CXCR4 for diagnosis of pediatric sepsis

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There was a highly significant difference in the level of CXCL12 and MFI of CXCR4 expression on lymphocytes in prediction of mortality (outcome) among sepsis group. CXCR4 at a cutoff point of 98.4 had sensitivity of 100%, specificity of 93.3%, accuracy of 95.6%, positive predictive value of 88.9%, negative predictive value of 100%, and area under the curve of 0.98, in the prediction of mortality, which is excellent. P value was less than 0.001, which was highly significant, and 95% of confidence interval of area under the curve was 0.94–1.0 [Table 6].
Table 6: Prognostic validity of C-reactive protein, CXCR4, and CXCL12 in prediction of mortality (outcome) among sepsis group

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According to the level of CXCL12, there was a highly significant difference between died and survived group (P < 0.001) at a cutoff point of 89.0, with sensitivity of 100%, specificity of 100%, accuracy of 100%, positive predictive value of 100%, negative predictive value of 100%, and area under the curve of 1.0, which is excellent. P value was less than 0.001, which is highly significant, and 95% of confidence interval of area under the curve was 1.0–1.0 [Table 6].

The diagnostic accuracy of CRP between died and survived group was 73.9%, with a sensitivity of 75%; a specificity of 73.3%; a positive predictive value of 60%; and a negative predictive value of 84.6% at cutoff value of 72 mg/l. Area under the curve was 0.782, which is excellent; P value was 0.04, which is significant; and 95% of confidence interval of area under the curve was 0.56–0.95 [Table 6].


  Discussion Top


Sepsis, multiple organ dysfunctions syndrome, and septic shock are the main leading causes of death among critically ill children. Anticipation and early diagnosis of sepsis improve the overall outcome. Moreover, close monitoring of the patients with sepsis is critical and increases the chance of the patient survival, decreases hospital cost of treatment, and makes rehabilitation easier [12].

Effective immune response requires the recruitment of functionally distinct leukocyte subsets to appropriate tissue sites (e.g., the direction of hemopoietic progenitors and naive lymphocytes to lymphoid organs and mature lymphocytes to peripheral sites of inflammation). This recruitment process is believed to be mediated in part by chemokines, soluble messenger molecules secreted by target tissue cells to signal their status as lymphoid organs or inflamed tissue [13].Differential localization of leukocyte subsets is mediated in part by their differential expression of chemokine receptors [14]. CXCR4 is heterogeneously expressed through the lymphocyte gate and many of its subsets. It is expressed significantly on naive T cells, B cells with significantly lower expression on mature cells, and almost undetectable in natural killer cells [15]. CXCR4 and its ligand stromal-derived-factor-1 or CXCL12 can mediate lymphocyte trafficking in different inflammatory conditions [16].

This study was designed to assess the value of measuring the serum level of CXCR4 and CXCL12 in the diagnosis of pediatric sepsis in children clinically suspected and proved to have sepsis.

There was no significant difference between group I (cases) and group II (controls) regarding age and sex. A significant difference regarding weight was present, being lower in group I (cases) than in group II (controls), as previously reported by De Benedetti et al. [17] in neonates and infants of age group below 1 year, who found that decreased weight is significantly associated with increased frequency of sepsis. On the contrary Ghaly [18] reported contrary finding.

There was a highly significant difference between group I (cases) and group II (controls) regarding presence of SIRS and sepsis as previously reported. Dellinger et al. [11] revealed that presence of parameters used to diagnose systemic inflammatory response syndrome (SIRS) (body temperature, total leukocytes count (TLC), Heart rate (HR), and Respiratory rate (RR)) and presence of infection are the most important clinical sign to identify sepsis.

In the current study, Gram-negative bacilli bacteria were the most frequent isolates from blood cultures followed by Gram-positive cocci and Gram-negative bacilli bacteria + candida; this comes in agreement with Kayange et al. [19] who observed that in most of the developing countries, Gram-negative bacteria form the majority of the isolates in sepsis. Hashemi and Garebaghi [20] reported  Escherichia More Details coli and nonfermentative Gram-negative bacillus as the most common bacterial agents isolated from cultures in sepsis. An another study done by Layseca-Espinosa et al. [21] reported that most of the blood cultures demonstrated the presence of the Gram-negative bacillus (Klebsiella pneumonia) in the group of proven sepsis. Variations in the isolated organisms between different areas could be explained by the difference in the environment, the microbial etiology of sepsis, and supportive care practice between centers [21].

The organism responsible for infection with cultures of no growth could not be identified in five patients, who represent 21.7% of the all patients studied. Near similar results were seen in the work done by El-Mashad et al. [22], where 47.5% of their patients with sepsis did not have a positive culture. Patriawati et al. [23] identified the organism only in 50% of their patients. Negative cultures can be owing to many factors, one of the most important is the use of antibiotics before sampling, which leads to sterilization of blood in few hours [24].

CRP levels were significantly higher in the septic group than the control group. This comes in agreement with the results of the studies of Ganesan et al. [25].

Regarding CXCR4 and its ligand, CXCL12, there were highly significant increases in CXCR4 expression and CXCL12 serum levels in patients with sepsis at the time of diagnosis compared with control group.

Similar findings were reported by Elhanafy et al. [26] and Tunc et al. [6], who found that the levels of CXCR4, CXCL12, and IL-6 increased significantly in the sera of the patients with sepsis.

Moreover, similar agreement was found in the study by Ding et al. [27] in which the CXCR4 expression on the surface of circulating blood lymphocytes was up-regulated during sepsis or after lipopolysaccharide stimulation, suggesting that CXCR4 may be important in lymphocyte infiltration into tissues and subsequent systemic inflammatory responses during sepsis or endotoxemia.

Similarly, Stefano et al. [28] conducted a study to determine serum CXCR4 and CXCL12 levels in patients with sepsis and to assess their possible value in diagnosis of sepsis and to predict mortality in patient with severe sepsis and septic shock, and they suggested a possible role for CXCL12 as a diagnostic and a prognostic marker in severe sepsis/septic shock.

CXCL12 and CXCR4 had very high performance in the diagnosis of pediatric sepsis. The diagnostic accuracy of CXCL12 in diagnosis of pediatric sepsis was 92.1%, with sensitivity 100% and specificity 80% at a cutoff value of 89.3 pg/ml, whereas the diagnostic accuracy of CXCR4 expression on lymphocyte population in diagnosis of pediatric sepsis was 92.1%, with a sensitivity of 95.6% and a specificity of 86.7% at a cutoff value of 120.2. When combining CXCR4 and CXCL12 in the diagnosis of pediatric sepsis, it showed sensitivity of 100%, specificity of 86.7%, positive predictive value of 92%, negative predictive value of 100%, and diagnostic accuracy of 94.7%.

A study by Tamamis and Floudas [7] found that the best cutoff value of serum CXCR4 (measured by ELISA) for diagnosis of sepsis was 185 pg/ml with a sensitivity of 86% and a specificity of 95%. The best cutoff value of CXCL12 for diagnosis of sepsis was 200 pg/ml with a diagnostic sensitivity of 83% and a specificity of 95%.

In our study regarding the comparison between the survived and died patient among the diseased group, we found that there was a highly significant difference between group I (survived) and group II (died) regarding the serum level of CXCL12 and MFI of CXCR4 expression on lymphocytes. This agrees with Stefano et al. [28] who conducted a study to determine serum CXCR4 and CXCL12 levels in patients with sepsis and to assess their possible value in diagnosis of sepsis and to predict mortality in patient with severe sepsis and septic shock, and they suggested a possible role for CXCL12 as a diagnostic and a prognostic marker in severe sepsis/septic shock. However, this disagrees with the study of Elhanafy et al. [26], which revealed that there was no significant difference between died and survived cases regarding levels of CXCR4 and CXCL12 (P > 0.05).

Duration of hospital stay was highly significant statistically different between the two groups (died and survived) (P < 0.001), which comes in agreements with Saad et al. [29]. who found that cases that stayed more in PICU were associated with higher risk of mortality, but this disagrees with Gurpreet et al. [30], who demonstrated that duration of PICU stay was not statistically significantly different between the two groups (died and survived).

The combined ROC curve of CXCL12 in prediction of mortality (outcome) among sepsis group had a sensitivity 100%, specificity 100%, and accuracy 100%, with cutoff point of 89 pg/ml, whereas lymphocyte expression levels of CXCR4 in prediction of mortality (outcome) among sepsis group had a sensitivity 100%, specificity 93.3%, and accuracy 95.6%, with a cutoff point of 98.4 pg/ml.

Moreover, on using ROC curve of CRP in prediction of mortality (outcome) among sepsis group, it had a sensitivity of 75%, specificity of 73.3% and accuracy of 73.9% with a cutoff point of 72 mg/l. This comes in agreement with the results of the studies of Malbon et al. [31]. This disagrees with the study of Ganesan et al. [25], in which the best cutof value of CRP for diagnosis of sepsis was 13.495 mg/l with diagnostic sensitivity of 80% and specificity of 65.7%.

Using the CXCR12 in diagnosis of pediatric sepsis, sensitivity, specificity, positive predictive value, and negative predictive value were 100%.

Our results revealed that diagnostic sensitivity, specificity, and accuracy of CXCL12 and CXCR4 are more predictive than CRP.

It is important to notify that studying the performance of these new markers in other inflammatory conditions like sepsis with positive culture in absence of blood infection and also in noninfectious inflammatory conditions in pediatrics can add more insights into the performance characteristics of CXCL12 and CXCR4 in diagnosis of pediatric sepsis; however, our result suggests a very promising sensitivity, specificity, and accuracy of CXCL12 and CXCR4 in diagnosis and prognosis of pediatric sepsis.

It is important to notify that studying the performance of these new markers in other inflammatory conditions like sepsis with positive culture in the presence of blood infection and also in noninfectious inflammatory conditions in pediatrics can add more insights into the performance characteristics of CXCL12 and CXCR4 in the diagnosis of pediatric sepsis; however, our result suggests a very promising sensitivity, specificity, and accuracy of CXCL12 and CXCR4 in diagnosis and prognosis of pediatric sepsis.


  Conclusion Top


Serum CXCL12 and lymphocyte expression levels of CXCR4 were increased significantly in septic children and may be used as promising novel biomarkers in diagnosis and prognosis of pediatric sepsis. However, to determine the diagnostic importance of CXCR4 and CXCL12 measurements in pediatric sepsis, it is important to conduct additional trials in a larger number of children with a wider spectrum of inflammatory diseases including septic and nonseptic conditions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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