|Year : 2018 | Volume
| Issue : 2 | Page : 681-688
Stromal-derived factor-1 (CXCL12) and its receptor (CXCR4) in neonatal sepsis
Fady M El-Gendy1, Hassan S Badr1, Mohamed A Helwa2, Ahmed M. S. El-Hanafy3
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, Shebin El-Kom Teaching Hospital, Shebin El-Kom, Egypt
|Date of Submission||29-Nov-2016|
|Date of Acceptance||29-Jan-2017|
|Date of Web Publication||27-Aug-2018|
Ahmed M. S. El-Hanafy
Department of Pediatrics, Shebin El-Kom Teaching Hospital, Shebin El-Kom, Menoufia Governorate 32511
Source of Support: None, Conflict of Interest: None
Neonatal sepsis remains a major cause of morbidity and mortality in newborns. The C-X-C motif chemokine 12 (CXCL12) and its receptor α-chemokine receptor type 4 (CXCR4) are now known to play an important role in inflammatory states and mediate lymphocyte migration in response inflammation. However, it is unclear how chemokines respond to late-onset neonatal sepsis (LOS).
The aim of this study was to assess the value of measuring the serum levels of stromal-derived factor-1, also named CXCL12, and lymphocyte expression levels of its receptor CXCR4 in the diagnosis of LOS in relation to clinical and hematological sepsis scores.
Patients and methods
Levels of CXCL12 in serum and lymphocyte expression of CXCR4 were determined using enzyme-linked immunosorbent assay technique and flow cytometry, respectively, in 38 full-term neonates; 23 cases of LOS (13 male and 10 female) and 15 healthy neonates (six male and nine female) were included in the study.
Serum levels of CXCL12 and lymphocyte expression levels of CXCR4 were significantly higher in neonates with LOS when compared with nonseptic neonates. At a cutoff point of 30 pg/ml, the diagnostic accuracy of CXCL12 in the diagnosis of neonatal sepsis was 100%, with a sensitivity of 100% and a specificity of 100%, whereas the diagnostic accuracy of mean fluorescence intensity of lymphocyte expression of CXCR4 in the diagnosis of neonatal sepsis was 84%, with a sensitivity of 87%, specificity of 80%, positive predictive value of 87%, and negative predictive value of 80% at a cutoff point of 150.
CXCR4 and CXCL12 levels increase significantly in septic neonates and they are valuable markers in the diagnosis of neonatal sepsis.
Keywords: chemokines, cysteine-X-cysteine, neonates, sepsis
|How to cite this article:|
El-Gendy FM, Badr HS, Helwa MA, El-Hanafy AM. Stromal-derived factor-1 (CXCL12) and its receptor (CXCR4) in neonatal sepsis. Menoufia Med J 2018;31:681-8
|How to cite this URL:|
El-Gendy FM, Badr HS, Helwa MA, El-Hanafy AM. Stromal-derived factor-1 (CXCL12) and its receptor (CXCR4) in neonatal sepsis. Menoufia Med J [serial online] 2018 [cited 2018 Nov 19];31:681-8. Available from: http://www.mmj.eg.net/text.asp?2018/31/2/681/239761
| Introduction|| |
Neonatal sepsis is one of the leading causes of morbidity and mortality both among term and preterm infants. Although advances in neonatal care have improved survival and reduced complications in preterm infants, sepsis is still a significant cause of mortality and morbidity among very-low-birth-weight neonates who are less than 1500 g in neonatal ICUs .
It is known that early diagnosis and management of neonatal infection is a determinant for outcome . Clinical difficulties in identifying the infection early in neonates necessitated the evaluation of several biomarkers, including hematologic parameters, acute phase proteins, chemokines, cytokines, and cell-surface antigens . Neonatal sepsis is considered as early onset if it is diagnosed in the first 72 h of life and as late onset (LOS) if it is diagnosed after this period .
Chemokines are chemotactic cytokines that give directional guidance for leukocyte migration. They are classified into some subgroups on the basis of the position of the first two conserved cysteine residues near the amino terminus. Cytokines, leukotrienes, proteases, integrins, and bacterial products have been implicated in bone marrow neutrophil release; however, attention has centered on cysteine-X-cysteine (CXC) chemokine and toll-like receptor signaling during leukocyte release .
α-Chemokine receptor type 4 (CXCR4), also called CD184, is specific for stromal-derived factor-1 (SDF-1), also called C-X-C motif chemokine 12 (CXCL12), a potent molecule involved in chemotactic activity for lymphocytes . CXCL12 belongs to the CXC group of chemokines. It is a potent chemoattractant involved in angiogenesis, leukocyte trafficking, and other disorders . CXCR4 expression on the surface of circulating blood lymphocytes was demonstrated to be upregulated during sepsis or after lipopolysaccharide stimulation .
Previous studies have suggested that CXCL12 and its receptor CXCR4 play an important role in HIV infection, neurodegenerative diseases, cancer development, and progression .
Moreover, CXCR4 is intensively studied in different autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and autoimmune disorders of the central nerve system, such as multiple sclerosis, for its involvement in leukocyte chemotaxis in specific inflammatory conditions .
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 .
This study aimed to determine the diagnostic characteristics of serum CXCL12 and expression levels of CXCR4 in neonatal sepsis in correlation with clinical and hematological scoring systems of sepsis.
| Patients and Methods|| |
This study was conducted on 38 full-term neonates of matched age and sex who attended the Neonatology Unit of Menoufia University Hospitals. The study was carried out from February 2016 to June 2016 at Pediatrics and Clinical Pathology Departments, Faculty of Medicine, Menoufia University. The study was approved by the Ethics Committee of Faculty of Medicine, Menoufia University. Informed written consent was obtained from parents. The studied newborns were divided into two groups. Group I, the case group, included 23 full-term neonates with a diagnosis of LOS as postnatal age was at least 72 h in the presence of nonspecific signs of sepsis (temperature instability, apneic spells, need for supplemented oxygen, need for ventilation, tachycardia/bradycardia, hypotension, feeding intolerance, abdominal distension, and necrotizing enterocolitis) . They were thought to have sepsis according to the clinical and hematological sepsis scores (HSS) , and confirmed with positive blood culture. The case group included 13 male and 10 female neonates. Group II, the control group, included 15 healthy neonates, six male and nine female, without any symptoms or signs of sepsis.
The current study excluded newborns with multiple congenital anomalies, suspected chromosomal abnormalities, intrauterine growth retardation, and prematurity, babies born to mothers with clinical chorioamnionitis, and babies diagnosed with sepsis within 72 h of life.
All studied neonates were subjected to full detailed history taking and thorough clinical examination with special emphasis on evidence of sepsis and clinical sepsis score. Blood cultures were prepared for cases suspected with sepsis using neonatal bottles with daily subculturing on blood and McConkey agar plates both in aerobic and in anaerobic conditions. If no growth occurred after 10 days of incubation, blood culture was considered negative.
Other investigations included complete blood count and Leishman-stained blood smears, C-reactive protein (CRP) quantitative assay, serum levels of CXCL12, and expression levels of CXCR4 on lymphocytes. The hematological scoring system according to Makkar et al.  was applied to identify septic cases. It includes total leukocyte count (TLC) and its differential, platelet count, nucleated red blood cell count (to correct total white blood cell count), and assessment of degenerative and toxic changes in polymorphs.
Samples of venous blood were obtained from a peripheral or central vein under aseptic conditions from all septic and nonseptic newborns at the time of initial laboratory evaluation. Three milliliter of blood was drawn; 2 ml was collected into a plain vacutainer tube, and then centrifuged and serum was separated for the 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 until the time of assay of CXCL12 using enzyme-linked immunosorbent assay provided from Sunred Biological Technology (Shanghai, China) according to manufacturer's instructions.
The other 1 ml was delivered to an EDTA vacutainer tube for assay of CBC using 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 using flow cytometry (BD FACS Calibur; BD Immunocytometry Systems, San Jose, California, USA) using the anti-human CXCR4 PE monoclonal antibodies provided by Affymetrix eBioscience (catalog number 12-9999-41; Thermo Fisher Scientific, Waltham, Massachusetts, USA) where 100 μl of peripheral blood was added to a tube (after adjusting the TLC to 10 000/μl), followed by 5 μl of CXCR4 (CD184) PE monoclonal antibodies. An isotypic control and an auto control tube were involved.
The tubes were mixed thoroughly and gently and incubated for 15 min in the dark at room temperature (18–25°C). Cells were subjected to red blood cell lysis with 2 ml of lysing solution for 3 min. Thereafter, the tubes were washed three times PBS and finally the cells were suspended in 200 μl of PBS for final flow cytometric analysis. The mean fluorescence intensity (MFI) of CXCR4 expression on lymphocyte population was measured and used for statistical analysis.
The data collected were tabulated and analyzed using statistical package for the social science software version 2 on IBM compatible computer (SPSS 20. SPSS. Inc., Chicago, Illinois, USA). Quantitative data were expressed as mean ± SD (X ± 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 the Mann–Whitney U-test was applied. Qualitative data were expressed as number and percentage and analyzed by applying the χ2-test and for 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. ROC curve was used to determine cutoff points, sensitivity, and specificity for quantitative variables.
| Results|| |
There were no significant differences between group I (cases) and group II (controls) as regards postnatal age and sex (P > 0.05), but there was a significant difference as regards weight, being lower in group I than in group II (P < 0.05) [Table 1].
No significant difference was present between septic and nonseptic neonates as regards mode of delivery, consanguinity, and gestational age (P > 0.05) [Table 2].
A significant difference was present between group I and group II as regards hemoglobin (Hb) concentration, whereas a highly significant difference was present between the two groups as regards platelets, immature-to-total neutrophil (I/T) ratio, immature-to-mature neutrophil (I/M) ratio, immature neutrophil count, and hematological scoring system. No significant difference was present between group I and group II as regards TLC [Table 3].
The most common organism in our study was Gram-negative bacilli (65.2%), followed by Gram-positive bacilli (26.1%) and Gram-positive cocci (8.7%) [Table 4].
The level of CRP was higher in septic neonates than in normal controls (P < 0.001) [Table 5].
There was a highly significant difference between group I and group II as regards the serum levels of CXCL12 [Table 6] and MFI of CXCR4 expression, being higher in septic neonates compared with nonseptic ones [Table 6] and [Figure 1].
|Table 6: Comparison between cases and controls as regards MFI of CXCR4 expression on lymphocytes and serum CXCL12 levels|
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|Figure 1: α-Chemokine receptor type 4 (CXCR4) (CD184) expression on lympocytes. (a) Normal control; (b) septic neonate.|
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There was no significant difference between died and survived cases as regards the levels of CXCR4 and CXCL12 (P > 0.05) [Table 7].
There was a highly significant positive correlation between CXCL12 and each of clinical sepsis score, HSS, I/T ratio, I/M ratio, immature polymorphs, and CRP with a negative correlation between CXCL12 and platelet count with no significant correlation between the level of CXCL12 and either of Hb and TLC. Similarly, there was a highly significant positive correlation between CXCR4 and each of clinical sepsis score and the HSS, I/T ratio, and I/M ratio with a negative correlation with platelet count and no correlation with Hb and TLC [Table 8].
|Table 8: Correlation between CXCR4 and CXCL12 to different laboratory data and sepsis score systems|
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The diagnostic accuracy of CXCL12 in the diagnosis of neonatal sepsis was 100%, with a sensitivity, specificity, positive predictive value, and negative predictive values of 100% at a cutoff value of 30 pg/ml. The diagnostic accuracy of MFI of CXCR4 expression on lymphocytes in the diagnosis of neonatal sepsis was 84%, with a sensitivity of 87%, a specificity of 80%, a positive predictive value of 87%, and a negative predictive value of 80% at a cutoff value of 150 [Table 9].
|Table 9: Diagnostic validity of CXCL12, CXCR4, CRP, and combined CRP and CXCR4 for the diagnosis of neonatal sepsis|
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The diagnostic accuracy of CRP in the diagnosis of neonatal sepsis was 84%, with a sensitivity of 86%, a specificity of 80%, a positive predictive value of 86%, and a negative predictive value of 80% at a cutoff value of 12.5 mg/l. The diagnostic accuracy of combined MFI of CXCR4 expression and CRP at a cutoff value of 150 and 12.5 mg/l, respectively, was 100% with a sensitivity, specificity, positive predictive value, and negative predictive value of 100% [Table 9].
| Discussion|| |
Effective immune response requires the recruitment of functionally distinct leukocyte subsets to appropriate tissue sites (e.g., 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 . Differential localization of leukocyte subsets is mediated in part by their differential expression of chemokine receptors . 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 . CXCR4 and its ligand SDF-1 or CXCL12 can mediate lymphocyte trafficking in different inflammatory conditions .
Neonatal sepsis remains one of the leading causes of morbidity and mortality both among term and preterm infants . This study was designed to assess the value of measuring the serum level of CXCR4 and CXCL12 in the diagnosis of LOS in neonates clinically suspected and proved to have neonatal sepsis.
There was no significant difference between group I (cases) and group II (controls) as regards age and sex. A significant difference as regards weight was present, being lower in group I (cases) than in group II (controls) as previously reported by De Benedetti et al. , Gomella et al. , and Gerdes , who found that lower birth weight was significantly associated with an increased frequency of sepsis. However, Ghaly did not report such a finding.
The mode of delivery was not associated with an increased frequency of sepsis. This is in agreement with the finding of Mathai et al. andMustafa et al. . However, Stoll  observed that babies born by means of normal vaginal delivery were more likely to have early-onset sepsis than those delivered by means of cesarean section (CS). This may be related to good sterilization and intrapartum chemoprophylaxis, which dramatically decreased the risk for sepsis in neonates delivered by means of CS. In contrast, this is in disagreement with the study by El-Gendy et al.  and Utomo , who observed that infants delivered through CS had a higher risk of developing sepsis than those delivered by means of vaginal delivery.
Our study revealed that there was a significant decrease in Hb and a highly significant decrease in platelet count in the patient group compared with the control group. There were highly significant increases in I/T ratio, I/M ratio, immature neutrophils, and HSS in the patient group than in controls, with no significant difference between the two groups as regards TLC.
This is in agreement with findings of Ghaly  and Ottolini et al. , who found that Hb level was affected in septic neonates being toward the anemic side. This could be attributed to the increased red cell breakdown and marrow depression associated with sepsis as well as the frequent blood sampling.
Thrombocytopenia was frequently associated with sepsis and indicated poor prognosis. This is thought to be due to increased platelet destruction, sequestration secondary to infections, failure in platelet production due to reduced megakaryocytes, damaging effects of endotoxin, increased peripheral consumption as in disseminated intra-vascular coagulation (DIC), or the presence of an immune component due to increased levels of platelet-associated immunoglobulins. This was evident in various other studies conducted by Torkaman et al. , Gorlin and Goorin , and Makkar et al. .
Narasimha and Harendra Kumar  and Abou El-Ela et al.  found that I/T ratio and I/M ratio were increased in neonates with sepsis and can be used in the early diagnosis of neonatal sepsis. Pamela et al.  and Fanaroff et al.  reported that I/T ratio was significantly associated with neonatal sepsis. Yousef  and Fergany  reported that HSS was significantly higher in patients with infections than in patients with no infection and that HSS of the septic group was more than or equal to 3.
Our findings are in agreement with those of Manucha et al. , who stated that the TLC is of little clinical use in the diagnosis of neonatal infection because of the wide variation in values and the overlap between normal and abnormal values. It is in agreement with the findings of Andres et al. , who observed that as many as 50% of cases of culture-proven sepsis had normal white blood cell counts.
In contrast, Ghaly , Mah et al. , and Fanaroff et al. found that TLC was different between septic and nonseptic neonates.
In the current study, Gram-negative bacilli bacteria were the most frequent isolates from blood cultures, followed by Gram-positive bacilli and Gram-positive cocci. This is in agreement with the findings of Kayange et al. , who observed that, in most of the developing countries, Gram-negative bacteria form the majority of the isolates in neonatal sepsis. Variations in the isolated organisms between different areas could be attributed to the difference in the environment, the microbial etiology of sepsis, and supportive care practice between centers .
CRP levels were significantly higher in the neonatal sepsis group than in the control group. This is in agreement with the results of the studies of Ganesan et al. , Mally et al. , and Stoll .
As regards CXCR4 and its ligand CXCL12, there were highly significant increases in CXCR4 expression and CXCL12 serum levels in septic patients at the time of diagnosis compared with the control group with highly significant positive correlations between serum CXCL12 levels and expression levels of CXCR4 on lymphocytes and each of clinical sepsis and the HSS.
This is in agreement with the study by Tunc et al. , who found that the levels of CXCR4, CXCL12, and IL-6 increased significantly in the sera of neonates with LOS. Moreover, this is in agreement with the study by Ding et al. , in which the CXCR4 expression on the surface of circulating blood lymphocytes was upregulated 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.
Our study showed that the best cutoff value of CRP for the diagnosis of sepsis was 12.5 mg/l with a diagnostic sensitivity of 86%, specificity of 80%, and accuracy of 84%.
Khattab et al.  reported levels of CRP ranging from 6 to 192 mg/l in LOS patients and found that about 10% of their patients had a negative CRP test in the setting and 3.3% of them had positive blood cultures. Gendrel et al.  presented similar findings. Ganesan et al.  described that at a cutoff value of 13.495 mg/l, CRP had a diagnostic sensitivity of 80% and a specificity of 65.7% for the diagnosis of neonatal sepsis.
CXCL12 and CXCR4 had very high performance in the diagnosis of neonatal sepsis. The diagnostic accuracy of CXCL12 in the diagnosis of neonatal sepsis was 100%, with a sensitivity and specificity 100% at a cutoff value of 30 pg/ml, whereas the diagnostic accuracy of CXCR4 expression on lymphocyte population in the diagnosis of neonatal sepsis was 84%, with a sensitivity of 87% and a specificity of 80% at a cutoff value of 150. When combining CXCR4 and CRP in the diagnosis of neonatal sepsis, the sensitivity, specificity, positive predictive value, and negative predictive value were 100%.
A study by Tunc et al.  found that the best cutoff value of serum CXCR4 (measured using enzyme-linked immunosorbent assay) for the diagnosis of sepsis was 185 pg/ml with a sensitivity of 86% and a specificity of 95%. The best cutoff value of CXCL12 for the diagnosis of sepsis was 200 pg/ml with a diagnostic sensitivity of 83% and a specificity of 95%.
It is important to notify that studying the performance of these new markers in other inflammatory conditions such as sepsis with positive culture in the absence of blood infection and also in noninfectious inflammatory conditions in neonates can add more insights into the performance characteristics of CXCL12 and CXCR4 in the diagnosis of neonatal sepsis; however, our result suggests a very promising sensitivity, specificity, and accuracy of CXCL12 and combined CXCR4 and CRP in the diagnosis of neonatal sepsis.
| Conclusion|| |
Serum CXCL12 and lymphocyte expression levels of CXCR4 increased significantly in septic neonates and may be used as promising novel biomarkers in the diagnosis of neonatal sepsis. However, to determine the diagnostic importance of CXCR4 and CXCL12 measurements in LOS, it is important to conduct additional trials in a larger number of newborns with a wider spectrum of inflammatory diseases including septic and nonseptic conditions.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]