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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 1  |  Page : 19-26

Predictive value of neutrophil gelatinase-associated lipocalin and E-selectin in pediatric sepsis


1 Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt

Date of Submission21-Jan-2019
Date of Acceptance22-Feb-2019
Date of Web Publication9-Sep-2019

Correspondence Address:
Hanan A El-Sattar El-Halaby
Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura Gomheria Street, Mansoura 35516
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AJOP.AJOP_11_19

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  Abstract 


Background Sepsis is a leading cause of death in infants and children; early prediction could save patients’ lifes.
Aim The aim of this study was to explore the role of neutrophil gelatinase-associated lipocalin (NGAL) and E-selectin in measurements in diagnosing and predicting mortality in patients with suspected sepsis and to identify whether their concentrations differ with blood culture results.
Patients and methods This is a two-phase study; the first is a comparative and the second is a cross-sectional one, performed in Mansoura University Children’s Hospital from January to December 2017. The study involved100 children with clinically suspected sepsis and 40 healthy children (the control group). NGAL, E-selectin, C-reactive protein, total leukocyte count, and blood culture were assessed. Patient survival was recorded within 30 days of hospital admission. The study was performed after local institutional review board approval. For parametric data, t-test was used and for threshold value detection receiver operating characteristic curves were used.
Results Significantly higher NGAL, E-selectin, C-reactive protein, and total leukocyte count levels were recorded in patients with clinically suspected sepsis than healthy participants; also, they were significantly higher in nonsurvivors. receiver operating characteristic curves for 30-day patients’ mortality showed E-selectin was a good discriminator (area under the curve=0.841), whereas area under the curve was 0.667 for NGAL. E-selectin was significantly higher in the culture-positive group (P=0.012), whereas NGAL did not differ significantly (P=0.153).
Conclusion E-selectin and NGAL are diagnostic markers for sepsis. E-selectin is a sensitive prognostic biomarker in patients with clinically suspected sepsis whereas NGAL is less sensitive. E-selectin is significantly higher in blood culture-positive patients with sepsis whereas NGAL did not differ significantly.

Keywords: children, E-selectin, neutrophil gelatinase-associated lipocalin, prediction, sepsis


How to cite this article:
El-Sattar El-Halaby HA, Zeid MS, Zaki ME. Predictive value of neutrophil gelatinase-associated lipocalin and E-selectin in pediatric sepsis. Alex J Pediatr 2019;32:19-26

How to cite this URL:
El-Sattar El-Halaby HA, Zeid MS, Zaki ME. Predictive value of neutrophil gelatinase-associated lipocalin and E-selectin in pediatric sepsis. Alex J Pediatr [serial online] 2019 [cited 2020 Aug 3];32:19-26. Available from: http://www.ajp.eg.net/text.asp?2019/32/1/19/266405




  Introduction Top


Sepsis is a serious illness that continues to affect all pediatric age groups with serious outcomes despite the advancement in the medical management of the affected patients [1]. Clinical and laboratory biomarkers for the prediction of this illness may improve patients’ outcome. Studies of biomarkers for sepsis in the pediatric age group are limited when compared with studies in adults or neonates [2].

The diagnosis of sepsis relies on nonspecific clinical signs plus bacteriological evidence of infection [3]. This results in diagnostic vagueness, either overestimated diagnosis with overuse of antibiotics, or the failure to identify patients who might benefit from antibiotics and immune-modulatory therapies [2]. There is a need for reliable sepsis biomarkers that can help in the prediction of sepsis, early diagnosis, correct decision-making for antibiotic administration, aid in the identification of its severity and monitoring of the response to therapy [4]. Many studies had been conducted to find a reliable biomarker in sepsis that confirms or eliminates its suspicion. Of these biomarkers, C-reactive protein (CRP) [4],[5], total leukocyte count (TLC) [6], neutrophil gelatinase-associated lipocalin (NGAL), [7],[8] and E-selectin [9],[10] have been studied.

CRP is an easily available biomarker and of low cost. It is increased in response to inflammation and infection reaching its serum highest level of 36–50 h after an inflammatory trigger but its sensitivity and specificity in detecting bacterial infection are variable [2]. TLC with its differential can differentiate between viral and bacterial infections and could be a diagnostic marker for sepsis when combined with other clinical scores but not alone [6].

The sequences of sepsis are recognized to be caused by atypical leukocyte response with marked activation and recruitment to host tissues leading to damage of the vascular endothelium in different organs. Different mediators such as cytokines and endotoxins provoked the recruitment of leukocytes and the release of multiple adhesion molecules to the blood. One of these adhesion molecules is E-selectin that is normally present in low level in the blood but it is increased in response to infection [11].

NGAL is a protein marker that is synthesized in the kidneys and is expressed in neutrophils; its level is increased in response to infection. In-vitro studies have shown strong correlations between its concentration and different mediators such as interleukin-6 and tumor necrosis factor-α [12].

Therefore, we conducted this study to explore the role of measurement of NGAL and E-selectin in diagnosing sepsis and predicting mortality in infants and children with suspected sepsis and to identify whether their concentrations differ with the blood culture results.


  Patients and methods Top


This is a two-phase study; the first is a comparative study including 100 children with suspected or proven sepsis (systemic inflammatory response syndrome in association with suspected or proven infection using the international consensus sepsis definition) [3] admitted to the pediatric ICU (PICU) in a tertiary care university hospital from January to December 2017. In addition, 40 uninfected healthy infants and children, with no clinical signs of local or systemic infection, age-matched and sex-matched with the study group were collected from the outpatient clinic of Mansoura University Children’s Hospital as a control group. The second phase is a cross-sectional study that searched the 100 children with suspected sepsis admitted to the PICU. They were investigated for the blood culture results and for NGAL, E-selectin, CRP, and TLC.

The patients were aged from 1 month until 16 years, with suspected or proven sepsis. For those included in the study diagnosis of sepsis was made according to Goldstein et al. [3]. Patients were excluded from the study if they had noninfectious causes of systemic inflammatory response syndrome development (such as trauma, operation, burn, or pancreatitis) or terminal stage of diseases, for example, malignant cancer of any type, AIDS, or end-stage liver or renal disease. Fully informed consents were obtained from the parents of each child before entering the study. Mansoura Faculty of Medicine Institutional Review Board approved the study code number ‘R.18.09.281.’ In the PICU, Mansoura University Children’s Hospital, there are eight beds, nurse-to-patient ratio is 1–2 or 3; average number of yearly hospital admission is 150 patients (two-thirds only of the PICU admitted patients were enrolled in this study as they were admitted for causes other than sepsis).

Each child was subjected to full medical history and full clinical examination. Full laboratory investigations were performed for each patient including blood culture, complete blood counts, CRP by turbidimetry and creatinine for renal function. Samples for NGAL and E-selectin concentration assessment were withdrawn on admission to the PICU. Patients’ survival was recorded within 30 days of hospital admission.

From each child either patient or control 5 ml blood was drawn under complete sterile conditions and sera were separated and kept frozen at −20°C for further determination of E-selectin and NGAL levels by enzyme immunoassay method.

Data were collected from 132 patients, of whom only 100 were eligible for the study. In all, 32 patients were excluded; eight patients did not sign the consent, nine did not complete data, and 15 patients lost the 30-day follow-up and cannot reach them after discharge from the hospital. Of the 100 patients with suspected sepsis, sepsis was confirmed in 51 patients by colonization on blood culture. There were 53 patients with acute kidney injury (AKI) and 47 without defined according to modified RIFLE in critically ill children [13].

NGAL ELISA (Quantikine ELISA; R&D Systems, Abingdon, UK)

The kit used a monoclonal antibody specific for human lipocalin-2 in sandwich enzyme-linked immunoassay method. The plate was coated with an antibody to react with NGAL found in serum and standard supplied with the kit. After incubation wash was performed to remove the unbound NGAL and a second enzyme-linked monoclonal antibody specific for human lipocalin-2 was added. Following a wash to remove any unbound antibody–enzyme reagent, a substrate solution was added to the wells and color developed in proportion to the amount of lipocalin-2 bound in the initial step. The color development was stopped, and the intensity of the color was measured. The concentration was expressed in ng/ml. One clinical pathologist assessed the readings.

E-selectin ELISA (Quantikine ELISA)

The kit used a monoclonal antibody specific for human E-selectin measurement which used a monoclonal antibody specific for human E-selectin measurement in the quantitative sandwich enzyme-linked immunoassay technique. The plate was coated with a monoclonal antibody to attach to the E-selectin present in serum samples and in the standard supplied with the kit. After incubation, they were washed to remove any unbound antibody–enzyme reagent, a substrate solution was added, and color developed in proportion to the amount of E-selectin bound in the initial step. The color development was stopped, and the intensity of the color was measured. The concentration was expressed as µg/ml. One clinical pathologist assessed the readings.

Statistical methodology

Data entry and statistical analyses were performed using the statistical package for data entry and statistical analyses were performed using the statistical package for social sciences, version 21 (IBM SPSS Inc., Chicago, Illinois, USA). The data normality was tested with a Kolmogorov–Smirnov test. Data were presented as either mean±SD for parametric statistical analysis or median, minimum and maximum for nonparametric. Independent sample t-test, Mann–Whitney and χ2 tests were used for group comparison. Pearson and Spearman correlations were used to study the correlation in parametric and nonparametric variables, respectively. The sensitivity and specificity at different cutoff points were evaluated by receiver operating characteristic (ROC) curves. For all the above-mentioned statistical tests, the threshold of significance is below 5% (P).


  Results Top


The clinical characteristics and laboratory data of the study groups are summarized in [Table 1]. There were no significant differences in age or sex between the patients with clinically suspected sepsis group and the healthy group. Plasma NGAL, E-selectin, CRP, and TLC in patients with suspected sepsis group were significantly higher compared with the corresponding values in the healthy participants’ group (P<0.001 for all).
Table 1 Clinical characteristics and laboratory data of the study groups

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In [Table 2], on comparing clinical characteristics and laboratory data in culture-positive (n=51) and culture-negative patients (n=49), we observed nonsignificant differences regarding age, sex, underlying causes of admission to the PICU or 30-day patients’ mortality. On assessing the clinical patients’ presentation on admission to the PICU, we observed nonsignificant differences in fever, hypotension, oliguria, or apnea between culture-positive and culture-negative patients, whereas bradycardia was significantly more in the culture-positive group. Nonsignificant differences in plasma NGAL and TLC between culture-positive and culture-negative patients were observed whereas CRP and E-selectin were significantly higher in the culture-positive group (P<0.001 and 0.012, respectively).
Table 2 Clinical characteristics and laboratory data in patients with culture-positive and culture-negative in patients with suspected sepsis (n=100)

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Significantly higher NGAL, E-selectin, CRP, and TLC were recorded in nonsurvivors on comparison with survived patients with suspected sepsis as shown in [Table 3].
Table 3 Comparison between different laboratory biomarkers in survived and nonsurvived children with suspected sepsis (n=100)

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The ROC curves plotted for comparing areas under the curve (AUCs) of the studied biomarker for the prediction of 30-day patients’ mortality in children with sepsis are shown in [Table 4] and [Figure 1]. AUC for NGAL, E-selectin, CRP, and TLC were 0.667, 0.841, 0.762, and 0.690, respectively). The sensitivity and specificity of these laboratory biomarkers, using the optimal cutoff points were tested and showed that E-selectin is the most sensitive (82.8%) followed by CRP (72.4%), then NGAL (65.5%), and lastly TLC (62.1%) whereas as regards specificity, TLC was the most specific (77%) followed by CRP (66.2%), then NGAL (63.4%), and the least was E-selectin (62%).
Table 4 Receiver operating characteristic curve analysis of different laboratory biomarkers in association with 30-day patients’ mortality in children with suspected sepsis (n=100)

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Figure 1 Receiver operating characteristic (ROC) curve analysis of neutrophil gelatinase-associated lipocalin and E-selectin in association with 30-day patients’ mortality in children with suspected sepsis (n=100); area under the curve=0.841 for E-selectin and 0.667 for neutrophil gelatinase-associated lipocalin (NGAL).

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  Discussion Top


Sepsis is known for centuries and still a current challenge as a leading cause of death in infants and children. Proper management requires early diagnosis, specific, and reliable diagnostic biomarkers. In this study, NGAL, E-selectin, CRP, and TLC had been investigated for their validity as biomarkers for prediction and early diagnosis of sepsis in patients admitted to the PICU.

In this study, patients with suspected sepsis group and healthy group are cross-matched. Plasma NGAL level in the suspected sepsis group was significantly higher compared with the corresponding values in the healthy participants’ group; on analysis of the suspected sepsis patients, there were 53 patients with AKI and 47 without. Plasma NGAL level was significantly higher in both subgroups (patients with AKI and patients without) than the healthy participants. This indicates that the cascade of sepsis by itself augment the production of plasma NGAL in critically ill patients even irrespective of the presence of AKI. Similar results were concluded by previous adult studies [14],[15].

In this study, it was observed that E-selectin, in the suspected sepsis group, was significantly higher than the healthy group; many studies have shown similar results [10],[16]. This supports the theory that E-selectin is one of the adhesion molecules that is produced from the recruitment of host leukocytes in response to infection in critically ill patients.

It was shown that CRP in the suspected sepsis group was significantly elevated compared with the healthy group; this is because the CRP level is increased in response to inflammation, infection, or body damage. This observation is in agreement with many previous studies which assessed CRP in sepsis [4],[5].

It was noticed that TLC in the suspected sepsis group was significantly more than the corresponding values in the group of healthy participants; similar findings were detected in neonatal sepsis [6]. In contrast, other authors reported that leukocyte count alone is insensitive and nonspecific and other stressful conditions as seizure or vomiting may cause leukocytosis [17].

In this study, only 51% of the suspected sepsis patients were culture-positive. This finding may be explained by many patients who may have received antibiotics before hospital admission, thus obscuring conventional cultures. Another possible explanation is that sepsis is caused by unusual organisms that are difficult to identify in routine practice. Similar findings were reported in a previous cohort study where culture-negative patients with suspected sepsis were 41.5% [18] and also Marik [17] reported that blood cultures were only positive in 20–30% of patients with sepsis.

When comparing culture-positive and culture-negative patients, most (76.47%) of the detected organisms in the culture-positive subgroup were due to infection with gram-negative organisms, whereas only 13.73% were due to gram-positive organisms. Similarly, Phua et al. [19] found that isolated gram-negative bacteria are more common than gram-positive bacteria [19]. In this study, none of the underlying causes of admission to the PICU was significantly associated with the culture-positive condition. However, respiratory tract infections were the most common and renal and urinary tract infections were the least common. Similarly, Phua et al. [19] noticed that the respiratory tract was a more common site of infection than the urinary tract. There were nonsignificant differences in clinical signs of infection between culture-positive and culture-negative patients; this is apart from bradycardia that was significantly more in the culture-positive group. This triggers us to say that the clinicians cannot predict the results of the culture from the severity of clinical signs of infection. Similar results are reported in a previous study conducted by Phua et al. [19].

In relation to patients’ mortality, neither the culture results nor the results of colonization significantly affect mortality. As the mortality did not differ between culture-positive and culture-negative patients, this may be due to rapid initiation of empiric antibiotic therapy once the patients were admitted to the PICU. This is in agreement with Denis et al. [20] but in contrast with Sakellariou et al. [21], where culture-positive patients who were colonized with extended-spectrum β-lactamase  Escherichia More Details coli had increased mortality.

On comparing patients with culture-positive and culture-negative, E-selectin was significantly higher in culture-positive than culture-negative patients. This may be explained by the fact that E-selectin is an early mediator of leukocyte–endothelial adhesion and is expressed on activated endothelium in response to inflammation and infection, thus shedding of E-selectin would reduce collateral damage in the host [16]. Higher E-selectin in culture-positive patients was observed in many previous studies [9],[10]. Also, CRP was significantly higher in culture-positive subgroup. CRP is an acute-phase protein produced in response to inflammation and release of interleukin-6. It reaches its peak concentration of between 36 and 50 h after infection has started. This may explain its high level in the culture-positive subgroup. Similar results were observed by Póvoa et al. [22] with significantly higher CRP in culture-proven infected patients versus noninfected cases.

Plasma NGAL level in the culture-positive group was higher than in the culture-negative group but with a statistically insignificant difference. This is in agreement with Zappitelli et al. [7], who studied a heterogeneous pediatric population (aged 1 month to 21 years) and found no difference in NGAL concentration in patients with culture-positive and with culture-negative subgroups. However, Parravicini et al. [8] found that the mean NGAL concentration was significantly higher in the culture-positive sepsis group than in the group with negative cultures even without a decrease in renal function [8]. This may be explained as NGAL is a protein that rises dramatically when epithelial organs undergo signaling, as a response to sepsis, which is usually associated with cell damage, including ischemia–reperfusion injury.

TLC in culture-positive patients is insignificantly higher than culture-negative patients; it may be due to that some culture-negative patients had SIRS, not due to infections or may be due to the infection with atypical organisms, not cultured by ordinary methods or nonmicrobiologically confirmed cases. In agreement with our results, Su et al. [23] found that absence of elevation of TLC or neutrophil count does not exclude sepsis, whereas a study conducted by Newman et al. [24] had a reverse opinion.

In this study, there was a significantly higher level of plasma NGAL in nonsurvivors. On plotting ROC curves of plasma NGAL level for the prediction of 30-day patients’mortality in children with suspected sepsis, AUC was 0.667 with a cutoff point of 250 ng/ml, indicating a poor discriminating power with a sensitivity of 65.5% and specificity of 63.4%. Numerous previous studies have documented the poor prognostic power of NGAL in suspected sepsis patients as in another Egyptian study conducted by Saleh et al. [25] in which120 critically ill children admitted to the PICU were explored for NGAL level at 2 fixed days per week. He found that NGAL had a fair predictive value for 30-day mortality in pediatric sepsis; the AUC was 0.74. Also, Parravicini et al. [8] stated that the sensitivity is 75% and specificity is 84%. Also, Zhang et al. [26] concluded from his study that plasma NGAL had poor predictive values for 90-day mortality in severe sepsis; the AUC was 0.71.

This study shows a significantly higher level of E-selectin in nonsurvivors. In addition, the ROC curve was plotted and AUC of E-selectin for prediction of 30-day patients’mortality was 0.841. E-selectin was the most sensitive biomarker for the prediction of mortality but the least specific when compared with NGAL, CRP, and TLC. Sensitivity was 82.8% and specificity was 62% using a cutoff value of 110 µg/ml. In contrast to our results, Edgar et al. [27] showed that serum E-selectin is a diagnostic biomarker for sepsis but not a predictor for mortality, whereas other authors found that E-selectin is a poor predictor of sepsis and mortality [16].In this study, significantly higher levels of CRP in nonsurvivors were noted. Furthermore, from the ROC curve, AUC of CRP for the prediction of 30-day patients’mortality is 0.762, the sensitivity of CRP was 72.4%, and specificity was 66.2%. Comparable results were reported by Sorsa [6], the sensitivity and specificity of CRP were 78.5 and 66%, respectively. Different kinds of literature reported a wide range of sensitivity and specificity of CRP in the prediction of mortality, ranging from 50 to 95% for sensitivity and 85–95% for specificity [22],[28]. These extreme variations of findings from different kinds of literature could be justified by the study inclusion criteria, clinical situations of the patients, time of sampling, and quality of latex reagent. On the reverse, Al-Subaie et al. [29] found that CRP did not predict patient death.

In the existing study, a significantly higher level of TLC in nonsurvivors was explored. AUC from the ROC curve that plotted TLC for the prediction of 30-day patients’ mortality in children with suspected sepsis was 0.690. The sensitivity and specificity were moderate 62.1 and 77%, respectively, with a cutoff value of 16×1000/ml. Similarly, Lawrence et al. [30] found that extreme leukocytosis (>25×109/l) was associated with prolonged hospitalization and higher mortality rate. In contrast, Suberviola et al. [31] showed no prognostic effect for TLC on patient mortality.

There were some observed limitations to this study; an important practical one is that the kits cannot be opened for just one patient admitted to the PICU, but samples should be frozen until the whole number of samples to be economically attained. This will limit the use of the test as an emergency one. Another limitation was that the study was conducted in a single-center PICU with a relatively small number of studied patients.


  Conclusion Top


The studied biomarkers of sepsis: NGAL, E-selectin, CRP, and TLC are significantly higher in patients with suspected sepsis than the healthy participants. E-selectin is a sensitive biomarker for 30-day patients’ mortality in suspected sepsis patients, with 82.8% sensitivity and 62% specificity using a cutoff value of 110 µg/ml, whereas NGAL is less sensitive (65.5%) with 63.4% specificity using a cutoff point of 250 ng/ml. E-selectin and CRP are higher in patients with blood culture-positive patients with sepsis, whereas NGAL did not significantly differ. Clinical signs of infection did not significantly differ with the blood culture results in children with suspected sepsis. Future researches that involve study of risk factors and complications of sepsis beside these laboratory biomarkers in multicenter PICUs on a larger number of patients should be encouraged to universally apply the results.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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