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ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 3  |  Page : 998-1003

Fibroblast growth factor-23 for diagnosis of neonatal sepsis


1 Department of Pediatric, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, National Liver Institute, Menoufia, Egypt
3 Department of Pediatric, El-Bagour General Hospital, Menoufia, Egypt

Date of Submission11-Jul-2020
Date of Decision06-Aug-2020
Date of Acceptance16-Aug-2020
Date of Web Publication18-Oct-2021

Correspondence Address:
Aliaa A Sharf El-Din
Menoufia University, Menoufia, Shbin Elkom
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_212_20

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  Abstract 


Objective
This study aimed to test whether clinical characteristics, laboratory parameters, and measurements of serum fibroblast growth factor-23 (sFGF23) can discriminate between babies with neonatal sepsis and normal babies.
Background
Neonatal sepsis is associated with severe morbidity and mortality in the neonatal period, especially in developing and underdeveloped countries.
Patients and methods
This was a prospective (case–control) study conducted between April 2018 and November 2018, at the Neonatal ICU, Menoufia University Hospital, Menoufia, Egypt. The study comprised 79 full-term neonates. The neonates were categorized in two groups based on International Pediatric Sepsis Consensus Conference and Biochemical Markers, including complete blood count, C-reactive protein, and blood culture: first, control group included 30 neonates with routine screening; and second, sepsis group comprised 49 neonates with clinical sepsis (32 with sepsis and 17 with severe sepsis) (clinical and laboratory signs of infection with or without positive blood culture). Receiver operating characteristic curves were used for the determination of thresholds for the infection group vs healthy neonate group.
Results
A total of 79 neonates were enrolled in this study. sFGF23 increased in order of infection severity, being higher in patients with clinical sepsis than healthy subjects. Sensitivity, specificity, positive predictive value, and negative predictive value for sFGF23 levels were 89.8, 76.67, 86.3, and 82%, respectively. sFGF23 (cutoff point for sFGF23 >21.68 pg/ml) (P < 0.001), and there was a positive correlation between sFGF23 level and severity of sepsis (r = 0.37, P = 0.004).
Conclusion
sFGF23 may be a valid and early diagnostic marker of neonatal infection. Moreover, sFGF23 is associated with severity of sepsis.

Keywords: blood culture, C-reactive protein, fibroblast growth factor-23, neonatal sepsis, severity of sepsis


How to cite this article:
Hassan FM, El Zayat RS, Diab KA, Sharf El-Din AA. Fibroblast growth factor-23 for diagnosis of neonatal sepsis. Menoufia Med J 2021;34:998-1003

How to cite this URL:
Hassan FM, El Zayat RS, Diab KA, Sharf El-Din AA. Fibroblast growth factor-23 for diagnosis of neonatal sepsis. Menoufia Med J [serial online] 2021 [cited 2024 Mar 28];34:998-1003. Available from: http://www.mmj.eg.net/text.asp?2021/34/3/998/328316




  Introduction Top


Neonatal sepsis is described as bacteremia within the first month of life followed by signs of systemic infection, which causes ~750 000 annual deaths worldwide [1].

Early diagnosis of neonatal bacterial infections is difficult, because clinical signs are nonspecific, variable, and may initially be subtle. Isolation of microorganism from blood, cerebrospinal fluid, and urine is the gold standard method to diagnose a neonatal sepsis, but microbiological culture is not available until at least 36–48 h [2]. So, accurate laboratory tests are required to rule out infection and reduce unnecessary antibiotic treatment [3].

In recent years, hematological and biochemical markers such as total leukocyte count, absolute neutrophil count, C-reactive protein (CRP), and various cytokines have been suggested as being useful indicators for early identification of septic neonates [4],[5], but CRP and procalcitonin have shown varied sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) [6], so, markers are needed to find truly and early infected neonates.

Systemic inflammation may affect serum fibroblast growth factor-23 (sFGF23) (circulating 26 kDa peptide formed by osteocytes) [7] production indirectly by alterations of regulators of sFGF23 (calcium, phosphate, and vitamin D metabolism), inflammation-induced excessive bone resorption, osteoclasts secretion of paracrine, paracrine release of matrix bound components, and/or local increase in phosphate and calcium, which contribute to sFGF23 elevation during inflammation [8],[9], and also associations between inflammatory markers and sFGF23 have been reported in many inflammatory diseases [10],[11].

This study aimed to measure and compare the sFGF23 level of septic neonates with those of weight-matched, age-matched, and sex-matched controls and to test its diagnostic value for sepsis in neonates.


  Patients and methods Top


This was a prospective (case–control) study conducted between April 2018 and November 2018, at the Neonatal NICU and Emergency Department in Menoufia University Hospital, Menoufia, Egypt. A total of 79 neonates were eligible for the study. We got parental informed consent for every patient and normal newborn before admission to the study. This study was done with approval of the Ethical Committee of Menoufia, Faculty of Medicine.

The reasons for the admission were suspicion of early or late infection or disturbances in neonatal period (mainly respiratory distress, hyperbilirubinemia, and failure to thrive). We categorized the neonates based on their clinical presentation, complete blood count, CRP, and blood culture Those who were diagnosed with sepsis or localized infection (pneumonia) of mild course created the sepsis group (N = 32). Other infected newborns, presenting with severe sepsis and/or septic shock, formed the severe sepsis group (N = 17). Newborns observed in the NICU and declared as non-infective cases (defined as having no clinical or laboratory signs of sepsis, which refer to clinic for screening tests or physiologic hyperbilirubinemia) constituted the control group (N = 30). Clinical evaluation of the study group is presented in the [Table 1].
Table 1: Comparison among the three studied groups according to demographic data

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Inclusion criteria were positive clinical signs of sepsis, which were defined as two or more of the following clinical signs: respiratory compromise (tachypnea, grunting, intercostal retractions, apnea, and need to ventilation), gastrointestinal compromise (feeding intolerance and abdominal distension), neurological changes (seizure and irritability), cardiovascular compromise (hypotension and cyanosis), and general signs (fever and lethargy). Sepsis was defined as Systemic inflammatory response syndrome (SIRS) and evidence of infection (positive microbiological culture and clinical symptoms). Severe sepsis was identified when the course of sepsis was complicated by dysfunction of two or more organs or systems. The septic neonates had laboratory evidence of infection: CRP greater than 10 mg/l, platelet count less than 150 000/cm3, and white blood cells greater than 12 000/cm3.

Exclusion criteria were history of congenital malformations, age over 28 days, preterm babies less than 37 weeks of gestation, and neonates with abnormal serum calcium or phosphate.

Blood culture, cerebrospinal fluid culture, urine culture, complete blood count with differential, platelet count, CRP, and sFGF23 were determined at the ask of the clinicians at first evaluation.

From each neonate (under aseptic condition venipuncture took), 1 ml of blood sample was taken for sFGF23, serum bilirubin measurement, or other routine tests. Plasma was separated by centrifugation and then stored in aliquots at −70°C until analysis. sFGF23 enzyme-linked immunosorbent assay kit was used to figure the serum level of sFGF23. All samples were run in duplicate. Plasma CRP concentrations were measured immunoturbidimetrically. Levels greater than 10 mg/dl were defined as abnormal.

Statistical analysis was done by using the SPSS V.21 program (Statistical Package for the Social Sciences; SPSS Inc., Chicago, Illinois, USA). Data were collected and statistically analyzed. A comparison of different variables in various groups was done using the Kruskal–Wallis test (nonparametric test) and analysis of variance test (parametric test). χ2-test was used to compare the frequency of qualitative variables among various groups. Fisher's exact test was used to compare two groups regarding one qualitative variable in a 2 × 2 contingency table when the expected count of the cells was less than 5. Mann–Whitney test (nonparametric test) and independent t test were also done. Correlation coefficient test (Person test) is a test of significance for correlation between two quantitative variables. For all tests, a probability P less than 0.05 was significant and P less than 0.001 was considered highly significant.

This work complies with the ethical standards of the Egyptian National Research Committee and with the Helsinki Declaration of 1964, as revised in 2013, and has been approved by the Ethical Committee of Menoufia, Faculty of Medicine. We obtained informed consent from the guardian of each neonate included in the study.


  Results Top


A total of 79 consecutively full-term neonates (37–41 weeks gestation) were included. Their birth weights ranged from 2.4 to 4 kg, and 41 (51.9%) of the neonates were boys. Overall, 32 neonates were diagnosed as having sepsis, whereas seventeen neonates as severe sepsis. Neonates in whom sepsis was ruled out were used as a control group. Sepsis was confirmed by blood culture in 11 (13.9%) of the neonates. Coagulase negative staphylococci was the most common organism isolated (5/11), followed by Klebsiella pneumoniae (3/11), Escherichia Coli (2/11), and Pseudomonas aeruginosa. Of the 79 neonates, 17 (21.5%) neonates died. Of these, four neonates were blood culture positive.

[Table 1] shows that the severe sepsis group had significantly lower platelet count and hemoglobin level than sepsis and control groups; in addition, the sepsis group had significantly higher white blood cells, alanine transaminase, and CRP than the control group.

The demographic, clinical, and laboratory data of the septic group and controls at the start of the observational period are shown in [Table 1], [Table 2], [Table 3].
Table 2: Comparison of biochemical marker between nonsurvivors and survivors

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Table 3: Correlation between serum FGF23 with laboratory data in the septic group

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In the nonsurvivor group (n = 17), duration of hospitalization, alanine transaminase, partial thromboplastin time, international normalized ratio, and CRP were significantly higher than in the survived ones (n = 62), and also, nonsurviving neonates had significant lower hemoglobin level and platelet number than survived ones [Table 2].

Our study showed that the mean level of sFGF23 was significantly higher in the septic group than in controls, with P value less than 0.001 [Table 4], and levels of sFGF23 were higher in neonates with severe sepsis than in neonates with sepsis and in controls [Table 1].
Table 4: Receiver operating characteristic curve for FGF23 and CRP to diagnose sepsis in studied neonates

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Moreover, we found a significant correlation between sFGF23 level and CRP (r = 0.511, P = 0.001) [Table 3].

The cutoff value of sFGF23 to detect sepsis was 21.68 pg/ml (area under the curve = 0.873) with a sensitivity of 89.80%, a specificity of 76.67%, a positive predictive value (PPV) of 86.3%, and a NPV of 82.1% [Figure 1].More importantly, sFGF23 level measured at the start of the observational period in nonsurviving neonates was 2.9 times higher than in surviving neonates (mean level: 76.77 vs 26.36 pg/dl, P < 0.001) [Table 2].
Figure 1: Receiver operating characteristic curve for fibroblast growth factor-23 diagnose sepsis in studied neonates.

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  Discussion Top


Exact and early diagnosis of neonatal sepsis remains challenging to the clinicians and the biochemists [12]. The management of suspected neonatal sepsis would be simplified if there was a single reliable marker of infection with results available soon after onset of signs and symptoms. A reliable prediction of the absence of infection would be most useful in the clinical setting as antibiotics could be prohibited in more infants than is in current practice [13]. We have found that sFGF23 concentrations were significantly higher in neonates who had sepsis than healthy neonates. sFGF23 concentrations in our neonates with sepsis (mean ± SD: 45.21 ± 43.99, range: 15.51–272.90 pg/dl) were higher than in healthy neonates (mean ± SD: 24.14 ± 30.69, range: 11.41–185.30 pg/dl). Moreover, sFGF23 was positively correlated with CRP levels (r = 0.511, P = 0.001) and white blood cells (r = 0.316, P = 0.005) and negatively correlated with platelet count (r=−0.510, P = 0.001). This is in agreement with Rousseau et al. [14], who reported a positive correlation between sFGF23 and CRP (r = 0.59 P = 0.0032). Moreover, this is in agreement with Dounousi et al. [10], who found that inflammation increases sFGF23 production. Receiver operating characteristic curve analysis suggested that the cutoff value of sFGF23 to detect sepsis is 21.68 pg/ml (area under the curve = 0.873), with a sensitivity of 89.80%, a specificity of 76.67%, PPV of 86.3%, and NPV of 82%. This is in agreement with Bai et al. [15], who found that sFGF23 level was significantly higher in patients with sepsis than controls (P = 0.032). Our results showed that the more severe the sepsis, the higher the level of sFGF23 measured. This is in agreement with Leaf et al. [16], who found a positive correlation between sFGF23 level and severity of sepsis (r = 0.35, P = 0.007).

In the present study, serum concentrations of sFGF23 in nonsurviving neonates were 2.9 times higher than in surviving neonates. Among neonates with sepsis, nonsurviving neonates [mean: 76.77 (, 95% confidence interval for mean: 44.28–109.25)] had higher levels than in survivors [mean: 26.36 (95% confidence interval: 20.66–32.05)] (P < 0.001)], which was a predictor of mortality [Table 3]. This is nearly in line with Fayed et al. [17], who found sFGF23 levels were significantly higher among patients with AKI who died than in the survivor group (mean level: 544.2 vs 59.3 pg/ml, P = 0.004). The findings suggest that sFGF23 level is related to severity of systemic inflammation. Inflammatory cytokines are direct regulators of sFGF23 production in cardiac fibroblasts [18] and osteoblasts [19],[20]. Here, in this study, CRP level correlated positively with sFGF23 concentration.

Chemokines and proinflammatory cytokines are essential for host defense against microbial infection [21], but excessive influx of activated leukocytes coupled with exaggerated production of potent proinflammatory mediators can contribute to deleterious consequences, leading to widespread small-vessel damage and multiorgan dysfunction [22]. sFGF23 inhibits synthesis of the antimicrobial molecule LL37 in peripheral blood monocytes as many monocytes in circulation will not have enough effect on killing microbes in the presence of high level of secreted sFGF23 [23]. Consistent with our findings, no other clinical studies have shown increased plasma levels of sFGF23 in neonatal sepsis. Larger clinical studies on infection risk with sFGF23 are not yet available. We need to discover markers for diagnosis of sepsis to reduce in a cost-effective manner unnecessary antibiotic therapy for nosocomial bacterial infections in newborn infants.


  Conclusion Top


The results show that in full-term neonates, peripheral blood sFGF23 can serve as promising markers of early diagnosis of sepsis. sFGF23 was significantly higher in neonates with sepsis than healthy neonates, before the blood culture being positive. Among the septic neonates group, nonsurviving neonates had significantly higher sFGF23 levels than surviving neonates.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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    Figures

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    Tables

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



 

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