|Year : 2020 | Volume
| Issue : 1 | Page : 32-37
Activin A is a novel biomarker in early screening of neonatal sepsis
Ahmed Saleeh1, Mohamed Fouad2, Badr-Eldin Mosbah1, Abdelmoneim Khashana1
1 Department of Pediatrics and Neonatology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
|Date of Submission||01-Aug-2019|
|Date of Decision||07-Oct-2019|
|Date of Acceptance||12-Oct-2019|
|Date of Web Publication||29-Jan-2020|
Dr. Abdelmoneim Khashana
Faculty of Medicine, Suez Canal University, 41111 Ring Road, Ismailia
Source of Support: None, Conflict of Interest: None
Introduction: Septicemia is the common cause of neonatal mortality in the world, with a higher incidence in the developing world. As timely diagnosis and effective management is the best method to reduce complications, it is vital to find new biomarker like Activin A, to reach the diagnosis as early as possible. Materials and Methods: The study type was Analytic cross-sectional comparative study performed on 55 neonates distributed into two groups; study group, 30 neonates with sepsis and control group: 25 healthy neonates. We measured the level of Activin A plus complete blood count, C-reactive protein, and blood culture in neonates who were diagnosed by clinical examination while we measured only serum Activin A in neonates who were completely healthy and came to follow-up at primary health center. Results: There was a significant difference in the level of Activin A between septic and healthy neonates (4.89±2.85 and 1.61± 0.92 pg/ ml, P < 0.05). The data were analyzed and show a lot a significant importance of Activin A as new biomarker for early diagnosis of sepsis as analysis of receiver operating characteristic curve of the optimal cutoff point of serum Activin A in diagnosis of sepsis among neonates which was ≥2.49 with 96.7% sensitivity and 86% specificity. Conclusion: We recommend using Activin A as a novel biomarker of diagnosis of neonatal sepsis and also use it to early detect infection especially at the first 2 days of life to start the treatment early.
Keywords: Activin A, marker, neonates, sepsis
|How to cite this article:|
Saleeh A, Fouad M, Mosbah BE, Khashana A. Activin A is a novel biomarker in early screening of neonatal sepsis. J Clin Neonatol 2020;9:32-7
|How to cite this URL:|
Saleeh A, Fouad M, Mosbah BE, Khashana A. Activin A is a novel biomarker in early screening of neonatal sepsis. J Clin Neonatol [serial online] 2020 [cited 2020 Apr 7];9:32-7. Available from: http://www.jcnonweb.com/text.asp?2020/9/1/32/277228
| Introduction|| |
The first 28 days of life is a very critical period and one of the most dangerous complications which may affect life is neonatal sepsis with a long-term morbidity and increased incidence of mortality; it is the third reason of neonatal mortality and a major neonatal period problem, especially if complicated with circulatory collapse.,,
Although we have some laboratory investigations like complete blood count (CBC), immature to total neutrophil ratio and C-reactive protein (CRP) to diagnose sepsis yet, they do not have the optimum sensitivity principally if evaluated in the early onset of the progression of sepsis. Hence, scientists are trying to find new markers to be used in the early detection of infants with bacterial sepsis have been a pinpointing challenge., Another challenge in the diagnosis of neonatal sepsis is that utilizing the conventional ways like blood, cerebrospinal fluid, or urine cultures, is normally reached after a lag of about 3 days and may be also restricted by false-negative results.
Throughout the pathogenesis of infections, there is a discharge of inflammatory mediators, like cytokines and chemokines that participate actively in the neonatal defense in opposition of the invading pathogens. Activin A is a pleiotropic cytokine belong to the converting of the growth factor-β1 superfamily and enact an essential part in the primary biological processes, like stem cell pluripotency, and also tissue repair.
Rising proof proposes that Activin A is similarly induced throughout inflammatory processes like calprotectin and particularly during infections.,, For instance, administration of bacterial endotoxin in vivo causes a rapid release of Activin A in the circulation within about half an hour. Activin A expression is detected at a former time point as assessed with that of tumor necrosis factor α and the release of interleukin (IL)-6. Moreover, Activin A levels are considerably augmented after in vitro stimulus with toll-like receptor ligands with bacteria and viruses or pro-inflammatory cytokines in a broad collection of cells, for instance, monocytes, dendritic cells, epithelial, lymphocytes, and endothelial cells. Activin A is notably amplified in the amniotic fluid in pregnant females with premature rupture of the membranes at birth.
The value of diagnosis of neonatal septicemia and finding a novel biomarker is to assist in discovering the occurrence of sepsis as soon as possible to begin the proper management to lower mortality and also long term morbidity. In the existing study we pointed to assess the sensitivity and accuracy of using Activin A as a biomarker for timely diagnosis of neonatal sepsis to start management early to reduce deaths from neonatal infection in that vulnerable group.
| Materials And Methods|| |
Type of the study
It was an analytic cross-sectional comparative study.
Setting of the study
The study was conducted in the neonatal intensive care unit (NICU) of Pediatric Department in Suez Canal University Hospital in Ismailia city, Egypt, from September 2017 to April 2018.
The studied population was distributed into two groups: study group, included neonates diagnosed with neonatal sepsis and control group, included full-term and preterm neonates without sepsis from a healthy mother having no antenatal or postnatal problems, had not received antibiotic treatment, with no history of prenatal asphyxia, no observed congenital anomalies, no postpartum disorders, and no suspicion of neonatal sepsis or infections.
Inclusion criteria of the study group
Preterm and full-term neonates with both sexes, diagnosed with neonatal sepsis based on clinical and laboratory results. We used clinical (temperature instability, respiratory rate >60 breaths/min plus grunting or desaturations, heart rate 180 beats/min or 100 beats/min, lethargy/altered mental status, glucose intolerance (plasma glucose >10 mmol/l) and feed intolerance) and laboratory criteria (thrombocytopenia, leukopenia, leukocytosis, CRP >10 mg/l or 2 standard deviation above normal value, immature neutrophils >10%, immature: total neutrophil ratio >0.2) plus positive blood cultures for diagnosis of neonatal sepsis.
We excluded neonates with central nervous system malformations, birth asphyxia, and intracranial hemorrhages from the study as the level of Activin A may increases in these cases.
The sample size was calculated grounded on the following equation:
n = is the sample size required in each group, σ = is the estimate of the standard deviation in the study group = 0.27,Zα/2 = 1.96 (the critical value that divides the central 95% of the Z distribution from the 5% in the tail),Zβ= 0.84 (the critical value that separates the lower 20% of the Z distribution from the upper 80%), μ1= mean in the sepsis group = 1.49,μ2= mean in the control group = 1.25. The required sample size was 20 participants in each group.
A conventional nonrandomized sampling of septic neonates admitted to the NICU of Suez canal university hospital and healthy neonates at primary healthcare centers Ismailia city, Egypt.
All neonates included in the study were subjected to the following: complete history including, complete clinical examination and laboratory investigations (CBC and serum CRP) while, blood cultures were done for all the neonates of the study according to clinical assessment, also Activin A was measured in all neonates involved in the study, both groups.
Measurement of serum Activin A procedure
Serum Activin A was measured using human Activin A ELISA kit (Glory Science Co., Ltd) 2400 Veterans Blvd. Suite 16-101, Del Rio, TX 78840, USA, according to the manufacture's instruction.
Gathered data were processed using SPSS version 22 (SPSS Inc., Chicago, IL, USA). Quantitative data were expressed as means ± standard deviation (SD) while qualitative data were expressed as numbers and percentages. Student's t-test was used to test the significance of difference for quantitative variables and Chi-square was used to test significance of difference for qualitative variables. Post hoc Tukey's test was also used and also receiver operating characteristic (ROC) curve was used to detect cutoff value of Activin A to diagnose neonatal sepsis. A probability value of P < 0.05 was considered as statistically significant.
An informed written consent was taken from all the participants before taking any data or doing any investigations and ethical committee approval was taken from faculty of medicine ethical committee, Suez Canal University, number 3214, date 10/9/2017.
| Results|| |
The study was done and 55 neonates were recruited in the sample population. They were classified into two groups; study Group (A) and control Group (B); there was no statistical significant difference (P >0.05) between the 2 groups regarding age, gender, maturity, weight and mode of delivery [Table 1].
The weight of the neonates was classified into three groups; neonates weighted from 1.5 kg to 2.5 kg were bigger than in sepsis and healthy group with 40% and 48%, respectively [Table 1].
In the sepsis group, the percentage of neonates who were delivered by normal vaginal delivery was (53.3%) in opposite the percent of cesarean section was 64% in healthy neonates [Table 1].
All the control group has negative culture, negative CRP and did not receive antimicrobial treatment, and these differences were statistically significant (P< 0.05) between the two groups. Concerning culture, 36.7% were Escherichia coli, 26.7% were Group B Streptococcus, and 36.6% were others. Most of the septic neonates, i.e., 63.3% had positive CRP and received antimicrobial treatment.
Activin A was higher among the septic neonates, and this difference was statistically significant between the two groups 4.89 ± 2.85 pg/ml in the study group while in the nonseptic group was 1.61 ± 0.92 pg/ml with (P< 0.05) [Table 2].
In addition, Activin A was higher significantly (P < 0.05) during the first 2 days of life than next days of life with mean ± SD, 6.99 ± 3.43 pg/ml.
The best cutoff value of 2.49 pg/ml was the optimum to diagnose sepsis with 96.7% sensitivity and 86% specificity, which means when Activin A level is ≥2.49 pg/ml; the case is likely to be septic was statistically significant (P ≤ 0.05).
Activin A was higher among 1–2 days of life than 3–5 days and 6–8 days; however, there was no statistical significant difference (P >0.05) between 3–5 days and 6–8 days. The level of serum Activin A, mean ± SD during first 2 days of life is 6.99 ± 3.43 pg/ml which is significantly high in comparison to two groups. Post hoc Tukey's test of Activin A level and age was run, it showed that statistical significant differences (P< 0.05) as follows: Activin A was higher among 1–2 days than 3–5 days and 6-8 days; however, there was no statistical significant difference (P > 0.05) between 3–5 days and 6–8 days [Table 3].
Activin A was higher among full term 6.31 ± 3.27 pg/ml while it was lower in preterm septic neonates, and these differences were statistically significant (P< 0.05) [Table 4].
|Table 4: Relation of Activin A level and maturity among the septic neonates|
Click here to view
There was no statistical significant relation between Activin A level and results of culture (P > 0.05) among septic neonates involved in the study. Activin A was higher among those who had negative CRP, and this difference was statistically significant (P< 0.05).
| Discussion|| |
Neonatal septicemia, hypoxia, and circulatory collapse are leading reasons of neonatal death. Neonates, especially premature infants, are more liable to infections than children at any other age phase as innate immunity is disturbed by impaired cytokines production, reduced response to chemotactic factors, and also lessened expression of adhesion molecules in neutrophils. In spite of the fact that clinical diagnosis of neonatal sepsis is problematic to be established, timely diagnosis and prompt management is the effective method to lessen neonatal deaths, most of conventional tests we used to practice in the diagnose of sepsis among neonates are not precise and unsatisfactory enough to make a decision to start treatment.
The findings of this study discover and declare Activin A as a novel biomarker that can help efficiently in quick diagnosis of neonatal sepsis. Although earlier studies have proved of the use Activin A throughout infections in animal models and in adults and also some studies have been done to show the role of Activin A in diagnosis hypoxic ischemia encephalopathy in neonates;, we do not have a clear previous study to use it in diagnosis of neonatal infection.
As described before, the present study shows that the mean level of Activin A was significantly higher among the septic neonates than healthy one and this difference was statistically significant (P < 0.05) between the two groups (4.89 ± 2.85) pg/ml in sepsis group while (1.61 ± 0.92) pg/ml in the healthy group. These findings are similar to those published by Florio et al. who described significant differences between healthy and asphyxiated neonates groups, another different study showed that peritoneal macrophages release activin A upon stimulation with toll-like receptor agonists.
Florio study findings which showed that cutoff value was 2.5 pg/ml for hypoxic ischemic encephalopathy, while the current study showed that the best cut-off value was 2.49 pg/ml to diagnose neonatal sepsis. In comparison, Activin A in early discover cutoff point of interventricular hemorrhage in Sannia et al.'s study was 0.08 ng/L. These results can be attributed to the nature and the role of Activin A as a significant modulator of cytoprotection and tissue repair; therefore, when the infection happens in new born infants, inflammatory course starts and tissue damage appears by inflammatory process and cells; Activin A is founded in septic neonates to play its role and begin tissue restoration.
The present study gives an evidence that the level of Activin A converts according to diverse factors, as this study presents that Activin A serum level was significantly higher (P = 0.04) among septic neonates in the initial 2 days than 3–5 days and 6–8 days which were 6.99 ± 3.43 pg/ml, 4.01 ± 2.21 pg/ml and 3.67 ± 1.41 pg/ml correspondingly. This finding resembles to Petrakou study which showed a significantly increased of Activin A in neonates with the first, 3rd and 5th days postinfection, as compared to those of healthy condition.
The result of the present study declared that Activin A serum level was significantly (P = 0.002) higher among full-term septic neonates comparing with preterm infants which was 6.31 ± 3.27 pg/ml and 3.27 ± 0.68 pg/ml respectively. Florio study showed the same significant difference (P < 0.05) in their study between preterm and full-term asphyxiated neonates.
This dissimilarity of Activin A expression in the serum of septic neonates could be elucidated by the stimulation of an endogenous protecting mechanism to organize inflammatory reactions noticed during initial days of neonatal sepsis. The release of Activin A from neonatal peripheral blood mononuclear cells is mediated according to level of inflammation and tissue injury and not associated with the type of the causative organisms.
In agreement with the current study, other studies have proved that Activin A is elevated in the circulation in the course of septicemia in adults and related to the severity of inflammation. Furthermore, Activin A is augmented in the cerebrospinal fluid in meningitis in animal models and also adults.
The results of the present study showed that the level of CRP was negative in all healthy neonates while it was positive in about 63% of studied septic neonates which reveal that CRP is not a precise marker of neonatal sepsis diagnosis particularly, it was notified that the sensitivity of CRP is known to be the lowest during the early phases of infection. Therefore, single CRP determination at the time of first sepsis evaluation is not the optimum and CRP should combine with another infection marker to get the best diagnostic tool of sepsis. The increase in Activin A expression at an early time point in septic neonates could be part of a negative feedback circuit directing to manage the earlier release of CRP and other pro-inflammatory mediators.
In the present study, the results shows that Activin A was higher among the septic neonates and analysis of ROC curve of the optimum cutoff point of serum Activin A in diagnosis of sepsis among neonates was ≥2.49 pg/ml with 96.7% sensitivity and 86% specificity. In comparison to using IL-6 for diagnosis of neonatal sepsis, Hu et al. revealed that high sensitivity and specificity of IL-6 for the diagnosis of neonatal sepsis were 0.79 and 0.83, respectively. This shows that Activin A is more precise as marker for sepsis in the initial days of neonates.
Comparing the role of Activin A and IL-8 in the diagnosis of neonatal sepsis, Zhao et al.'s study reveals that based on the ROC curve, once the cutoff value of serum IL-8 was 54 pg/mL, the sensitivity, specificity and accuracy of serum IL-6 for the detection of neonatal septicemia were 77.6%, 63.8%, and 67.2%, correspondingly. With the use of both serum IL-6 and IL-8 levels, the sensitivity, specificity, and accuracy were 71.4%, 86.2%, and 82.6%, correspondingly. This shows that Activin A in the present study is more precise in prompt diagnosis of neonatal sepsis.
Vouloumanou et al. evaluated the serum procalcitonin as a diagnostic indicator for neonatal sepsis in systematic review and meta-analysis which revealed the sensitivity and specificity were 81% and 79%, correspondingly. The area under the ROC curve was 0.87. The diagnostic accurateness of procalcitonin appeared higher for neonates with late onset septicemia than for those with early onset septicemia; this was approximately alike to what the present study shows about the rise of Activin A in the initial 2 days of septic neonates.
The present study suggests the significant of clinical implications for the usage of Activin A as a novel, sensitive biomarker and of more specifically in the early diagnosis of neonatal sepsis.
Further studies are required to establish the prognostic importance of Activin A in neonatal sepsis and to compare and assess the level of Activin A and other inflammatory marker to achieve the most appropriate criteria for neonatal sepsis diagnosis to begin management as soon as possible in favor of lessening mortality of sepsis in this vulnerable age group.
| Conclusion|| |
Activin A is a novel biomarker for diagnosis of neonatal sepsis and also use it to early detect infection.
I am deeply indebted to our patients who inspired us greatly to work in this research.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]