During the neonatal and pediatric periods, various diseases may threaten the individual life. These diseases may be congenital or have developed in the course of the person’s life, with an example being infectious diseases . As much as 26.5% of the global burden of disease and 25% of pediatric mortality in the world are related to the infections [2,3]. The infectious diseases lead to development of numerous complications including various psychological and physical disorders for the patient . One of these infectious diseases is sepsis. Sepsis is the systematic reaction of the body to invade microorganisms including bacteria and fungi, and is one of the diseases which can lead to hospitalization in ICU . Indeed, sepsis is a life-threatening associated disorder which occurs because of the irregular responses of the person to infection, and may cause septic shock for the patient, thereby confronting the patient with serious challenges and crises [6-8]. In this regard, WHO has currently considered sepsis as an important threat for patient safety and health as well as the global health regarding prevention, diagnosis, and treatment of this disease, and thus has special emphasis on them .
In the US, annually about 300 per 100,000 cases of sepsis occur causing high economic burden for the patients . Sepsis is very important in children and neonates, claiming 10% of mortalities related to children under five, which is highly notable . Various factors affect the development of sepsis as well as prognosis of these patients. One of these factors is the clinical status of children and neonates. Underlying diseases as well as low birth weight are among the risk factors affecting poor prognosis of this disease [12,13]. Quantification of statistics and reports regarding the prevalence and the capacity to prevent sepsis can provide the significant implications for planning on the reduction of this disease. Through identifying the causes, factors, and its reduction methods, the huge healthcare costs as well as complications can be prevented that occur for these patients [14,15].
Diagnosis of sepsis is made based on clinical symptoms and laboratory findings, in which the clinical symptoms may be specific or nonspecific. The laboratory variables can provide more suitable findings for the earliest possible diagnosis of the disease as well as the appropriate solutions for improving and treating patients [16-18]. In patients suspected to have sepsis, various tests are checked each of which can provide specific clinical findings to the healthcare specialist. One of these tests is D-Dimer. DD is one of the products resulting from degradation of fibrin in the body which can be measured in the blood. With the increase of the fibrin lysis process in coagulation disorders, its value increases in the blood causing aggravation of disease. The DD elevation has been observed in patients with local or systemic identified infections, and it is associated with more severe disease, and also the need to provide more healthcare services. Likewise, this laboratory test is used for diagnosing venous thromboembolism, diffusing intravascular coagulation, and for screening patients [19-21].
Identifying suitable methods for diagnosing and treating diseases is one of the tasks and priorities of healthcare specialists, where systematic review can provide them with proper evidence. Accordingly, the present study was performed with the aim of D-dimer for diagnosis of pediatric/neonatal sepsis via a systematic review method on papers which have examined sepsis in children and neonates.
Materials and methods
Database search strategy
This study is a systematic review paper performed with the aim of D-dimer for diagnosis of pediatric/neonatal sepsis worldwide. The researchers performed search across domestic databases of Iran (SID, MagIran, IranMedex, and IranDoc) as well as international databases (Google scholar, Cochrane, Embase, ScienceDirect, Scopus, PubMed, and Web of Science) with no time constraint. The search was performed using Persian and English keywords according to the MESH system.
Selection of studies
The researchers extracted all papers that had been published with the aim of examining pediatric and neonatal sepsis, and then they investigated them according to the inclusion and exclusion criteria, and finally included them. The availability of full text of papers, measurement of DD in pediatric and neonatal groups, Persian or English papers, and the statistical population age being in the pediatric and neonatal age group were considered as the inclusion criteria. On the other hand, case report, case series and meta-analyses, and the studies with unknown and repeated methodology, were excluded from the study. In this scrutiny, PICO criterion includes the following:
P: Pediatric/Neonatal diagnosis with sepsis;
I: Amount of DD in Pediatric/Neonatal diagnosis with sepsis;
C: Comparison of DD levels in healthy infants and children with sepsis;
O: Report on the Test value DD.
Paper selection and data extraction
In the first stage, all published papers were investigated, and then the papers which met the inclusion criteria were included. For data extraction, a checklist captured surname of the author, sample size, age range of patients, the country in which the research had been done, name of the place of hospitalization, mortality rate, age as well as the association of DD with clinical status of patients. The search was performed by two MSc students in nursing, and in case of any difference in the acquired results, the issue would be investigated by two pediatricians available in the research. Furthermore, all papers were introduced into EndNote software, and in the case of any similarity in them, the duplicate papers would be removed.
After the final conclusion and removal of repeated papers, the results were reported using data frequency distribution table.
In this study, in the initial search, 176 papers were found; after the initial and final screenings, the number reached 10 papers to be included in the SR stage. The total number of patients was 2075, for whom four studies had been conducted on neonatal age group and six on children’s age group. Besides, considering hospitalization in the ward, three studies had been done in NICU, 4 in PICU, and three studies in the pediatric ward. Moreover, mortality of patients arranged from 0.9% in the study by Zallocco et al.  in Italy to 52.7% in the study by Bay et al.  in Turkey. In all examined studies, it was observed that the patients with more severe clinical status or those who had died had higher levels of DD compared to other patients (Table 1). Figure 1 displays the flowchart of articles submitted to the SR stage.
Paying attention to the infectious patients, especially patients with a high prevalence, is one of the priorities of the medical staff . The early diagnosis of the disease is the first and the most vital step in patients’ management. Conducting tests is considered as the initial line of patient evaluation which provides complete information to the physicians [33,34]. For this reason, this study was performed as the primarily SR study on pediatric and neonatal age group suffering from sepsis worldwide.
Since no specific previous study had been done on the role of DD in sepsis diagnosis in pediatric and neonatal groups, the results of this study will be compared with other studies. According to the findings, DD level was significantly higher in patients with sepsis. In the meta-analysis by Yan et al., who examined the relationship between DD and joint infection, eight papers were analyzed in the patient group suffering from joint infection worldwide. According to the findings, DD can function as a suitable and practical method for joint infection especially in patients with no history of coagulation disorders . In another meta-analysis study, Li et al. analyzed seven papers on the patients suffering from joint infection worldwide. They demonstrated that DD had higher sensitivity compared to plasma D-dimer. It was also found that the sensitivity of serum DD in diagnosis of infection was higher than that of ESR and CRP tests . This is in line with the results of this SR study in which DD has been higher in patients with sepsis.
Another study performed on the role of DD in characterizing the clinical status of patients was SR study by Vidali et al., in which 16 papers published on COVID-19 patients had been included. They noted that DD status were evaluated in patients with COVID-19, and it was found that DD was higher in patients with COVID-19 and those with infection . In the study by Shah et al. exploring the relationship between extent of DD and morbidity and mortality rate, it was found that in patients with positive DD in contrast to negative DD, comorbidity and mortality were two and four times higher, respectively . In SR study by Varikasuvu et al., in which 13 papers had been included in the SR stage, it was observed that in patients with higher levels of DD, the risk of disease progression is higher . In the present SR study, again DD was higher in patients with more severe clinical condition, which is in line with the results of the previous study.
It is recommended to use drug therapy in order to improve the status of laboratory variables in patients. In the study of Balavandi et al., It was revealed that the status of laboratory variables in heart patients has improved with drug therapy . Likewise, in the study of Taheri et al., it was indicated that antibiotic therapy can improve sepsis in infants . For this reason, it is recommended that medical interventions be performed in the field.
Since this study has been performed for the first time worldwide and has novelty, it is indeed the strong point of this study. Besides, this study has been performed through systematic review method; however, the meta-analysis statistical analyses have not been performed in it, which is a limitation. As such, it is suggested to perform meta-analysis study on D-dimer for diagnosis of Pediatric/Neonatal sepsis.
In patients with more serious clinical status or those that had died, DD level was reported higher compared to other patients. It seems that DD level can be used as a factor for disease diagnosis and prognosis of patients.
Ilam University of Medical sciences, Ilam, Iran.
Jasem Mohamadi: https://orcid.org/0000-0001-8832-9617
Neda Khaledian: https://orcid.org/0000-0003-1019-1704
Mohamad Moradi: https://orcid.org/0000-0002-7850-2751
Behrouz Soltany: https://orcid.org/0000-0002-3015-4241
Milad Borji: https://orcid.org/0000-0002-8124-9398
Asma Tarjoman: https://orcid.org/0000-0002-5191-916X
How to cite this article: Jasem Mohamadi, Neda Khaledian, Atieh Okhli, Mohamad Moradi, Behrouz Soltany, Milad Borji, Asma Tarjoman. D-dimer as a diagnostic biomarker for pediatric/neonatal sepsis: A systematic review. Eurasian Chemical Communications, 2022, 4(10), 976-984. Link: http://www.echemcom.com/article_150303.html
Copyright © 2022 by SPC (Sami Publishing Company) + is an open access article distributed under the Creative Commons Attribution License(CC BY) license (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.