Role of plasma D-dimer levels as diagnostic and prognostic marker in neonatal sepsis: An insightful support

Abstract

Neonatal sepsis remains a serious health problem with significant morbidity and mortality. Clinical diagnosis at presentation is often challenging due to nonspecific signs and symptoms. Laboratory biomarkers, blood cultures, and other diagnostic/prognostic tools such as the hematological scoring system developed by Rodwell and the neonatal organ failure assessment are not considered reliable for routine clinical use. Basiouny et al conducted a two-center prospective case-control study investigating the diagnostic and prognostic utility of D-dimer and heparin-binding protein in neonatal sepsis. Despite several limitations of their study, the present research provides novel insight into the role of plasma D-dimer levels in the diagnosis and prognosis of neonatal sepsis. While future multicenter studies with larger patient populations are required, these findings suggest the utility of D-dimer inclusion into sepsis multi-marker diagnostic models for newborns in order to complement rather than replace existing tools.

Key Words: D-dimer; Neonatal sepsis; Diagnosis; Prognosis; Assessment tool

Core Tip: Despite advances in neonatal care, sepsis remains a serious health problem with significant morbidity and mortality. Clinical diagnosis at presentation is often challenging due to nonspecific signs and symptoms. Laboratory biomarkers, blood cultures, and other diagnostic/prognostic tools are not considered reliable for routine clinical use. Basiouny et al conducted a two-center prospective case-control study investigating the diagnostic and prognostic utility of D-dimer and heparin-binding protein in neonatal sepsis. While future multicenter studies with larger patient populations are required, these findings indicate the utility of D-dimer inclusion in sepsis diagnostic models.

TO THE EDITOR

I read with great interest a recent study by Basiouny et al[1]. This study reported the superior diagnostic accuracy of D-dimer to C-reactive protein (CRP) and heparin-binding protein (HBP) in neonatal sepsis and the superior prognostic accuracy of D-dimer to the neonatal organ failure assessment (nSOFA) in outcome prediction.

Despite advances in neonatal care, sepsis remains a serious health problem and key contributor to neonatal morbidity and mortality, with an incidence of approximately 4000 newborns per 100000 live births[2,3]. Clinical diagnosis of neonatal sepsis is often challenging due to nonspecific signs and symptoms. Laboratory biomarkers, blood cultures, and other diagnostic/prognostic tools such as the hematological scoring system developed by Rodwell[4,5] and the nSOFA are not considered reliable for routine clinical use[6,7]. Novel laboratory tests to assist healthcare providers in the management of neonatal sepsis are therefore crucial.

D-DIMER

D-dimer is generated via the activity of the enzymes thrombin, activated factor XIII, and plasmin, leading to the degradation of crosslinked fibrin during fibrinolysis. The analysis of D-dimer is generally used as a diagnostic marker of deep vein thrombosis, pulmonary embolism, aortic dissection, and disseminated intravascular coagulation[8]. In recent years, D-dimer has been investigated as a diagnostic and prognostic marker of certain pediatric pathologies. Noteworthy, studies on D-dimer can be easily conducted due to the fact that it could be added to routine blood exams without any additional costs. A systematic review and meta-analysis by Huang et al[9] found that D-dimer levels were significantly higher in children with refractory Mycoplasma pneumoniae pneumonia than in the nonrefractory group. Moreover, peripheral blood D-dimer levels were found to be significantly higher in pediatric patients with Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis than in infectious mononucleosis patients[10]. Significantly elevated D-dimer levels were reported in patients with severe acute respiratory syndrome coronavirus 2 infections with severe outcomes[11-13] and an elevated D-dimer value appeared to be an independent risk factor for predicting poor outcomes in childhood influenza-associated encephalopathy[14]. D-dimer has also proven a reliable biomarker for predicting mortality in pediatric hematological-oncological patients with severe infections and poorer outcomes in children with Wilms tumor[15,16]. Notably, the diagnostic appropriateness of preoperative D-dimer levels for adnexal torsion in children and adolescents with the aim of reducing unnecessary surgery is under analysis at our institution, with promising results.

D-dimer, in combination with other laboratory markers, has demonstrated value in the diagnosis and prognosis assessment of pediatric sepsis[17,18]. Nonetheless, there is a lack in the literature of meta-analyses and systematic reviews evaluating D-dimer in pediatric and neonatal sepsis to date. Moreover, knowledge gaps in current evidence, such as the absence of standardized neonatal reference ranges or assay variability, limit the biomarker’s clinical translation. The present study employed a well-structured methodology and confirmed results described in the pediatric population, expanding the utility of D-dimer as a diagnostic and prognostic biomarker to neonates. Remarkably, Basiouny et al’s research[1] aligns with the study by Al-Biltagi et al[19] published in the World Journal of Critical Care Medicine in 2022 and Lungu et al[20] published in Cureus in 2024. The authors prospectively enrolled 90 neonates who met the inclusion criteria for sepsis from two different centers. They noted that D-dimer performed better than CRP and HBP in predicting sepsis [area under the curve (AUC): 99.5%, 84.5%, and 91.03%, respectively]. Moreover, D-dimer was significantly higher in nonsurvivors, outperforming nSOFA in predicting mortality (AUC: 97.8% vs 79.2%; P value < 0.0001 vs 0.02, respectively). They concluded that D-dimer demonstrated superior diagnostic accuracy to CRP and HBP and superior prognostic accuracy to nSOFA. However, the comparison between D-dimer and nSOFA requires caution. In fact, nSOFA integrates multiorgan dysfunction parameters, while D-dimer reflects a single biochemical axis. The strength of the research by Basiouny et al[1] is that it is one of the few prospective studies comparing HBP and D-dimer concurrently in neonatal sepsis. In terms of limitations, the study by Basiouny et al[1] did not take into consideration the biological and physiological variability of D-dimer levels in neonatal coagulation systems. In addition, further potential confounders that may influence D-dimer levels in neonates such as gestational age, mode of delivery, maternal conditions, or concurrent thrombosis were not investigated.

CONCLUSION

Future multicenter studies with larger patient populations are required; also, exploration of D-dimer kinetics during infection could be advisable. However, these findings suggest the utility of D-dimer inclusion in sepsis multi-marker diagnostic models for newborns in order to complement rather than replace existing tools.