Abstract
Background
To assess the value of combined Monocyte Distribution Width (MDW) and Procalcitonin (PCT) detection in diagnosing and predicting neonatal sepsis outcomes.
Methods
This retrospective study, conducted from January 2022 to December 2023.A retrospective analysis of 39 neonatal sepsis and 30 non-infectious systemic inflammatory response syndrome (SIRS) cases was conducted. MDW, PCT, and CRP levels were compared. Relationships between variables were analyzed with Pearson correlation and Cox regression models; diagnostic performance was assessed using ROC curves.
Results
MDW, PCT, and CRP were significantly elevated in sepsis cases (p < 0.001). In non-survivors, MDW was higher and correlated with CRP, PCT, and SNAP scores. MDW was identified as an independent predictor of 28-day mortality. Optimal MDW, PCT, and CRP cut-offs (21.3, 1.23 ng/ml, 32.8 mg/L) achieved AUCs of 0.80, 0.84, and 0.60, respectively. Combined MDW/PCT detection achieved an AUC of 0.90 with 88.2% sensitivity and 88.7% specificity.
Conclusion
MDW, especially when combined with PCT, improves diagnostic accuracy for neonatal sepsis management.
Keywords: Monocyte distribution width, Procalcitonin, Neonates, Sepsis, Diagnostic
Introduction
Neonatal sepsis is among the most prevalent and severe infectious conditions affecting neonates, posing a high risk of mortality and long-term complications [1]. However, due to the immature immune systems of neonates, early symptoms are often nonspecific, which frequently complicates the diagnostic process and increases the likelihood of delayed or missed diagnoses. Traditional diagnostic methods for sepsis rely primarily on blood cultures and inflammatory markers such as procalcitonin (PCT). Nevertheless, blood cultures are time-consuming, often requiring over 48 h to yield results, and their sensitivity is influenced by multiple factors. Consequently, research into serum biomarkers has gained importance in improving the efficiency and accuracy of sepsis diagnostics.
In recent years, monocyte distribution width (MDW) has emerged as a novel inflammatory marker with considerable potential in sepsis diagnosis [2]. Studies have shown that monocyte volume changes in response to infection, which results in elevated MDW levels [3–6]. Notably, increased MDW has demonstrated high diagnostic sensitivity and specificity in distinguishing sepsis from localized infections and non-infectious systemic inflammatory response syndrome (SIRS). Furthermore, MDW testing is rapid, convenient, and does not require additional blood samples, which makes it especially suitable for critically ill patients.
Despite these advantages, research on the application of MDW specifically in neonatal sepsis is currently limited. Therefore, this study aimed to assess the diagnostic value of MDW in neonatal sepsis and to compare its effectiveness with traditional inflammatory markers such as PCT and CRP. We hypothesized that MDW, either alone or in combination with PCT, can improve the diagnostic and prognostic accuracy for neonatal sepsis. The findings are detailed in the following sections.
Methods
Study subjects
This retrospective analysis included 39 cases of neonatal sepsis diagnosed in the Neonatal Intensive Care Unit (NICU). A control group consisted of 30 cases of non-infectious systemic inflammatory response syndrome (SIRS) hospitalized during the same period. The data collection was conducted from January 2022 to December 2023 in Donghai Hospital Affiliated to Kangda College of Nanjing Medical University. Eligible participants were enrolled consecutively during the specified. Inclusion period criteria were as follows: (1) gestational age ≥ 35 weeks and birth weight ≥ 2.0 kg; (2) no antibiotic treatment prior to sample collection; (3) positive blood culture results. Sample size was estimated based on the expected AUC of MDW in diagnosing sepsis, aiming for 80% power at a significance level of 0.05.Exclusion criteria encompassed (1) congenital abnormalities, congenital metabolic diseases, perinatal asphyxia, neonates born to mothers with diabetes (We excluded infants of diabetic mothers because maternal diabetes can significantly affect the newborn's immune system, metabolic function, and the risk of sepsis.); (2) previous treatment with glucocorticoids or other immunosuppressants; (3) presence of other severe organic diseases; (4) history of surgical intervention; (5) 5-min Apgar score < 6; (6) incomplete clinical and laboratory data.(7) Cases with contaminated blood culture results were excluded. A total of 44 patients with sepsis were initially included. After excluding 2 cases with antibiotic treatment prior to sample collection, 1 case of a neonate born to a diabetic mother, and 2 cases with incomplete clinical and laboratory data, 39 cases were finally included in the study. The control group consisted of 30 neonates hospitalized during the same period who exhibited clinical symptoms of systemic inflammation but did not meet the diagnostic criteria for neonatal sepsis. These neonates were diagnosed with alternative conditions, including respiratory distress syndrome (RDS) (N = 15), transient tachypnea of the newborn (TTN) (N = 10), and other non-infectious inflammatory conditions (N = 5). Inclusion criteria for the control group were identical to those for the sepsis group, except for the absence of positive blood culture results or clinical signs indicative of sepsis. Data collection commenced at ICU admission, with a 28-day follow-up period for survival assessment. Based on outcomes, patients were divided into survival and non-survival groups, and their neonatal acute physiology scores (Score for Neonatal Acute Physiology, SNAP) were calculated. Clinical characteristics and routine examination results, including complete blood count (CBC) and measurements of C-reactive protein (CRP) and procalcitonin (PCT), were recorded for all patients.
Blood sample collection and analysis
Blood samples were collected in EDTA-anticoagulated vacuum tubes. Blood cell analysis occurred within 2 h of collection using the UniCel DxH900 hematology analyzer with corresponding reagents (Beckman Coulter). monocyte distribution width (MDW) was calculated using version 1.1.0 of the DxH 900 software. CRP levels were measured using the Mindray 7500 hematology analyzer with immunoturbidimetric reagents (Shenzhen Mindray), while PCT levels were analyzed on centrifuged serum (800 g) using the DXI800 chemiluminescence analyzer with PCT reagents (Beckman Coulter). Blood culture was used as the reference standard, and samples were collected under sterile conditions. No adverse events were reported during the performance of the tests, as all procedures adhered to standard clinical protocols.The cutoff values for MDW (21.3), PCT (1.23 ng/mL), and CRP (32.8 mg/L) were pre-determined based on prior studies and confirmed by ROC analysis in this study.
Statistical methods
Data analysis was conducted using SPSS 22.0 statistical software. Normally distributed data were expressed as mean ± standard deviation, while skewed data were presented as median (M) and interquartile range (IQR). Independent sample t-tests or Mann–Whitney U tests were employed for group comparisons. Pearson correlation analysis assessed the correlation between variables, and Cox proportional hazards regression analyzed the impact of multiple variables on survival time. Cases with missing values in MDW, PCT, or CRP measurements were excluded from the analysis. The diagnostic accuracy of MDW, PCT, and CRP was evaluated through receiver operating characteristic (ROC) curve analysis, with calculations for area under the curve (AUC), sensitivity, and specificity. While no pre-specified analyses of variability in diagnostic accuracy were conducted, exploratory analyses were performed to assess the robustness of the diagnostic metrics. Statistical significance was set at P < 0.05.
Ethical approval
This study was approved by the hospital's ethics committee (Ethics Approval No.: LJYY2022-01). Informed consent was obtained from the parents or guardians of each participant in accordance with ethical guidelines.
Results
Basic clinical characteristics of study subjects
The study comprised 69 neonates (45 males and 24 females). There were no significant differences in age, delivery method, or gender distribution between the groups. The average weight in the control group was 3.0 kg, compared to 2.81 kg in the sepsis group (P = 0.039). The sepsis group had a significantly longer average hospital stay (18.9 days) than the control group (10.3 days, P = 0.012). Additionally, WBC levels were significantly higher in the sepsis group compared to the control group (P < 0.01), whereas hemoglobin and platelet levels were significantly lower in the sepsis group (P < 0.01). Refer to Table 1 for details.
Table 1.
Basic clinical characteristics of study subjects
| Variable | Sepsis Group (n = 39) | Control Group (n = 30) |
P Value |
|---|---|---|---|
| Gestational age (weeks) | 36 (35.0, 37.0) | 36 (35.7, 37.0) | > 0.05 |
| Delivery method | |||
| Cesarean delivery | 23 (59.0%) | 16 (53.3%) | > 0.05 |
| Vaginal delivery | 16 (41.0%) | 14 (46.7%) | |
| Gender | |||
| Male | 27 (69.2%) | 18 (60.0%) | > 0.05 |
| Female | 12 (30.8%) | 12 (40.0%) | |
| Age (days) | 7.8 (2.4, 6.7) | 8.8 (2.1, 7.5) | > 0.05 |
| Weight (kg) | 2.72 ± 0.44 | 3.1 ± 0.24 | < 0.05 |
| Hospitalization days (days) | 18.9 ± 51.6 | 10.3 ± 3.2 | < 0.05 |
| Mortality | 13 (33.3%) | ||
| Complications | 1 (7.7%) | ||
| Hypoxic-ischemic encephalopathy | 1 (7.7%) | ||
| Pneumonia | 4 (30.8%) | ||
| Disseminated intravascular coagulation | 1 (7.7%) | ||
| Heart failure | 2 (15.4%) | ||
| Necrotizing enterocolitis | 4 (30.8%) | ||
| WBC (× 10.9/ml) | 16.0 ± 4.8 | 13.6 ± 2.6 | < 0.05 |
| Hemoglobin (g/L) | 129.8 ± 8.8 | 158.7 ± 9.5 | < 0.01 |
| Platelets (× 10^9/ml) | 192.6 ± 79.7 | 256.6 ± 60.1 | < 0.01 |
Comparison of laboratory indicators between sepsis and control groups
Laboratory findings indicated that MDW, PCT, and CRP levels were markedly elevated in the sepsis group relative to the control group, with P values < 0.01 for all comparisons. See Table 2 for further details.
Table 2.
Comparison of laboratory indicators between sepsis group and control group
| Variable | Sepsis group (n = 39) | Control group (n = 30) | t/u | P |
|---|---|---|---|---|
| MDW (mean ± SD) | 24.2 ± 2.6 | 18.8 ± 2.0 | 8.85 | < 0.001 |
|
PCT (ng/mL) M (IQR) |
3.65 (2.12, 12.5) |
1.12 (0.23, 2.43) |
89.0 | < 0.001 |
|
CRP (mg/L) M (IQR) |
65.3 (43.2, 109.8) |
33.35 (20.98, 32.5) |
124.5 | < 0.001 |
Correlation between MDW and CRP, PCT, and SNAP scores in neonates with sepsis
Figure 1 illustrates that MDW in neonates with sepsis was positively correlated with CRP, PCT, and SNAP scores, with correlation coefficients of r = 0.503 (P = 0.0122), r = 0.662 (P = 0.0004), and r = 0.787 (P < 0.0001), respectively.
Fig. 1.
ROC curves of MDW, PCT, and CRP in diagnosing sepsis
Diagnostic performance of MDW, PCT and CRP for sepsis
ROC curve analysis assessed the diagnostic performance of MDW, PCT, and CRP for sepsis (see Fig. 1 and Table 3). At optimal cut-off values of 21.3 for MDW, 1.23 ng/mL for PCT, and 32.8 mg/L for CRP, the AUC values were 0.80, 0.84, and 0.60, respectively. MDW demonstrated a sensitivity of 80.3% and specificity of 77.4% for sepsis diagnosis, whereas PCT and CRP had sensitivities of 78.3% and 56.6%, and specificities of 79.7% and 51.2%, respectively. When MDW was combined with PCT (MDW-PCT), the AUC reached 0.89, with sensitivity and specificity values of 88.2% and 88.7%, respectively. The positive predictive values for MDW-PCT, MDW, PCT, and CRP were 79.7%, 63.4%, 65.3%, and 50.3%, while negative predictive values were 80.0%, 70.1%, 72.9%, and 60.2%, respectively.
Table 3.
Performance analysis of MDW, PCT, and CRP in diagnosing sepsis
| Variable | AUC |
Sensitivity(%) 95%CI |
Specificity(%) 95%CI |
PPV(%) | NPV(%) |
|---|---|---|---|---|---|
| CRP | 0.60 |
56.6 0.374–0.705 |
51.2 0.472–0.698 |
50.3 | 60.2 |
| PCT | 0.84 |
78.3 0.591–0.872 |
79.7 0.635–0.891 |
65.3 | 72.9 |
| MDW | 0.80 |
80.3 0.601–0.901 |
77.4 0.635–0.907 |
63.4 | 70.1 |
| PCT-MDW | 0.90 |
88.2 0.693–0.962 |
88.7 0.696–0.941 |
79.7 | 80.0 |
Predictive value of MDW for mortality risk in neonatal sepsis
Cox regression analysis, adjusted for age, gender, and underlying diseases, identified MDW as an independent predictor of 28-day mortality in neonatal sepsis patients (HR = 3.02, 95% CI: 2.02–4.04, P < 0.001). This finding suggests that each 0.1 increase in MDW correlates with a 3.0-fold increase in mortality risk.
Comparison of MDW results between surviving and deceased neonates
Among the sepsis cases, 26 neonates survived while 13 did not. The MDW values were significantly higher in the non-surviving group (26.4 ± 1.0) compared to the surviving group (23.1 ± 2.5), as demonstrated by statistical analysis (t = 6.07, P < 0.01). The distribution of MDW results for the two groups of newborns is shown in Fig. 2.
Fig. 2.
Correlation of MDW with CRP, PCT, and SNAP scores in sepsis patients. A MDW vs. CRP, B MDW vs. PCT, C MDW vs. SNAP)
Discussion
Neonatal sepsis remains a significant cause of mortality and morbidity worldwide, particularly in low- and middle-income countries [7, 8]. Due to the non-specific presentation of infection, early diagnosis of neonatal sepsis is challenging [9–11]. Blood cultures, though widely used, have limited sensitivity and require prolonged processing, which delays diagnosis [10]. While molecular diagnostic techniques offer higher accuracy, their high costs and technical complexity restrict routine clinical application [12]. (Fig. 3).
Fig. 3.
Relationship between MDW and prognosis
Consequently, recent research has focused on identifying rapid, sensitive, and non-invasive markers for early sepsis diagnosis. Among these, CRP and PCT are commonly used but show limited effectiveness in neonates. CRP, an acute-phase protein, is influenced by non-septic factors, which reduces its reliability [13]. PCT, while specific for bacterial infection, lacks the sensitivity needed for early sepsis detection [14]. MDW has emerged as a promising marker that reflects infection and inflammation through changes in monocyte volume. Studies have shown that MDW is significantly elevated in sepsis and closely correlates with disease severity [2]. Crouser et al. found that MDW offers high sensitivity and specificity for early sepsis diagnosis in adults, performing better than traditional markers [15]. Similarly, Piva et al. demonstrated that MDW could be a valuable prognostic indicator in sepsis [16].
This study evaluated MDW's diagnostic value in neonatal sepsis, finding significantly higher MDW levels in septic neonates compared to controls, supporting its diagnostic potential. ROC curve analysis assessed MDW's performance alongside PCT and CRP. At optimal cut-off values of 21.3 for MDW, 1.23 ng/mL for PCT, and 32.8 mg/L for CRP, AUC values were 0.82, 0.85, and 0.64, respectively. Sensitivity and specificity for sepsis diagnosis were 80.3% and 77.4% for MDW, 78.3% and 79.7% for PCT, and 56.6% and 51.2% for CRP, respectively. These findings suggest that MDW, with similar sensitivity and specificity to PCT, outperformed CRP, underscoring its diagnostic value. Although CRP is widely used, its limited utility in sepsis diagnosis aligns with previous findings [17]. Furthermore, combining MDW with PCT improved diagnostic accuracy, achieving an AUC of 0.90 and sensitivity and specificity of 88.2% and 88.7%, indicating this combination as a promising early diagnostic tool.
This study also explored MDW as a prognostic marker by comparing levels between survivors and non-survivors. MDW was significantly higher in non-survivors (t = 6.07, P < 0.0001) and positively correlated with CRP, PCT, and SNAP scores, with coefficients of r = 0.503 (P = 0.0122), r = 0.662 (P = 0.0004), and r = 0.7865 (P < 0.0001), respectively. This strong correlation with SNAP scores suggests that elevated MDW levels are closely linked to disease severity in neonates, consistent with Crouser et al.’s findings [14]. Cox regression analysis identified MDW as an independent predictor of 28-day mortality in neonatal sepsis (HR = 3.02, 95% CI: 2.02–4.04, P < 0.001), with each 0.1 increase in MDW corresponding to a threefold rise in mortality risk.
To enhance study validity, neonates with systemic inflammatory response syndrome (SIRS) were selected as controls rather than healthy or locally infected neonates. Prior studies often use healthy neonates or those with localized infections as controls, which may not adequately reflect the pathophysiology of sepsis. In contrast, SIRS patients present with similar clinical and pathological features to sepsis, providing a more accurate basis for evaluating MDW, PCT, and CRP's diagnostic performance. This design minimizes confounding factors and strengthens the validity of the findings. Furthermore, MDW, as a routine hematologic parameter, is cost-effective and easily accessible in clinical practice without additional reagents.
Study limitations
This study has some limitations. The relatively small sample size, single-center nature, and retrospective design may limit the generalizability of the findings and introduce potential selection bias. Additionally, the use of a specific patient population (neonatal sepsis cases) may not fully reflect the broader clinical application of MDW and PCT. To address these limitations, future prospective studies with larger, multi-center cohorts are needed to validate the diagnostic and prognostic value of MDW and PCT in diverse clinical settings..
Conclusion
MDW shows promise as a biomarker for neonatal sepsis diagnosis. The combined detection of MDW and PCT enhances diagnostic sensitivity and specificity, offering a potentially valuable tool for early diagnosis. Furthermore, MDW may aid in assessing disease severity and prognosis, supporting its role in the clinical management of neonatal sepsis.
Acknowledgements
Not applicable.
Abbreviations
- MDW
Monocyte Distribution Width
- PCT
Procalcitonin
- CRP
C-Reactive Protein
- SIRS
Systemic Inflammatory Response Syndrome
- ROC
Receiver Operating Characteristic
- AUC
Area Under the Curve
- SNAP
Score for Neonatal Acute Physiology
- CBC
Complete Blood Count
- NICU
Neonatal Intensive Care Unit
- IQR
Interquartile Range
- EDTA
Ethylenediaminetetraacetic Acid
- HR
Hazard Ratio
- CI
Confidence Interval
- PPV
Positive Predictive Value
- NPV
Negative Predictive Value
- RDS
Respiratory Distress Syndrome
- TTN
Transient Tachypnea of the Newborn
Authors’ contributions
Approval of final manuscript: all authors. Jiaping Wang, Ming Hu, Huiyi Wu: Wang, Wang, Huang Conceptualization, Methodology, Software, data curation; Wang Writing-original draft preparation, Visualization,Investigation, Supervision, Wu:Validation. Wu, Li Writing-reviewing and Editing.
Funding
None.
Data availability
The data and materials used in this study are available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
This study follows the ethical principles of the Declaration of Helsinki and has been approved by the Ethics Committee of Donghai Hospital Affiliated to Kangda College of Nanjing Medical University (Approval No.: LJYY2022-01).All participants provided signed informed consent.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jiaping Wang and Ming Hu co-first authors.
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Data Availability Statement
The data and materials used in this study are available from the corresponding author upon reasonable request.