Prevalence and overlap of white blood cell counts, procalcitonin and C-reactive protein in neonates with invasive bacterial infections

Introduction

Neonatal invasive bacterial infections (IBIs), including septicemia and meningitis, are the third leading cause of neonatal mortality, accounting for 12.8% of global newborn deaths in 2010 (1). This issue has been of great concern in the World Health Organization (WHO), which has proposed Sustainable Development Goal for eliminating preventable deaths among neonates and children under 5 years of age by 2030, with a particular emphasis on combating infectious diseases (2). Identifying those at high risk of IBIs rapidly and accurately is one of the most essential strategies since a delayed diagnosis and treatment are closely associated with poor outcomes.

Unlike older children, neonates with serious bacterial infections are often afebrile and characterized by nonspecific symptoms such as lethargy, poor feeding, and cyanosis (3). Due to the atypical signs and the fact that gold-standard pathogenetic investigations are costly and time-consuming, the reliability of some clinical laboratory markers that can be applied to identify IBIs rapidly is being evaluated. The most common ones include white blood cell (WBC) count, procalcitonin (PCT) and C-reactive protein (CRP) (4-6). However, most studies conclude that a biomarker stand-alone test is unreliable (7,8). For example, the clinical utility of CRP alone in early-onset sepsis evaluations remains controversial (9,10). Thus, researchers are coming to recognize that combinations of multiple indicators may yield superior performance for the risk assessment of IBIs (11-13). Nevertheless, the majority of existing research is either on febrile infants or across a wide range of ages, which potentially limits their results from being applied to neonates (14,15). Moreover, on account of the immaturity of immune system and the stress of labor, the dynamic changes of WBC counts, PCT, and CRP in the early postnatal period have specific patterns. This may cause their normal levels to be different in this period from thereafter. Therefore, using this large multicenter cohort study of neonates with IBIs, we sought to provide further insight into the prevalence and overlaps of the three markers and evaluate their performance in clinical practice. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-97/rc).

Methods

Study design, setting, and population

This is a retrospective cohort study of full-term neonates with IBIs admitted to neonatal intensive care units (NICUs) of 17 tertiary hospitals in eight municipalities/provinces across China, spanning from January 2012 to December 2021 (16). Subjects met all the four inclusion criteria below were included: (I) presence of suspected infections, including unexplained fever, unresponsiveness, pallor, poor perfusion, apnea, grunting, lethargy, irritability or seizures; (II) undergoing bacterial cultures/metagenomic next-generation sequencing (mNGS) both in blood and cerebrospinal fluid (CSF) within 72 hours of admission; (III) gestational age ≥37 weeks; and (IV) onset within 28 days after birth. Meanwhile, we excluded critically ill neonates who required emergent interventions such as cardiopulmonary resuscitation or intubation, or with complicated chronic conditions, such as multiple congenital malformations, immunodeficiencies, and inborn errors of metabolism. We also excluded neonates who received antibiotics within 3 days before admission (for neonates >3 days) or 3 days before delivery (for neonates ≤3 days), or lacked information on the first complete blood cell (CBC) parameters, CRP or PCT testing after onset, or those who did not finish CBC, CRP and PCT test within 24 hours after admission.

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Medical Ethical Committees of Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (approval No. XHEC-C-2017-084), and informed consent was taken from the legal guardian of each enrolled patient for collection of data and publication of this study. All participating hospitals were informed and agreed the study.

Covariates

For each eligible neonate suspected with IBIs, we extracted the demographic characteristics, and maternal risk factors including prenatal fever, premature rupture of fetal membranes, and chorioamnionitis. WBC counts, CRP, and PCT levels within 24 hours of the initial visit were recorded, as well as bacteriological identification in the blood and/or CSF. The laboratory testing methods of all participating hospitals were standardized.

We defined leukocytosis as a total WBC >30,000 cells/µL within 3 days and ≥15,000 cells/µL beyond 3 days after birth (17,18), while leukopenia as a WBC count below 9,000 cells/µL and 5,000 cells/µL in these two periods (17,19). Considering the postnatal physiologic increase of serum PCT level in healthy neonates, it was suggested that PCT level >2.5 ng/mL before 3 days of life and ≥0.5 ng/mL thereafter were pathological abnormalities (20). Moreover, abnormal CRP level was evaluated at 10 mg/L or greater at any time after birth (21,22).

Outcome measures

The primary outcome measure of this study was IBIs among full-term neonates including bacteremia and bacterial meningitis, which was defined as the isolation of pathogenic bacteria in blood and/or CSF cultures or mNGS respectively (23). Early-onset IBIs occurred within the first 72 hours of life, whereas late-onset IBIs appeared thereafter (24).

Statistical analyses

The continuous measures were presented as mean and standard deviation (SD), and categorical variables were presented as counts and percentages. Variables between groups were compared using Student’s t-test, Chi-squared test or Fisher’s exact test, as appropriate. Joinpoint regression technique was used to identify the temporal changes of proportion for IBIs cases with abnormal indicators over the study period. The whole specific-time-interval regression trend is presented as the average annual percent change (AAPC) (25). Logistic regression models were conducted to evaluate the relationship of WBC, PCT and CRP levels to the IBIs risks. Subsequently, restricted cubic splines (RCS) were plotted to illustrate the dose-response relationship between these markers and risk of IBIs (26). Finally, we further investigated the prevalence of IBIs by combinations of different levels of WBC counts, PCT and CRP in early- and late-onset cases respectively. Statistical analyses were conducted using R version 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria) and Joinpoint Regression Program (Version 4.9.1.0, Calverton, Maryland). Plots were performed using Origin 2021 (Origin Lab Co., Northampton, MA, USA).

Results

Prevalence and overlap of infectious markers in neonatal IBIs

Of the 3,219 full-term neonates with suspected infections who underwent blood and CSF cultures/mNGS, 1,825 (56.7%) were eligible for inclusion in this analysis, including 634 with an onset at 3 days or less postnatally and 1,191 with an onset more than 3 days (Figure 1). Among them, mothers in the early-onset group were more likely to have a prenatal fever and premature rupture of fetal membranes lasting over 18 hours than those in the late-onset group (P<0.05). No significant difference was found in gestational age, birth weight, gender and delivery method between these two groups (P>0.05) (Tables S1,S2). Of the 435 neonates with IBIs, more than one-third had two abnormal inflammatory markers (37.9%), followed by 3 (29.2%) and 1 marker (17.0%). Elevated CRP was the most prevalent abnormal indicator (61.2%) in early-onset IBIs, and so was elevated PCT in late-onset IBIs (70.7%). The prevalence of normal WBC counts was significantly higher in early-onset IBIs than in late-onset IBIs (74.4% vs. 43.9%). Regarding causative pathogens, a total of 23 pathogens were involved in this study. The four most common pathogens were Escherichia coli (148, 34.0%), Group B Streptococcus (128, 29.4%), Enterococcus spp. (61, 14.0%), and Staphylococcus aureus (43, 9.9%), which are listed in Figure 1 and Table S3.

Figure 1 Flow diagram of study subjects. ^‡, the neonates who received antibiotics within 3 days before admission (for neonates >3 days) or 3 days before delivery (for neonates ≤3 days); ^†, the critically ill neonates who required emergent interventions such as cardiopulmonary resuscitation or intubation; ^§, the neonates with complicated chronic conditions, such as multiple congenital malformations, immunodeficiencies, or inborn errors of metabolism; ^||, including Salmonella species, Proteus species, Enterobacter cloacae, Enterobacter aerogenes, Enterobacter sakazakii, and Enterobacter asburiae; ^※, including Streptococcus hemolyticus, Streptococcus gallolyticus, Streptococcus constellatus, Streptococcus bradycosa, Streptococcus salivarius, Streptococcus pneumoniae, and Streptococcus bovis. CBC, complete blood cell; CRP, C-reactive protein; CSF, cerebrospinal fluid; IBIs, invasive bacterial infections; mNGS, metagenomic next generation sequencing; PCT, procalcitonin.

The constituent ratio of overlapping infectious markers in IBIs and non-IBIs groups is illustrated in Figure 2. Neonates with normal WBC counts (9,000–30,000) cells/µL, PCT >2.5 ng/mL, CRP ≥10 mg/L in early-onset IBIs, and those with elevated WBC counts (≥15,000 cells/µL), PCT ≥0.5 ng/mL, CRP ≥10 mg/L in late-onset IBIs accounted for the highest proportion at 28.1% and 26.1%, respectively. The corresponding proportions of these two combinations were, unexpectedly, also top two or top three among early- and late-onset non-IBIs cases at 17.5% and 10.5%, respectively. On the other hand, the proportion of neonates with all three markers in normal ranges was expectedly the top one in non-IBIs cases but not at the bottom in either early- or late-onset IBIs group, with the former (24.8%) twice as much as the latter (12.4%).

Figure 2 The prevalence for various overlaps of infectious markers in IBIs and non-IBIs cases. The list of various combinations represents the prevalence and overlap of infectious markers in neonatal early-onset (A) and late-onset (B) IBIs and non-IBIs. It is ranked according to the proportion of different combinations in each subgroup. The colors of bars denote different subgroups and lines connect the corresponding combinations between subgroups for statistical analysis. CRP, C-reactive protein; IBIs, invasive bacterial infections; PCT, procalcitonin; WBC, white blood cell.

Dose-response relationship between infectious markers and risk of IBIs

Upon reflection of the past decade, the proportions of leukocytosis/leukopenia, elevated PCT and CRP among neonates with early- or late-onset IBIs remained stable (Figure S1). Multivariate logistic regression analysis in Figure 3 reveals that, in the fully adjusted model 3, elevated PCT and CRP are closely associated with high risk of IBIs, either in early-onset [adjusted odds ratio (aOR) =2.0, 95% confidence interval (CI): 1.3–3.1; aOR =2.8, 95% CI: 1.8–4.4], or late-onset (aOR =5.0, 95% CI: 3.7–6.7; aOR =3.7, 95% CI: 2.8–4.9). For WBC counts, in contrast to late-onset (WBC <5,000 cells/µL, aOR =3.1, 95% CI: 2.0–5.0; WBC ≥15,000 cells/µL, aOR =2.2, 95% CI: 1.7–3.0), no association of leukopenia/leukocytosis was observed in early-onset IBIs (Table S4).

Figure 3 The associations between infectious markers and IBIs risk in neonates. The forest maps exhibit the associations between infectious indicators and IBIs risk in early-onset (A) and late-onset (B) cases. Model 1 is adjusted no covariates. Model 2 is adjusted for age of onset, gender, gestational age, birth weight and mode of delivery. Model 3 is adjusted for age of onset, gender, gestational age, birth weight, mode of delivery, maternal age, prenatal fever, premature rupture of fetal membranes, and chorioamnionitis. The reference variables are WBC of 9,000–30,000 cells/µL, PCT of ≤2.5 ng/mL and CRP of <10 mg/L in early-onset group, while WBC of 5,000–14,999 cells/µL, PCT of <0.5 ng/mL and CRP of <10 mg/L in late-onset group. *, P<0.05. CI, confidence interval; CRP, C-reactive protein; IBIs, invasive bacterial infections; OR, odds ratio; PCT, procalcitonin; WBC, white blood cell.

To further investigate the potential dose-response relationship between WBC counts, PCT, CRP and the risks of IBIs, we constructed RCS models (Figure 4). On the whole, the risks of IBIs rose as PCT and CRP increased (all P<0.001). Remarkably, in late-onset cases, there was a distinct flection point at a PCT of 10.59 ng/mL, before which the risk of IBIs rose rapidly [aORs from 0.86 (95% CI: 0.84–0.89) to 10.0 (95% CI: 6.7–15.0), with a PCT increase about 10 ng/mL], followed by a decelerated escalation [aORs from 10.2 (95% CI: 6.8–15.3) to 12.1 (95% CI: 6.7–21.8), with a PCT augment of more than 50 ng/mL]. Regarding WBC, the RCS showed a U-shaped association between WBC counts and risk of late-onset IBIs (P for overall <0.001). In this subgroup, an apparent negative correlation was observed when WBC counts were below 5,776 cells/µL, and a significant positive correlation after WBC counts reached 12,109 cells/µL. In neonates in the early-onset group, we observed a monotonic but not statistically significant decline in IBIs risk as WBC increased.

Figure 4 Restricted cubic spline plots of dose-response relationship between infectious markers and IBIs risk in neonates. The restricted cubic spline plots illustrate the associations between infectious markers and IBIs risk in early-onset (A-C) and late-onset (D-F) cases. Results are adjusted for age of onset, gender, gestational age, birth weight, mode of delivery, maternal age, prenatal fever, premature rupture of fetal membranes, and chorioamnionitis. Restricted cubic spline regression models are conducted with 5 knots at the 5th, 27.5th, 50th, 72.5th and 95th percentiles of WBC counts, and 3 knots at the 10th, 50th, and 90th percentiles of PCT and CRP levels, to assess the dose-response relationship between these markers and IBIs risk, respectively. Odds ratios are indicated by solid lines and 95% CIs by shaded areas. The OR value of 1 corresponds to a WBC of 8,491 cells/µL, PCT of 2.46 ng/mL, CRP of 9.74 mg/L in early-onset cases, and WBC of 5,776 cells/µL or 12,109 cells/µL, PCT of 0.54 ng/mL, CRP of 10.0 mg/L in late-onset cases. CI, confidence interval; CRP, C-reactive protein; IBIs, invasive bacterial infections; OR, odds ratio; PCT, procalcitonin; WBC, white blood cell.

Overlapping effects of infectious markers in the risk assessment for neonatal IBIs

Figure 5 presents the heat map illustrating the risks of IBIs across overlaps of different WBC counts, PCT and CRP levels. The reference population was those having all three markers within normal ranges. The highest overlapping risks of early- (aOR =23.6; 95% CI: 5.7–98.4) and late-onset IBIs (aOR =30.3, 95% CI: 12.7–72.3) were both in leukopenic neonates with increased PCT and CRP levels. Specifically, 65.0% (13/20) of neonates with WBC <9,000 cells/µL, PCT >2.5 ng/mL, and CRP ≥10 mg/L developed early-onset IBIs, whereas 74.4% (29/39) with WBC <5,000 cells/µL, PCT ≥0.5 ng/mL, and CRP ≥10 mg/L developed late-onset IBIs. The secondary risk profile involved leukopenia with elevated PCT but normal CRP levels (early-onset IBIs: aOR =3.1, 95% CI: 1.1–8.8; late-onset IBIs: aOR =11.6, 95% CI: 3.5–38.4). This included 33.3% (6/18) early-onset cases with WBC <9,000 cells/µL, PCT >2.5 ng/mL, and CRP <10 mg/L, and 53.8% (7/13) late-onset cases with WBC <5,000 cells/µL, PCT ≥0.5 ng/mL, and CRP <10 mg/L. While in early-onset neonates with leukocytosis, elevated CRP and PCT, either individually or simultaneously, did not increase the risk of IBIs. In contrast, in late-onset cases with leukocytosis, both CRP and PCT contributed to a higher risk of IBIs, alone or in combination (all P<0.05) (Table S5). In neonates with leukopenia, PCT seemed to play a more important role than CRP in predicting IBIs risk. Furthermore, we disclosed a significant interaction effect between leukopenia and elevated PCT, whatever types of IBIs and whether CRP was normal or not (Table S6).

Figure 5 The risk assessment of IBIs in neonates with different overlaps of infectious markers. The heat maps present the risks of early-onset (A) and late-onset (B) IBIs in individuals with various combinations of WBC, PCT and CRP levels. The darkness of color red reflects the degree of risk level for each combination. The reference populations are the neonates with WBC 9,000–30,000 cells/µL, PCT ≤2.5 ng/mL and CRP <10 mg/L in early-onset cases, and WBC 5,000–14,999 cells/µL, PCT <0.5 ng/mL and CRP <10 mg/L in late-onset cases. Results are adjusted for age of onset, gender, gestational age, birth weight, mode of delivery, maternal age, prenatal fever, premature rupture of fetal membranes, and chorioamnionitis. *, P<0.05. CRP, C-reactive protein; IBIs, invasive bacterial infections; PCT, procalcitonin; WBC, white blood cell.

Discussion

Our findings demonstrated that approximately two-thirds of neonates with IBIs had an overlap in abnormal leukocyte counts, PCT and CRP levels. In both early- and late-onset IBIs, elevated PCT and CRP were positively associated with higher risk of IBIs, whereas the association of abnormal WBC counts and IBIs was more significantly observed in late-onset cases. The combination of leukopenia, elevated PCT and CRP had the highest risks in both types of IBIs. A statistical interaction effect between leukopenia and elevated PCT was disclosed.

The screening role of PCT in late-onset IBIs has been well established (13). In our study, the increase of aOR values decelerated beyond a PCT threshold of 10.59 ng/mL. This was an important hint that a PCT level exceeding 10 ng/mL had signified an extremely high risk of IBIs already, thereby underscoring the imperative for clinicians to implement more aggressive and powerful anti-infective interventions. In early-onset cases, some scholars argued that the physiologic increase of PCT complicated the interpretation of results (27). However, our findings revealed a positive but relatively flat correlation between PCT levels and IBIs risk in early-onset cases, verifying its reference value for infections in early life. As for CRP, although it has been proven to be of little value in the diagnosis and management of sepsis among adults (28), an essential contribution of CRP was validated in neonatal severe infections. In addition, leukopenia may be more suggestive for severe infections compared to leukocytosis, e.g., leukopenia was proven to increase the odds of neonatal bacterial meningitis sevenfold and was associated with adverse outcome (29,30). Conversely, the sensitivity of leukocytosis in early-onset IBIs screening was comparatively low. Thus, the suspicion of IBIs cannot be based on leukocytosis alone within the first three days after birth.

For the combinations, we reconfirmed that leukopenia overlapping with elevated PCT was highly indicative of risks for both types of IBIs, underlining its significant position in neonatal IBIs screening. Especially in early-onset type, the warning significance of leukopenia was just observed in the presence of increased PCT levels. This phenomenon may reflect the overlap of distinct pathophysiological mechanisms in neonatal IBIs: PCT elevation signals systemic inflammatory activation, while leukopenia indicates either bone marrow suppression or peripheral leukocyte sequestration during severe infection. Their convergence may thus mark a critical transition phase in host response dynamics, potentially correlating with bacterial load or immune dysregulation severity. Importantly, the additional evidence of interaction effect between leukopenia and PCT further supported our suggestion that it was likewise not rigorous to assess IBIs risk based on a single parameter solely, either PCT or WBC counts. This has not been mentioned in other research studies. Furthermore, the inclusion of CRP was found to assist PCT in identifying IBIs in our study. The overlapped increase of these two markers was detected in 41.3% and 59.2% of the early- and late-onset IBIs respectively. Through the interaction analysis, we observed a significantly synergistic effect between PCT and CRP in early-onset cases with leukopenia, as well as in late-onset cases with normal WBC counts. This also confirmed the inherent advantage of using overlapped biomarkers for disease assessment from another perspective.

Notably, a certain proportion of IBIs presented with normal WBC counts, PCT and CRP levels, particularly in the early-onset group. As shown in our results, 14.0% (30/214) of neonates with normal WBC counts, CRP, and PCT levels within 3 days after birth still developed early-onset IBIs, while 10.3% (39/378) with normal parameters after 3 days developed late-onset IBIs. This may be owing to the fact that some neonates were evaluated during a short duration of onset, at which the kinetics of these biomarkers just exhibited slight fluctuations in the initial stage of infection (31). In other words, IBIs cannot be casually ruled out even if the laboratory tests are normal, underlining the necessity of continuously monitoring inflammatory indicators in clinical practice. In contrast, the all-normal combination constituted only about one-third of non-IBIs, probably because all cases included in the study were at a high risk of infections.

There are some limitations in this study. First, the settings in the present study were only neonatal intensive care units of tertiary hospitals, which had a large probability of receiving patients with severe infections from surrounding institutions, leading to a relatively high prevalence of IBIs in the present study and a potential restriction on extrapolating our inference to primary health facilities. Second, although our heat map effectively demonstrated the correlation between various overlaps of indicators and the risk of IBIs, we are unable to further stratify PCT and CRP levels because of the limitations in study population size. Consequently, we cannot depict a dose-response effect in the heat map. Lastly, we defined the patients who had positive cultures of several pathogens as contaminants, some organisms, e.g., coagulase-negative Staphylococci, may be true positive pathogens in the neonatal population.

Conclusions

We have profiled the various manners by which WBC counts, PCT, and CRP are realistically combined in clinical practice, and assessed their prevalence and overlaps correlations with risk of neonatal IBIs. The contribution of WBC counts, PCT, and CRP and combinations thereof were unequal in the risk assessment of early- and late-onset IBIs. This multi-marker approach provides new perspectives on rapidly and conveniently identifying neonates with high-risk of IBIs for further administration. It also enables frontline clinicians in primary care settings to prioritize prompt referral, thereby reducing mortality and adverse outcomes.

Acknowledgments

We thank all the research coordinators in this multicenter survey and the participants involved in data collection. They are from Xinhua Hospital, Children’s Hospital of Shanghai, Shanghai Children’s Medical Center, Children’s Hospital of Fudan University, Obstetrics & Gynecology Hospital of Fudan University, International Peace Maternity and Child Health Hospital, Children’s Hospital of Nanjing Medical University, Affiliated Women’s Hospital of Jiangnan University, Changzhou Maternal and Child Health Care Hospital, Affiliated Hospital of Jiangsu University, Affiliated Hospital of Yangzhou University, Jiaxing University Affiliated Women and Children Hospital, First Affiliated Hospital of Zhengzhou University, the Affiliated Hospital of Qingdao University, Dongguan Children’s Hospital Affiliated to Guangdong Medical University, the Affiliated Hospital of Southwest Medical University, and Shengjing Hospital of China Medical University. This work would not have been possible without their collaboration and support.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-97/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-97/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-97/prf

Funding: This study was supported by the National Key R&D Program of China (No. 2022YFC2705300) and the Collaborative Innovation Program of Shanghai Municipal Health Commission (No. 2020CXJQ01).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-97/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Medical Ethical Committees of Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (approval No. XHEC-C-2017-084), and informed consent was taken from the legal guardian of each enrolled patient. All participating hospitals were informed and agreed the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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