Case Control Study Open Access
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Pediatr. Jun 9, 2024; 13(2): 92392
Published online Jun 9, 2024. doi: 10.5409/wjcp.v13.i2.92392
Diagnostic significance of complete blood cell count and hemogram-derived markers for neonatal sepsis at Southwest Public Hospitals, Ethiopia
Dereje Abebe Regassa, Rahel Shumi Nagaash, Bisirat Fikadu Habtu, Department of Medical Laboratory Sciences, Wolkite University, Wolkite 11330, Ethiopia
Woyesa Beyene Haile, Department of Medical Laboratory Sciences, Dire Dawa University, Dire Dawa 3000, Ethiopia
ORCID number: Dereje Abebe Regassa (0009-0000-5673-8061).
Author contributions: Regassa DA contributed to the conceptualization and design of the study; Regassa DA, Nagaash RS, Habtu BF, and Haile WB have participated in data acquisition, analysis, interpretation, and drafted the manuscript; all authors have read and approved the final version of manuscript for submission.
Institutional review board statement: Before the study began, our study obtained the approved ethical clearance from the local Institutional Review Board of Research (Ref. No BEFO176981/2023, Oromia Health Bureau, Ethiopia).
Informed consent statement: Before the study began, we obtained consent from the local Institutional Review Board of Research (Ref. No BEFO176981/2023, Oromia Health Bureau, Ethiopia) and received ethical clearance from Tulu Bolo General Hospital and Waliso General Hospital administration offices, as well as the Pediatric Intensive Care Unit head offices. Once we obtained permission from the hospital administrator and the head of the pediatrician clinic care unit, we collected the data from record data. We ensured the confidentiality and privacy of the obtained information. Our study adhered to the principle of the Helsinki Declaration (64th WMA General Assembly). Individual patient consent was not required as all data used in this study was acquired retrospectively from the laboratory information system and medical records without any additional blood sampling.
Conflict-of-interest statement: This research did not receive any specific grant from any funding agencies and the authors declare no conflicts of interest for this study.
Data sharing statement: The datasets analyzed during the current study are available from the corresponding author upon reasonable request via address sifaanabebe@gmail.com.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Dereje Abebe Regassa, MSc, Lecturer, Department of Medical Laboratory Sciences, Wolkite University, Gubre, Wolkite 11330, Ethiopia. sifaanabebe@gmail.com
Received: January 24, 2024
Revised: February 11, 2024
Accepted: April 12, 2024
Published online: June 9, 2024
Processing time: 135 Days and 4.1 Hours

Abstract
BACKGROUND

Neonatal sepsis is defined as an infection-related condition characterized by signs and symptoms of bacteremia within the first month of life. It is the leading cause of mortality and morbidity among newborns. While several studies have been conducted in other parts of world to assess the usefulness of complete blood count parameters and hemogram-derived markers as early screening tools for neonatal sepsis, the associations between sepsis and its complications with these blood parameters are still being investigated in our setting and are not yet part of routine practice.

AIM

To evaluate the diagnostic significance of complete blood cell count hemogram-derived novel markers for neonatal sepsis among neonates attending public hospitals in the southwest region of Oromia, Ethiopia, through a case control study.

METHODS

A case control study was conducted from October 2021 to October 2023 Sociodemographic, clinical history, and laboratory test results data were collected using structured questionnaires. The collected data were entered into Epi-data 3.1 version and exported to SPSS-25 for analysis. Chi-square, independent sample t-test, and receiver operator characteristics curve of curve were used for analysis. A P-value of less than 0.05 was considered statistically significant.

RESULTS

In this study, significant increases were observed in the following values in the case group compared to the control group: In white blood cell (WBC) count, neutrophils, monocyte, mean platelet volume (MPV), neutrophils to lymphocyte ratio, monocyte to lymphocyte ratio (MLR), red blood cell width to platelet count ratio (RPR), red blood width coefficient variation, MPV to RPR, and platelet to lymphocyte ratio. Regarding MLR, a cut-off value of ≥ 0.26 was found, with a sensitivity of 68%, a specificity of 95%, a positive predictive value (PPV) of 93.2%, and a negative predictive value (NPV) of 74.8%. The area under the curve (AUC) was 0.828 (P < 0.001). For WBC, a cut-off value of ≥ 11.42 was identified, with a sensitivity of 55%, a specificity of 89%, a PPV of 83.3%, and a NPV of 66.4%. The AUC was 0.81 (P < 0.001). Neutrophils had a sensitivity of 67%, a specificity of 81%, a PPV of 77.9%, and a NPV of 71.1%. The AUC was 0.801, with a cut-off value of ≥ 6.76 (P = 0.001). These results indicate that they were excellent predictors of neonatal sepsis diagnosis.

CONCLUSION

The findings of our study suggest that certain hematological parameters and hemogram-derived markers may have a potential role in the diagnosis of neonatal sepsis.

Key Words: Complete blood count; Hemogram-derived marker; Neonate; Sepsis; Ethiopia

Core Tip: It is try to show the importance of complete blood cell count and hemogram-derived markers for the neonatal sepsis, which are simple and accessible relative culture especially in developing countries like Ethiopia.
INTRODUCTION

A clinical condition known as neonatal sepsis is defined by signs and symptoms of infection and the presence of bacteremia within the first month of life[1]. Neonatal sepsis is the leading cause of mortality and morbidity in newborns[1,2]. It is characterized by the body's systemic inflammatory response to infection. When this occurs within the first 28 d of life, it is referred to as "neonatal sepsis"[3]. Evaluating a baby for suspected infection in neonatal sepsis nurseries is a challenging clinical task[4]. There are two types of neonatal sepsis. Type 1 is known as early-onset sepsis (EOS), which occurs within 0-7 d. The risk factors for EOS include trans-placental, ascending, or intrapartum transmission during the perinatal period before or during birth, up to postnatal day 3[5,6].

Blood culture is the current gold standard for diagnosing newborn sepsis[7]. Prematurity problems, infection, postnatal fluid changes, late umbilical cord clamping, sampling sites, method of delivery, and sample collection timing are all typical factors that alter the neonate's hematological profile. This profile distortion may also be caused by hypothermia, hypoxia, and other prematurity-related issues[8]. Preeclampsia and intrauterine growth restriction, together with prolonged hypoxia, may increase the formation of reticulocytes while decreasing the number and total mass of megakaryocytes and blunting platelet function[9,10].

According to studies from Asia and Africa, around five million neonates die each year, with 1.6 million (20%) dying as a result of sepsis[11]. In wealthy countries, the prevalence of neonatal sepsis ranged from 1 to 5 per 1000 live births[12]. In developing countries, however, the incidence of newborn sepsis has increased from 1.8 to 18 per 1000 live births, with a death rate of 12-68 per 1000 live births[13]. Sepsis also leads to hospitalization and death. The global hospitalization rate for sepsis is predicted to be 19.4 million people, with 14.1 million only surviving hospitalization[14,15]. According to studies, neonate sepsis is a third-stage illness that causes neonatal mortality with a 1%-20% mortality rate after a premature delivery and neonatal encephalopathy (perinatal asphyxia and trauma)[16].

Current diagnostic approaches for neonatal sepsis are poor, resulting in an inability to lead clinical treatment on time, compromising its therapeutic impact. According to a report, the global newborn sepsis death rate ranged from 1.0%-5.0%[17]. According to a 2021 estimate, there were around 2797879 live births and 29608 sepsis cases in 14 middle-income nations. In the total time frame, the random-effects estimation for newborn sepsis incidence was 2824 cases per 100000 live births, with an estimated 17.6% dying[18]. In Ethiopia, the disease is still a major cause of morbidity and mortality[19,20]. The most prevalent diagnosis in the neonatal intensive care unit (NICU) is sepsis, and antibiotics are the most commonly utilized medications in the NICU. The prospects are bleak if antibiotic treatment is postponed until overt clinical symptoms appear. However, overuse of antibiotics can result in a variety of negative effects, including antibiotic resistance. Resistant infections are now responsible for three out of every ten newborn sepsis deaths[21].

Currently, one of the most difficult difficulties confronting clinicians is the early detection of neonatal sepsis[22-24]. If the diagnosis of neonatal sepsis is delayed and treatment is ineffective, it can lead to systemic problems and a high fatality risk. Although blood culture is considered the gold standard diagnostic technique for newborn sepsis, it has several limitations. These are inaccessible in the majority of impoverished nations, have technological issues, and take more than three days to see at least the first preliminary result, with a positivity yield of 30%-70%[25,26]. As a result, the left percent of neonates with sepsis could not be diagnosed by blood culture; the diagnosis of neonatal sepsis is based on clinical assessment, and management is also based on empirical treatment protocol, which usually results in unnecessary hospitalization, increased irrational use of antibiotics, and additional costs for the family[25,26]. Although platelet, lymphocyte, and neutrophil counts are analyzed in a single mode, they may serve as clinical markers of underlying infections such as sepsis and associated immune dysfunctions[27-29]. In recent years, the platelet to lymphocyte ratio (PLR), neutrophil to lymphocyte ratio (NLR), immature to total neutrophil ratio, and immature to mature neutrophil ratio have been identified as prospective markers of systemic inflammation and infectious illness prognosis[27-30].

Because newborns' defense barrier function and immune system development are still insufficient, and the condition of neonatal sepsis advances rapidly, early identification and accurate treatment are critical to lowering death. The NLR and PLR markers derived from blood analysis are now gaining attention in the study of inflammation-related disorders. Furthermore, some research suggests that the NLR and PLR, can be employed as prognostic indicators for cancer and cardiovascular disease[31,32]. Adult sepsis studies revealed that NLR might be employed as a biomarker for assessing systemic inflammation[33]. According to one study, PLR is a good measure for assessing patients' inflammatory response and disease activity[34].

Researchers and previous understandings show a progressive increase in newborn sepsis mortality, morbidity, and economic burden around the world, specifically in developing nations. Though not a replacement for blood culture, hematological parameters and hemogram-derived markers have been proposed as indicators of neonatal sepsis. Though several studies have been conducted to test the usefulness of hematological parameters and hemogram-derived novel markers in neonatal sepsis diagnosis, there is not yet used very commonly in routine practice and results vary extensively among studies. Even though assessment and use of the hemogram-derived markers have infinite considerations in the forecast of diagnosis of neonatal sepsis patients in a simple, rapid, and inexpensive manner. To the best of our knowledge, no published article is in our perspective. Therefore, the goal of this study was to assess complete blood count (CBC) parameters and hemogram-derived novel markers convenience for neonatal sepsis diagnosis among neonates admitted at the NICU of Southwest Shoa Public Hospitals, Ethiopia from October 2021 to October 2023.

MATERIALS AND METHODS
Study design, period, and area

A retrospective case control study was conducted at Southwest Shoa Public from October 2021 to October 2023. Tulu Bolo General Hospital and Waliso General Hospitals are the hospitals found in Oromia Regional State and are found in Southwest Shoa Zone central Ethiopia, 47 km apart, southwest of Addis Ababa.

From both hospitals, Waliso referral hospital is located in Woliso town which is the capital city of Southwest Shoa zone at 114 km in the direction of the Southwest from Addis Ababa. It has a latitude and longitude of 8 32′N 37 58′E with an elevation of 2063 m above sea level. Currently, this hospital serves around 1.1 million people by having many departments such as a clinic for patients with tuberculosis, an rapid antiretroviral therapy (ART) clinic, an adult outpatients department, NICU, under-five outpatient departments, antenatal care (ANC), postnatal care, etc.

Tulu Bolo General Hospital is located in Southwest Shoa 90 km from Addis Ababa. Tulu Bolo has a latitude and longitude of 8 40′N 38 13′E with an elevation of 2193 m or 7195 feet above sea level. Also offers chronic care, NICU, emergency services, ART services, surgical, dental, medical services, ophthalmology, pediatrics, gynecology and obstetrics, radiology, physiotherapy, pathology services, pharmacy and laboratory services, and others. Both hospitals are currently giving followup services for neonates that include ICU services, physical examinations, and laboratory services such as determination of CBC parameters, serological, and chemistry. This study obtained needed information in those hospitals' central laboratories providing hematology and immunohematology, parasitology, microbiology, clinical chemistry, and serology services.

Study population, inclusion, and exclusion criteria

The study population of this study consisted of neonates aged 0-28 d. The cases group who showed clinical signs and symptoms of sepsis upon admission to NICU, or who developed sepsis during their hospitalization within the same age interval. The control group consisted of neonates within the same age range who did not show any sign of sepsis. Both groups met the inclusion criteria during the study period. The case group was comprised of neonates aged 0-28 d who were diagnosed with sepsis based on the systematic inflammatory response syndrome (SIRS) criteria. These criteria included the occurrence of at least two of the following: A fever greater than 38 °C or less than 36 °C, a heart rate greater than 90 beats per minute, a respiratory rate greater than 20 breaths per minute, a partial pressure of CO2 less than 32 mmHg, a white blood cell (WBC) count greater than 12000 or less than 40000 per liter. Additionally, these neonates had stayed in the hospital’s ICU for more than 24 h.

The control group consisted of neonates aged 0-28 d who were seen in the out-patient and in-patient departments and did not meet the SIRS criteria in their medical records. These neonates had normal total leukocyte counts, and had not been diagnosed with any infectious disease.

Both the cases and control groups had CBCs taken up to 24 h before admission to the ICU, and this data was archived in the hospital’s database system. All sociodemographic and clinical data were recorded in the computerized system of the hospitals during the study period. To minimize the influence of confounding factors, neonates in both groups with a history of hematological disease, those receiving chemotherapy, glucocorticoids, or antibiotics were excluded.

Additionally, patients with inaccessible or incomplete file information, patients with genetic disease, metabolic disease, congenital heart disease, perinatal asphyxia, and neonates with congenital and chromosomal anomalies were also excluded.

Sample size and sampling technique

The figure shows the study participant sampling procedure and processes (Figure 1).

Figure 1
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Figure 1  Sampling techniques and procedures for neonates suspected with sepsis attending Southwest Shoa Public Hospitals Oromia, Ethiopia.
Data collection procedure

Patient information, including age, gender, clinical history, and vital signs (such as body temperature, heart rate, respiratory rate, and systolic and diastolic arterial pressure) was obtained from the medical record department of Southwest Public Hospitals. The cases consisted of patients who were diagnosed with sepsis based on clinical features and laboratory examination findings by a specialist doctor. The control group consisted of healthy neonates who underwent a general check-up, and had no diagnosis of infectious diseases, with normal leukocyte counts on laboratory examinations.

All hematological parameter values were obtained from archived data on a hematological analyzer. The values for NLR, monocyte to lymphocyte ratio (MLR), red blood cell (RBC) width to platelet count ratio (RPR), mean platelet volume (MPV) to platelet count ratio (MPVPCR), and PLR were calculated by the lymphocyte count, dividing the red blood distribution width by the platelet count, calculating the lymphocyte to monocyte count ratio (LMR), dividing the platelet count by the lymphocyte count, calculating the MPV to platelet count, and calculating the MLR count.

Data quality management

To ensure data quality, questionnaires in English were translated into the local language and then retranslated back into English to ensure accuracy and consistency. Two data collectors (two clinical nurses) received a half-day training session on study objectives, data collection procedures, and the importance of maintaining confidentiality to reduce technical and observation bias.

To ensure the quality of the socio-demographic and clinical data, daily checks were conducted by on-site supervisors to ensure completeness and consistency. Codes were used to protect the confidentiality of participants' test results, and all records were stored in a secure, and inaccessible location. Feedback and corrections were provided as necessary throughout the data collection process.

Statistical data analysis and interpretations

Collected data was checked for completeness and consistency, then entered into Epi-Data version 3.1 (Epi-Data Association, Denmark), and analyzed using Statistical Package for Social Sciences (SPSS) software version 25 (inclusion body myositis SPSS Statistics, United States). Histograms, Kolmogorov-Smirnov, and Shapiro tests were used to check the normality of the data distribution. Results for categorical variables were presented as frequency and percentage. Statistical differences for these variables were determined using the chi-square test.

Since continuous parameters followed a normal distribution in the goodness-of-fit model test, the independent sample t-test was used. Data was reported as mean ± standard deviation. Receiver operating characteristic (ROC) curves were constructed to determine the sensitivity, specificity, cut-off value, area under the curve (AUC), positive predictive value (PPV), and negative predictive value (NPV) of hematogram-derived markers in distinguishing neonates with sepsis from neonates without sepsis. A P-value < 0.05 was considered statistically significant.

RESULTS
Socio-demographic and clinical characteristics of the study participants

Sociodemographic and clinical characteristics data showed that there were no significant differences in age, sex, birth weight, ANC visit, history of diarrhea, respiratory distress, reddish orogastric tube, cardiovascular disturbances, hypoglycemia, abdominal distention, and place of delivery between neonates diagnosed with sepsis and those without sepsis (P > 0.05). However, there were significant differences in the two groups in terms of the residence of mothers, blood pressure, body temperature, gestational age, mode of delivery, history of jaundice, seizure, chorioamnionitis, neonatal reflex, premature membrane rupture, and prolonged premature rupture of membrane (P < 0.05) (Table 1).

Table 1 Socio-demographic and clinical characteristics of the study participants, n (%).
Variables
Categories
Suspected neonatal sepsis
Control group
P value
Age in days (mean ± SD)11.48 + 8.1511.36 + 8.580.834
SexMale206 (79.2)162 (77.1)0.585
Female54 (20.8)48 (22.9)
Residence of mothersUrban143 (55)95 (45.2)0.035
Rural117 (45)115 (54.8)
Birth weight in grams< 1500 grams27 (10.4)21 (10)0.979
1500-2500 grams109 (41.9)87 (41.4)
> 2500 grams124 (47.7)102 (48.6)
Blood pressure in mmHgSystolic137.57 + 10.86148.87 + 11.077< 0.001
Diastolic96.79 + 9.29105.94 + 7.672
Body temperature in 0CHypothermia29 (11.2)17 (8.1)< 0.001
Fever210 (80.8)112 (53.3)
Normal21 (8.1)80 (38.1)
ANC visit< 4 visit108 (41.5)82 (39)0.584
> 4 visit152 (58.5)128 (61)
Gestational age28-32 wk108 (41.5)0 (0)< 0.001
33-36 wk124 (47.7)61 (29)
37-41 wk28 (10.8)149 (71)
Delivery place Home38 (14.6)26 (12.4)0.483
Hospital/health facilities222 (85.4)184 (87.6)
Mode of delivery Spontaneous vaginal delivery8 (3.1)162 (77.1)< 0.001
Cesarean section146 (56.2)17 (8.1)
Forceps extraction106 (40.8)31 (14.8)
Respiratory distressNo104 (40)74 (35.2)0.29
Yes156 (60)136 (64.8)
Reddish orogastric tubeNo106 (40.8)74 (35.2)0.22
Yes154 (59.2)136 (64.8)
JaundiceNo99 (38.1)100 (47.6)0.037
Yes161 (61.9)110 (52.4)
SeizureNo107 (41.2)109 (51.9)0.02
Yes153 (58.8)101 (48.1)
DiarrheaNo101 (38.8)82 (39)0.96
Yes159 (61.2)128 (61)
Cardiovascular disturbancesNo100 (38.5)74 (35.2)0.472
Yes160 (61.5)136 (64.8)
Hypoglycemia Abdominal distentionNo103 (39.6)74 (35.2)0.33
Yes157 (60.4)136 (64.8)
ChorioamnoticNegative107 (41.2)176 (83.8)< 0.001
Positive153 (58.8)34 (16.2)
Premature rupture membraneNegative218 (83.8)192 (91.4)0.014
Positive42 (16.2)18 (8.6)
Duration of premature rupture membrane< 18h11 (26.2)13 (72.2)0.001
> 18h31 (73.8)5 (27.8)
Neonatal reflexIntact88 (33.8)148 (70.5)< 0.001
Depressed172 (66.2)62 (29.5)
Age at onset of sepsisEarly onset sepsis134 (51.5)-
Late-onset sepsis126 (48.5)-
Pulse rate100-145 b/m67 (25.8)101 (48.1)< 0.001
146-180 b/m193 (74.2)109 (51.9)
Data are expressed as frequency (percent), and mean ± SD. ANC: Antenatal care; SD: Standard deviation.

High blood pressure, high body temperature, a history of jaundice, seizures, chorioamnionitis, abnormal neonatal reflex, premature membrane rupture, and prolonged premature rupture of the membrane are clinical factors that may be induced in neonates due to sepsis. Some of these factors are directly linked to the alteration of CBC values and hemogram-derived markers, while others are indirectly linked to the alteration of CBC values and hemogram-derived markers.

Determination of hematological parameters and hemogram-derived novel markers among participants

Regarding the hematological parameters and novel markers derived from the hemogram, there is a significant increase in the values of RBC distribution width coefficient variation (RDWCV), total white cell count, neutrophils, MPV, NLR, MLR, RPR, MPVPCR, and PLR, in the case group compared to the control group (P < 0.05). Conversely, the values of RBC count, absolute lymphocyte count, and platelet count were significantly decreased in the case group compared to the control group (P < 0.05). However, the values of absolute eosinophil count and LMR did not show significant differences between the two groups (P > 0.05) (Table 2).

Table 2 Comparisons of complete blood count values and hemogram derive novel markers between neonates diagnosed with sepsis and neonates without sepsis.
Hematological parameters and hemogram-derived markers
Suspected neonatal sepsis
Control group
P value
RBC3.58 ± 0.84.46 ± 0.61< 0.001
RDWCV14.9 ± 2.613.27 ± 1.67< 0.001
WBC12.58 ± 3.758.35 ± 2.77< 0.001
NEUTR8.66 ± 3.055.2 ± 2.37< 0.001
LYMPH1.097 ± 0.642.23 ± 1.11< 0.001
MONO2.08 ± 1.590.29 ± 0.69< 0.001
EOS0.67 ± 0.380.6 ± 0.350.44
PLT189.78 ± 56.56244.7 ± 95.3< 0.001
MPV13.43 ± 5.310.35 ± 1.06< 0.001
NLR8.29 ± 18.023.96 ± 5.59< 0.001
PLR449.11 ± 996.92161.2 ± 165.4< 0.001
MLR6.14 ± 16.880.17 ± 0.57< 0.001
RPR0.085 ± 0.030.06 ± 0.02< 0.001
LMR10.59 ± 20.8453.9 ± 91.360.061
MPVPCR0.081 ± 0.050.05 ± 0.02< 0.001
Data are expressed as mean ± SD, P < 0.05 is significant. RBC: Red blood cell; RDWCV: RBC distribution width coefficient variation; WBC: White blood cell; NEUTR: Neutrophils; LYMPH: Lymphocyte; MONO: Monocyte; EOS: Eosinophils; PLT: Platelet count; MPV: Mean platelet volume; NLR: Neutrophils to lymphocyte ratio; PLR: Platelet to lymphocyte ratio; MLR: Monocyte to lymphocyte ratio; RPR: RBC width to platelet count ratio; LMR: Lymphocyte to monocyte count ratio; MPVPCR: MPV to platelet count ratio; SD: Standard deviation.

Determination of predictive values of hemogram-derived novel markers as indicators for neonate sepsis among neonates admitted at Southwest Shoa Public Hospitals, Oromia, Ethiopia, by ROC analysis.

An analysis was conducted to determine the efficacy of novel markers derived from the hemogram in predicting neonatal sepsis among neonates admitted to public hospitals in Southwest Shoa, Oromia Ethiopia. The results showed that a WBC cut-off value ≥ 11.42 had a sensitivity of 55%, specificity of 89%, PPV of 83.3%, NPV of 66.4%, and an AUC of 0.81 (P < 0.001). This indicates that WBC can differentiate between neonates suspected of having sepsis and control neonates.

Similarly, neutrophils can distinguish between neonates diagnosed with sepsis and neonates without sepsis with a sensitivity of 67%, specificity of 81%, PPV of 77.9%, NPV of 71.1%, and AUC of 0.801. The cutoff value for neutrophils is ≥ 6.76 (P = 0.001).

The MLR can also differentiate between neonates diagnosed with sepsis and neonates without sepsis. The cutoff value is ≥ 0.26 with a sensitivity of 68%, specificity of 95%, a PPV of 93.2%, NPV of 74.8%, and an AUC of 0.828 (P < 0.001).

Furthermore, the analysis revealed that the NLR can distinguish between neonates diagnosed with sepsis and those without sepsis. The cutoff value is ≥ 4.29, with a sensitivity of 57%, specificity of 80%, PPV of 74%, NPV of 65%, and AUC of 0.74 (P < 0.001). The PLR can differentiate between neonatal sepsis and non- neonatal sepsis at a cutoff value of ≥ 903.7, with a sensitivity of 90%, specificity of 100%, PPV of 100%, NPV of 90%, and an AUC of 0.69 (P < 0.001).

The RPR can distinguish between neonates diagnosed with sepsis and those without sepsis at a cut-off value of ≥ 0.051% with a sensitivity of 82%, specificity of 44%, PPV of 59.4%, NPV of 71%, and AUC of 0.586 at (P < 0.001). However, LMR was unable to differentiate between neonates diagnosed with sepsis and those without sepsis in our data from the ROC analysis (Table 3 and Figure 2).

Figure 2
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Figure 2 Predictive values of some complete blood count parameters and hemogram-derived markers for neonate sepsis. ROC: Receiver operating characteristic; RDWCV: Red blood cell distribution width coefficient variation.
Table 3 Determination of predictive values of some complete blood count values and hemogram-derived markers for neonate sepsis.
Hemogram derived markers
Sensitivity
Specificity
PPV
NPV
Cut-off value
AUC
95%CI
P value
WBC558983.366.4> 11.420.81(0.722-0.848)< 0.001
NEUTR678177.971.1> 6.760.801(0.763-0.84)< 0.001
MONO679593.174.2> 0.860.782(0.74-0.825)< 0.001
NLR57807465> 4.290.740(0.695-0.785)< 0.001
PLR9010010090> 903.70.69(0.642-0.737)< 0.001
MPVPCR479285.563.4> 0.1870.718(0.673-0.764)0.394
MLR689593.274.8> 0.260.828(0.791-0.865)< 0.001
RPR824459.471.0> 0.0510.586(0.534-0.638)0.001
LMR845364.176.8< 0.40.169(0.132-0.206)< 0.001
Data are expressed as percentage, frequency, P < 0.05 is considered as significant. PPV: Positive predictive value; NPV: Negative predictive value; AUC: Area under the curve; 95%Cl: At 95% confidence interval; WBC: White blood cell; NEUTR: Neutrophils; MONO: Monocyte; NLR: Neutrophils to lymphocyte ratio; PLR: Platelet to lymphocyte ratio; MPVPCR: Mean platelet volume to platelet count ratio; MLR: Monocyte to lymphocyte ratio; RPR: Red blood cell width to platelet count ratio; LMR: Lymphocyte to monocyte count ratio.
DISCUSSION

Early diagnosis and therapy are crucial in preventing morbidity and mortality caused by neonatal sepsis. However, there is no excellent biomarker available for accurately evaluated the sensitivity and specificity of diagnostic markers for neonatal sepsis including hematological parameters and hemogram-derived markers.

However, the results of these studies vary widely, the widespread attention given to the use of hemogram derived markers for predicting the diagnosis of neonatal sepsis in a simple, rapid, and inexpensive manner; to the best of our knowledge, no published article is in our perspective.

Current studies have shown that MPV is a marker of activated platelets and is associated with various inflammatory conditions such as diabetes mellitus, cardiovascular disease, peripheral artery disease, and cerebrovascular disease. Increased MPV levels are associated with a low degree of inflammatory status. The MPVPCR has been reported to be prognostic indicator of long-term mortality in several diseases, including ischemic cardiovascular diseases, sepsis, and nonalcoholic fatty liver disease. The RPR has been found to project the severity of liver fibrosis in nonalcoholic fatty liver disease[35]. According to this study, the values of RDWCV, WBC, absolute neutrophil count, and absolute monocyte count, MPV, NLR, MLR, RPR, PLR, and MPVPCR were significantly increased in the case group compared to the control group. Similar results were found in studies conducted in Turkey[28,36,37], China[34,38], Egypt[39-41], and Indonesia[33,42].

On the other hand, studies conducted in Indonesia[33], Turkey[28], Egypt[41], and China[38] found dissimilarities to our findings. This divergence may be attributed to various reasons, such as the treatment received before the CBC was conducted, the manner in which blood pressure was controlled, and the duration of acquired nephrotic syndrome in both current and previous study participants. Failure to control these risk factors may serve as sources for the rise of WBC, monocyte, neutrophil and their derivatives in nephrotic syndrome patients.

A low RBC count is a sign of sepsis, which can be caused by several mechanisms. These mechanisms include functional iron depletion, diminished erythropoietin production, infection, inflammation, RBC loss during sepsis due to pre-existing clinical conditions (such as cancer, liver disease, or renal impairment, as well as new-onset multi-organ dysfunction, especially of the liver and kidney). Disseminated intravascular coagulation (DIC), pathogen-associated hemolysis, hypo-adrenalism, and dietary insufficiency[43].

Similarly, several pathological mechanisms are thought to contribute to low platelet count such as DIC, which leads to the consumption of both platelets and coagulation factors. This paradoxically results in increased bleeding and clotting[44].

The body controls immune-mediated tissue damage by lymphocytes through apoptosis. As a result lymphocyte migration to the site of infection, lymphocytopenia is also observed in sepsis[28]. In line with this concept, our study found that, the values of RBC count, absolute lymphocyte count, and platelet count were significantly decreased in the case group compared to the control group. Consistent findings with our results have also been reported in studies conducted in China[34], Egypt[40,41], and Turkey[37,28].

On the other hand, studies conducted in Turkey[36], Indonesia[42], and Egypt[39] found an increased platelet count. This discrepancy may be due to the fact that in the previous studies the CBC conducted too late. Platelets are recognized as first-line indicators for detecting and responding pathogens, as well as for responding to injury signals in blood vessels and in the extracellular space. Information has revealed that during the initial stage of bacterial infection, there is a significant increase in the number of platelets in the bloodstream, which then deceased disproportionately[45].

Eosinopenia occurs during infection due to increased peripheral eosinophil sequestration, decreased eosinophil production, and eosinophil destruction. The increased release of corticotrophin-releasing hormone in response to inflammatory mediators such as interleukin 1 and 6, and tumor necrosis factor-alpha stimulates the pituitary gland to release adrenocorticotropic hormone, which in turn stimulates the synthesis and release of glucocorticoids that prevent the release of eosinophils from the bone marrow[46,47]. The current study states that the values of absolute eosinophil count; and LMR were not significantly different among the groups. Our study is consistent with the findings of studies conducted in Indonesia[42], Egypt[41], and Turkey[37].

Meanwhile, studies conducted in Turkey[36], and Egypt[39,40] have found that the LMR value is increased in the case group compared to the control group. This inconsistency may be due to the presence of confounding factors and differences in the lifestyle of the caregivers of the participants in the previous and current studies. Lifestyle dynamics could be an unmeasured confounding factor in this context, which could have various effects on multiple organs with cardiovascular and immune implication.

In the current study the ROC analysis showed that WBC, with a cut-off value ≥ 11.42 can differentiate neonates suspected with neonatal septicemia from the control neonates. The sensitivity was 55%, specificity was 89%, PPV was 83.3%, NPV was 66.4%, and the AUC was 0.81 (P < 0.001). Similar results have been reported in studies conducted in Egypt[42], China[48], United States[49,50], and Ethiopia[51].

In cases of severe neonatal infections, there is often an increase in the total leukocyte count. This increase may be due to the secretion of growth factors and cytokines that stimulate bone marrow production. However, virus-infected neonates typically have a normal or slightly reduced WBC count[27].

Also, absolute neutrophils were identified as predictors of neonatal sepsis, with a sensitivity of 67%, a specificity of 81%, a PPV of 77.9%, and a NPV of 71.1% with an AUC of 0.801. The cut-off value was determined to be ≥ 6.76 at significance level of P = 0.001. Similar findings were reported studies conducted in the Detroit, United States[49], Indonesia[52], California, United States[50], and Ethiopia[51].

Dynamic changes in neutrophils and lymphocytes occur during neonatal sepsis. These cells are mobilized from the bone marrow to the site of infection. The apoptosis process these cells is also affected. During sepsis, the lifespan of neutrophils increases due to decreased apoptosis, which is mediated by decreased levels of caspase3 level and activation of NF-kB. Neutrophils play a crucial role as the first-line of defense against invading microbes. They function through phagocytosis and are regulated by various factors at different stages[53].

Monocytes and lymphocytes are types of leukocyte cells that contribute to the immune system and are typically examined in a CBC. Lymphocytes play a role in the adaptive immune system. In the past, decreased lymphocyte counts, or lymphocytopenia, were used as indicators of bacteremia. In cases of sepsis and septic shock, lymphocytopenia can occur due to the migration and redistribution of lymphocyte into the lymphatic system, as well as increased lymphocyte apoptosis[54]. Monocytes, on the other hand, function as antigen-presenting cells and produce cytokines in response to infection. Infection stimulate the immune system, leading to an increase in monocytes and a decrease in lymphocytes[54,55].

As a result of this condition, the MLR is amplified. Therefore, at a cut-off value of ≥ 0.26 as identified as a potential indicators of neonatal septicemia, with a sensitivity of 68%, specificity of 95%, PPV of 93.1%, NPV of 74.8%, and an AUC of 0.828 (P < 0.001). Similar results were found in studies conducted in Indonesia[56] and United States[50].

Additionally, the ROC analysis demonstrated that the NLR can differentiate between neonates diagnosed with sepsis and those without sepsis. The cut-off value for NLR was found to be ≥ 4.29, with a sensitivity of 57%, a specificity of 80%, a PPV of 74%, and a NPV of 65%. The AUC was calculated to be 0.74, with a significance level of P < 0.001. Similar findings were reported in studies conducted in China[38,57], Egypt[39], Turkey[37,28], and California, United States[50].

Sepsis is a systemic inflammatory response disease triggered by infection, and inflammation plays a crucial role in its imitation and development. WBCs and their subpopulations are essential components of the immune system and provide defense against pathogen infections. Numerous clinical studies have shown that neutrophil counts, lymphocyte counts, and the NLR are predictive factors for sepsis. The NLR, in particular, is considered to be more reliable than absolute neutrophil or lymphocyte counts as it takes both into account. The NLR has gained significant attention due to its potential as a new risk factor for sepsis[58].

Studies have suggested that the renowned RPR is effective in human treatment for evaluating and predicting the degree of fibrosis and inflammation in several conditions, including hepatic cirrhosis, acute pancreatitis, severe burns, and acute kidney injury. It has been proposed that high RPR levels are associated with sepsis diagnosis and prognosis in adult and neonatal human patients. In all studies, non-survivors had higher RPR values than survivors. A recent study evaluated RPR as a tool to assist in diagnosing perinatal disease in neonatal thoroughbred foals. The study concluded that foals at risk of developing systemic disease had elevated RPR values[50]. The study identified a cut-off value of ≥ 0.051% with a sensitivity of 82%, specificity of 44%, PPV of 59.4%, NPV of 71% ,and an AUC of 0.586 (P < 0.001) as potential predictors of neonatal sepsis. Similar findings were reported in studies conducted in California, United States[50], and China[57].

The PLR was identified as a predictor of neonatal sepsis diagnosis with a cutoff value of 903.7, sensitivity of 90%, specificity of 100%, PPV of 100%, NPV of 90%, AUC of 0.69, and P < 0.001. Similar reports have been found in studies conducted in China[34,57], Egypt[39,40], Turkey[28,37], and Palembang[59]. Current research also indicates that platelets and lymphocytes play a critical role in the inflammatory progression. The PLR is serve as an indicators of the balance between inflammation and thrombosis. As a result, increased inflammation. Additionally, elevated platelet counts and decreased lymphocyte counts have been shown to be associated with both aggregation and inflammation, thus indicating a higher risk[60].

CONCLUSION

Our study findings suggest that certain hematological parameters and hemogram-derived marker values were significantly increased in the cases group compared to the control group. On the other hand, some hematological parameters were decreased in the cases group compared to the control group, while others showed no significant difference between the groups. Additionally, certain hematological parameters and hemogram derived markers were identified as potential indicators of neonatal sepsis.

ACKNOWLEDGEMENTS

We would like to express our gratitude to the staff members of Waliso General Hospital and Tulu Bolo General Hospital, as well as all the data collectors, study participants, and questionnaire interpreters for their invaluable support in conducting this study.

Footnotes

Provenance and peer review: Unsolicited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Pediatrics

Country/Territory of origin: Ethiopia

Peer-review report’s classification

Scientific Quality: Grade B, Grade C

Novelty: Grade B, Grade B

Creativity or Innovation: Grade B, Grade B

Scientific Significance: Grade B, Grade B

P-Reviewer: Liu C, China S-Editor: Luo ML L-Editor: A P-Editor: Guo X

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