Evaluation of systemic inflammatory indices in the diagnosis of early onset neonatal sepsis in very low birth weight infants

Abstract

BACKGROUND:

Previously, not six systemic inflammatory indices were evaluated in the diagnosis of early onset sepsis (EOS) in very low birth weight (VLBW, <1500g) premature infants.

OBJECTIVES:

We evaluated the effectiveness of systemic inflammatory indices in the diagnosis of EOS in VLBW infants.

METHODS:

Premature infants with birth weight <1500 g were included in the study. Six systemic inflammatory indices including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), pan-immune-inflammation value (PIV), and systemic inflammation response index (SIRI) were compared in patients with EOS (treatment group) and without EOS (control group).

RESULTS:

Of 917 infants enrolled, 204 infants were in the EOS group and 713 infants comprised the control group. NLR, MLR and SIRI values were significantly higher in the EOS group than in the control group (p < 0.001). The AUC value of SIRI for the predictivity of EOS was 0.803.

CONCLUSIONS:

The SIRI can be used together with other parameters as both an easily accessible and the reliable systemic inflammatory indices in the diagnosis of EOS in VLBW preterm infants.

Keywords

Early onset sepsis monocyte-to-lymphocyte ratio neutrophil-to-lymphocyte ratio systemic immune-inflammation index very low birth weight

1 Introduction

Sepsis is an important cause of morbidity and mortality for the very low birth weight infants (VLBW). Sepsis is an emergency for newborn infants [1]. The presence of a positive blood culture is defined as proven sepsis. In addition, clinical or suspected sepsis is recognized as an increase in inflammatory biomarkers with associated clinical symptoms despite negative blood culture [2]. Neonatal sepsis is divided into 2 categories correlating with timing of onset: early onset sepsis (EOS), occurring within the first 72 hours of life, and late onset sepsis (LOS), occurring after 72 hours of life. EOS can be transmitted ascendingly from the mother’s genital tract or through the transplacenta during the intrauterine period. The frequency and mortality of EOS increase inversely with the gestational week [3].

Early diagnosis and treatment of EOS can prevent the progression of systemic inflammatory response syndrome and prevents sepsis-related morbidity and mortality [2]. Maternal risk factors, as well as clinical and laboratory features are used in the diagnosis of EOS. Additionaly, clinical manifestations in neonatal EOS are nonspecific or unclear. Nonspecific clinical symptoms and lack of adequately accurate biomarkers in neonates may cause delay in diagnosis and initiation of treatment, prolonged hospitalizations, and increased antibiotic resistance secondary to misuse of antibiotics. Blood culture is the gold standard laboratory test in the diagnosis of EOS. This method has important limitations such as false negatives or low microorganism concentration due to maternal antibiotic use. In addition, blood culture requires 48 to 72 hours to result, and there is a risk of false positive results secondary to contamination [2]. Therefore, it is necessary to find an effective and reliable biomarker to diagnose EOS at an early stage. Many biomarkers, including acute phase reactants, interleukins, and immunoglobins are used in the diagnosis of EOS. Their specificity and sensitivity are not full sufficient because they are affected by factors other than sepsis and various peak concentration times in serum levels [2, 4].

During sepsis events, neutrophils, monocytes, lymphocytes, and platelets have critical roles in the inflammatory process. Therefore, it may be possible to diagnose sepsis and to predict mortality with systemic inflammatory indices obtained from these cells. These indices are both quickly accessible and cost-effective [2 , 5]. Few studies have evaluated the efficacy of neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII) and platelet-to-lymphocyte ratio (PLR) in the diagnosis of neonatal sepsis. Their results contradict each other, and the number of patients is small [2 , 5–9]. In addition to NLR, MLR, SIRI and PLR, the effectiveness of systemic inflammatory indices such as pan-immune-inflammation value (PIV) and systemic inflammation response index (SIRI) in the diagnosis of EOS in premature infants has not been evaluated before. Therefore, we aimed to evaluate the effectiveness of six systemic inflammatory indices in the diagnosis of EOS in premature infants with very low birth weight (VLBW, <1500 g).

2 Methods

2.1 Study design

VLBW infants, who were born and hospitalized in our tertiary neonatal intensive care unit between March 2018 and June 2021, were included in the study. The data of the patients were evaluated retrospectively and obtained from hospital records. Premature infants with birth weight (BW) <1500 g were included in the study. Premature infants with major congenital anomalies and BW ≥1500 g were excluded from the study. Major congenital anomalies were assumed as abnormalities that have medical, surgical, or cosmetic significance. Ethical approval was obtained from the local ethics committee before the study. The study was conducted in accordance with the principles of the Declaration of Helsinki.

2.2 Demographical features and clinical outcomes

Gestational age (GA), BW, antenatal steroid administration, gender, delivery route, premature rupture of membrane (PROM), chorioamnionitis, EOS and hemogram parameters of all patients were recorded.

2.3 Definition of early onset sepsis

EOS was defined as neonatal sepsis within <72 hours of life. Proven neonatal sepsis was defined as the presence of a positive blood culture with clinical signs of sepsis (apnea, cyanosis, body temperature changes, cutis marmaratus, respiratory distress, diarrhea or decreased bowel movements, abdominal distention, low and high blood sugar, reduced movements, reduced sucking, seizures, hypotension, slow or fast heart rate). Suspected neonatal sepsis was defined as negative blood culture when clinical signs and positive laboratory tests were present (leukopenia/leukocytosis, thrombocytopenia, high C-reactive protein (CRP), and high interleukin-6 (IL-6) level) [10, 11].

2.4 Laboratory analysis

All sepsis workup (CRP, IL-6, complete blood count analysis) were performed in newborns within 1 hour postnatally [6]. After birth, blood samples were taken into ethylenediaminetetraacetic acid tubes for complete blood count. Complete blood count was performed with Cell-Dyn 3700 automatic hemocytometer (Abbott, Abbott Park, IL, USA). Positive blood culture was defined by using the automatic blood culture detection system in the microbiology laboratory by inoculating blood samples in BACTEC FX (Becton Dickinson, Becton Dickinson, Sparks, Sparks, MD, USA) culture medium. The obtained blood samples were centrifuged at 3000 rpm for 10 minutes at room temperature and serum samples were separated. CRP and IL-6 levels from serum samples were studied. Serum CRP levels were measured with Roche Modular P analyzer (CRP latex HS, Roche kit, Roche Diagnostics, GmbH, Mannheim, German) and high sensitivity turbidimetric immunoassay method. Levels of IL-6 were analyzed by the IL-6 solidphase, enzyme-labeled, chemiluminescent sequential immunometric assay on the IMMULITE 1,000 analyzer (Siemens Diagnostic Product Corporation, Los Angeles, CA).

2.5 Systemic inflammatory indices evaluation

Leukocyte count (10³μ#x03BC;/L), platelet (P) count (10³μ#x03BC;/L), neutrophil (N) count (10³μ#x03BC;/L), monocyte (M) count (10³μ#x03BC;/L), and lymphocyte (L) count (10³μ#x03BC;/L) values were obtained from complete blood count and recorded. Systemic inflammatory indexes were calculated using following formulas, including NLR = N/L, PLR = P/L, MLR = M/L, SII = P × N/L, SIRI = N × M/L and PIV = P × N × M/L. Since all inflammatory indices are calculated as ratios, they do not have a unit [12].

Premature infants with proven and suspected sepsis were included in the EOS group, and all other premature infants without proven or suspected sepsis were included in the control group. The possibility of bacteria growth in blood culture, which is still taken in proper manner, may be small because of maternal usage of antibiotics during pregnancy, which diminishes the possibility of bacteria growth in blood culture of neonates with EOS. Because of this, we enrolled the newborns with suspected sepsis into EOS. Patients in the control and EOS groups were compared in terms of demographic features, clinical outcomes, laboratory and systemic inflammatory indices.

2.6 Statistical analysis

All data were evaluated with Statistical Package for Social Sciences (SPSS), version 20.0 (SPSS Inc, Chicago, IL, USA) analysis program. The conformity of the data to the normal distribution was evaluated with histogram and Kolmogorov-Smirnov/Shapiro-Wilk Test. Fisher’s Exact test or Pearson Chi-Square test was used for analysis of categorical data, and t test or Mann-Whitney U test was used for continuous data analysis. Normally distributed continuous data were presented as mean±standard deviation (SD); non-normally distributed data were presented as median and interquartile range (IQR), and the results of categorical data were presented as frequency. Receiver operating characteristics (ROC) curves analysis was used to determine the significance level of statistically significant variables. After performing the ROC analysis, the area under the curve (AUC) and the 95% confidence interval (CI), threshold values, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) levels of the AUC were found. A p value of <0.05 was considered significant.

3 Results

A total of 917 VLBW patients were included in the study during the study period. 204 patients were included in the EOS group and 713 patients in the control group. The frequency of EOS in VLBW patients was 22.2% (204/917). The mean GA of all patients included in the study was 28.1±1.2 weeks and the mean BW was 1061±232 g. GA (27.6±1.1 weeks) and BW (1035±222 g) in the EOS group were similar to GA (28.0±1.2 weeks) and BW (1068±238 g) in the control group (p = 0.070 and p = 0.083, respectively). The frequency of PROM (45.1%) and chorioamnionitis (24%) in the EOS group was statistically significantly higher than the frequency of PROM (20.7%) and chorioamnionitis (11.2%) in the control group (p < 0.001 and p < 0.001, respectively). The results were similar in terms of the frequency of antenatal steroid, gender and cesarean section in the EOS and control groups (p = 0.374, p = 0.378, and p = 0.639, respectively). The results were summarized in Table 1.

Table 1
Demographic characteristics and clinical outcomes in early onset sepsis and control groups

Characteristics EOS (n = 204) Control (n = 713) P value

Gestational age,^a 27.6±1.1 28.0±1.2 0.070

Birth weight, g^a 1035±222 1068±238 0.083

Antenatal steroid, n (%) 141 (69.1) 497 (69.7) 0.374

Male gender, n (%) 115 (56.3) 377 (52.8) 0.378

Cesarean section, n (%) 173 (84.8) 595 (83.4) 0.639

PROM, n (%) 92 (45.1) 148 (20.7) <0.001^*

Chorioamnionitis, n (%) 49 (24) 80 (11.2) <0.001^*

Characteristics	EOS (n = 204)	Control (n = 713)	P value
Gestational age,^a	27.6±1.1	28.0±1.2	0.070
Birth weight, g^a	1035±222	1068±238	0.083
Antenatal steroid, n (%)	141 (69.1)	497 (69.7)	0.374
Male gender, n (%)	115 (56.3)	377 (52.8)	0.378
Cesarean section, n (%)	173 (84.8)	595 (83.4)	0.639
PROM, n (%)	92 (45.1)	148 (20.7)	<0.001^*
Chorioamnionitis, n (%)	49 (24)	80 (11.2)	<0.001^*

^aMean±standard deviation. ^*P < 0.05 was considered statically significant. EOS, early onset sepsis; PROM, premature rupture of membrane.

The leukocyte, neutrophil and monocyte count levels in the EOS group were significantly higher than the control group, and the lymphocyte count was significantly lower in the EOS group compared to the control group (p = 0.003, p = 0.003, p = 0.001, and p = 0.003, respectively). In terms of platelet count, the results were similar between the EOS and control groups (p = 0.100). NLR, MLR and SIRI were statistically significantly higher in the EOS group than in the control group (p < 0.001, p < 0.001, and p < 0.001, respectively) (Fig. 1A, B, F). PLR, PIV, and SII results were statistically similar between the EOS and control groups (p = 0.719, p = 0.060, and p = 0.549, respectively) (Fig. 1C, D, E). CRP and IL-6 levels were statistically significantly higher in the EOS group than in the control group (p < 0.001 and p < 0.001, respectively). Statistical analyzes of laboratory results are presented in Table 2.

Fig. 1

Box plot of systemic inflammatory indices based on early onset sepsis.

Table 2

Systemic inflammatory indices in early onset sepsis

Parameters	EOS (n = 204)	Control (n = 713)	P value
Leukocyte count (10³μ#x03BC;/L)^a	13.100 (11.400)	11.000 (8.100)	0.003^*
Platelet count (10³μ#x03BC;/L)^a	210.500 (115.000)	223.000 (98.500)	0.100
Neutrophil count (10³μ#x03BC;/L)^a	2.400 (3.183)	2.321 (2.871)	0.003^*
Monocyte count (10³μ#x03BC;/L)^a	0.720 (0.788)	0.640 (0.558)	0.001^*
Lymphocyte count (10³μ#x03BC;/L)^a	7.112 (5.555)	8.176 (7.233)	0.003^*
NLR^a	0.051 (0.183)	0.034 (0.051)	<0.001^*
MLR^a	0.012 (0.016)	0.009 (0.010)	<0.001^*
PLR^a	3.171 (2.462)	3.411 (2.243)	0.719
PIV^a	41.576 (42.275)	49.226 (39.537)	0.060
SII^a	72.126 (72.442)	78.470 (76.789)	0.549
SIRI^a	0.452 (1.735)	0.208 (0.336)	<0.001^*
CRP, (mg/L)^a	1.140 (2.360)	1.030 (1.360)	<0.001^*
IL-6, (pg/ml)^a	227.950 (1431.920)	37.900 (86.680)	<0.001^*

^aMedian (interquartile range). ^*P < 0.05 was considered statically significant. CRP, C-reactive protein; EOS, early onset sepsis; IL-6, interleukin 6; MLR, monocyte to lymphocyte ratio; NLR, neutrophil to lymphocyte ratio; PIV, pan immune inflammation value; PLR, platelet to lymphocyte ratio; SII, systemic immune inflammation index; SIRI, systemic inflammation response index.

ROC analysis was performed to examine the predictivity value of NLR, MLR, SIRI, CRP and IL-6 in EOS. NLR had an AUC of 0.616 and cutoff level >0.0981 for EOS predictivity, MLR had an AUC of 0.599 and a cutoff level of >0.0127 for EOS predictivity, SIRI had an AUC of 0.803 and a cutoff level >0.591 for EOS predictivity. The AUC value of CRP for the predictivity of EOS was 0.574 and the cutoff level was >3.03 mg/L, the AUC value of IL-6 for the predictivity of EOS was 0.709 and the cutoff level was >120.3 pg/ml (p value for all: 0.0001) (Table 3 and Fig. 2).

Table 3

Receiver operating curve analysis of neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio and systemic inflammation response index

Parameters	AUC	95% Confidence interval	Cutoff level	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	P value
NLR	0.616	0.583–0.647	>0.0981	59	84	40	83	0.0001^*
MLR	0.599	0.567–0.631	>0.0127	54	67	32	83	0.0001^*
SIRI	0.803	0.772–0.834	>0.591	62	89	46	86	0.0001^*
CRP, (mg/L)	0.574	0.541–0.606	>3.03	27	88	40	81	0.0001^*
IL-6, (pg/ml)	0.709	0.678–0.738	>120.3	60	89	48	88	0.0001^*

^*P < 0.05 was considered statically significant. AUC, area under curve; PPV, positive predictive value; NPV, negative predictive value; NLR, neutrophil to lymphocyte ratio; MLR, monocyte to lymphocyte ratio, SIRI, and systemic inflammation response index; CRP, C-reactive protein; IL-6, interleukin 6.

Fig. 2

Receiver operating characteristic curves for NLR, MLR and SIRI.

4 Discussion

Systemic inflammatory indices such as NLR, MLR and SIRI were significantly higher in VLBW infants with EOS compared to controls. Other systemic inflammatory indices including PLR, PIV, and SII in VLBW were not discriminatory for the diagnosis of EOS. Considering the AUC values of NLR and MLR in the diagnosis of EOS, while NLR and MLR are slightly more significant than CRP, SIRI was the most accurate of the systemic inflammatory indices for the diagnosis of EOS.

EOS is a serious and potentially life-threatening disease in newborns, especially in premature infants [11]. The gold standard method in the diagnosis of sepsis is positive blood culture. In the presence of sepsis, positivity rates in blood culture vary between 8–73% [3 , 13]. The frequency of culture proven EOS is 0.5/1,000 live births in term babies, while it can be seen at a frequency of approximately 20% in VLBW babies. If there is EOS with clinical and culture positive sepsis, the frequency of EOS increase even more. The frequency of EOS in our results was consistent with the literature [1 –3]. The signs and symptoms of sepsis may be vague or nonspecific. Therefore, it is often necessary to use laboratory tests in addition to symptoms and signs for the diagnosis of sepsis. CRP and IL-6 are the most used laboratory biomarkers for the diagnosis of EOS [3 , 13]. In our study, these acute phase reactants were significantly altered in EOS. Due to the increase in acute reactants in a period of 4–6 hours, some systemic inflammatory indices that are rapidly accessible and helpful in the diagnosis of sepsis have started to be used [2 , 5–8]. In the field of neonatology, the data on the use of these indices are quite limited. To our knowledge, six systemic inflammatory indices such as NLR, MLR, PLR, PIV, SII, and SIRI have not been previously investigated for the diagnosis of EOS in VLBW premature infants.

Systemic inflammatory indices can become more valuable inflammatory markers than neutrophils, monocytes, lymphocytes, or platelets alone to predict infection. NLR, MLR, PLR are important markers for sepsis in adults [4, 14]. Data in neonatology are limited for the diagnosis of sepsis, but the use of inflammatory indices in EOS and especially these specific data is valuable. Especially, NLR and PLR elevation have been shown to be very valuable parameters in the diagnosis of neonatal sepsis [2, 3]. It has been found that NLR, MLR and PLR are not significant markers in the diagnosis of neonatal sepsis in term newborns with meconium-stained amniotic fluid [6]. In our study, we did not have a patient with meconium-stained fluid with signs of hypoxia. Our results highlighted only EOS in VLBW infants. Aydogan et al. evaluated 166 term infants with congenital heart disease and reported that NLR and SII had a diagnostic value for neonatal sepsis, but PLR was not significant in the diagnosis of neonatal sepsis [9]. In our study, PLR, PIV and SII were not significant for the diagnosis of EOS. Additionaly, MLR, NLR and SIRI were significant indices for the diagnosis of EOS. In addition, SIRI alone was more effective than NLR and MLR, and had diagnostic value for EOS as much as IL-6. A previous study, examining the relationship between six systemic inflammatory indices and neonatal hypoxic ischemic encephalopathy (HIE), declared that high NLR, PIV, SII, SIRI, and low MLR were diagnostically significant for HIE. PLR was not diagnostic for neonatal HIE [12]. In our study, we included only VLBW infants who were diagnosed EOS and not exposed to hipoxia. In adults, systemic inflammatory indices were found to increase in patients who died after coronary artery bypass surgery [15]. Additionally, among six systemic inflammatory indices, only PIV, or aggregate index of systemic inflammation (AISI), was increased in adult idiopathic pulmonary fibrosis patients [16]. The level of significance of each parameter in systemic inflammatory indices differs in various disease groups in the field of adult and neonatal medicine [17]. In neonatology, a high NLR has been shown to have a diagnostic value in inflammatory conditions such as intraventricular hemorrhage, LOS, HIE, and NEC [12 , 19]. Recent studies in the neonatal field were found that a high SII value is an indicator for respiratory distress syndrome and a high SIRI value is an indicator for bronchopulmonary dysplasia [20, 21].

According to our results, there was a difference between the groups since white blood cells such as neutrophils, monocytes, and lymphocytes are at the forefront in the pathophysiology of EOS. Therefore, NLR, MLR and SIRI were determined as significant parameters. Moreover, in our study, SIRI was the most significant parameter among 6 inflammatory indices, in the diagnosis of EOS. This shows that when neutrophils, monocytes and lymphocytes are evaluated together in EOS, it will have a more effective diagnostic value. Thus, low lymphocyte count and high neutrophil/monocyte count are indicators of physiological stress and severity of inflammation [2 , 22]. It should be noted that our results are valid only for premature infants with VLBW. Neonatal studies in term infants have similar and different aspects to our results. The main difference here is due to GA, BW, blood collection time, and diagnostic differences of the patients [3 , 12].

In the literature, there are significant differences in terms of cut-off values for clinical outcomes or diagnostic values in adult studies evaluating the relationship between systemic inflammatory indices and infectious diseases [4 , 23]. In the field of neonatology, data on the diagnostic value of sepsis and the cut-off values of systemic inflammatory indices are quite limited. While the cut-off value for NLR in the diagnosis of sepsis in term infants was between 1.77–2.7, it was reported to be 517.19 for SII [5 , 7–9]. Considering other systemic inflammatory indices, no cut-off value was reported in the diagnosis of neonatal sepsis. Six systemic inflammatory indices have been previously evaluated for the decision of therapeutic hypothermia in term infants with HIE. The cut-off value for NLR has been reported to be >1.12, MLR < 0.14, PLR≤40.4, PIV > 417, SII > 410, and SIRI > 1.29. In addition, it has been reported that NLR has the highest diagnostic power in HIE among six systemic inflammatory indices [12]. In our study, significant cut-off values in the diagnosis of EOS were >0.0981 for NLR,>0.0127 for MLR and >0.591 for SIRI. The predictivity of SII, PIV and SIRI in the diagnosis of EOS has not been evaluated before. In our study, SIRI was found to have the highest diagnostic power in EOS. It is noteworthy that these cut-off values are lower than previous adult and neonatal studies. The main reasons for this are that while the normal reference range values of neutrophil counts are lower, and normal reference range values for monocytes and lymphocyte counts are higher in term infants compared to adults [24, 25]. Moreover, there is a physiological decrease in the number of monocytes and lymphocytes in the postnatal days after birth [6]. In infants, as the gestational week decreases, the normal reference values of monocytes and lymphocytes increase, while neutrophil values decrease [26]. Therefore, difference in cut-off values of our results may be due to the fact that our patients were more premature and VLBW infants. In addition to this, when interpreting the relationship between systemic inflammatory indices and neonatal disease, together with pathophysiology of the disease, GA, BW, sampling times, and physiological kinetics must be taken into account.

Sensitivity increases as the number of true positives increases, whereas it decreases as the number of false negatives increases. The low PPV value of SIRI means that positive values may be affected by different factors other than sepsis. The high NPV value indicates that if SIRI is negative, it may be more meaningful in excluding sepsis. Other inflammatory indices, including SIRI, are the novel indices for the diagnosis of different diseases in recent years. In addition, there is no specific diagnostic laboratory test in the diagnosis of EOS, and SIRI may be a parameter that will help other clinical and laboratory findings. The results in our study were only VLBW infants and are single center data. The results of our study may shed light on future studies with larger case series. Thus, the place of systemic inflammatory indices in the diagnosis of EOS can be fully understood.

4.1 Limitations of our study

Strengths of our work; this is the first study to investigate the diagnostic value of six systemic inflammatory indices for EOS in VLBW infants with a large sample size. If the limitations of our study were listed, patient data belonged to a single center and was designed retrospectively. Furthermore, systemic inflammatory indices in the advancing postnatal days could not be evaluated, as the complete blood count values were obtained only in the first day from the patients. Therefore, inflammatory indexes could not be evaluated for the diagnosis of LOS. Additionally, the results of chorioamnionitis, placental culture, placental pathology, maternal blood count and inflammatory indeces results were not available.

5 Conclusion

Identifying a biomarker with high predictive value in the diagnosis of EOS is vital for early diagnosis, treatment, and prevention of adverse clinical outcomes of sepsis. Our study is the first to evaluate six systemic inflammatory indices in the diagnosis of EOS in VLBW premature infants. Although SIRI was the most valuable for the diagnosis of EOS among six systemic inflammatory indices, NLR and MLR were significant parameters as well. Systemic inflammatory indices, which are low cost, simple, easily accessible, and quickly available, may be useful to clinicians for the diagnosis of EOS in VLBW preterm infants. These parameters were altered in EOS, may be of some help, but that there is still lacking adequate laboratory markers for EOS with acceptable sensitivities and specificities. Our results need to be confirmed by prospective studies with larger case series.

Footnotes

Acknowledgments

None.

Funding

None.

Conflict of interest

None.

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