Utility of the NEUT-RI and NEUT-GI Parameters of Sysmex XN 2000 in Acute Intestinal Bacterial Infections

Abstract

Background

Bacterial infections constitute a predominant factor contributing to morbidity and mortality; effective management of patients necessitates an accurate and timely diagnosis.

Objectives

To evaluate, in the early diagnosis of intestinal bacterial infection, the quantitative variations in the values of two parameters related to the functional state and the performance of neutrophils, called NEUT-RI (neutrophil-reactivity intensity) and NEUT-GI (neutrophil-granularity intensity), correlating them with white blood cells (WBCs), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and procalcitonin (PCT).

Methods

A total of 57 intestinal bacterial infection–positive patients were retrospectively compared with 65 healthy subjects (control group). The identification of pathogens in fecal material samples was conducted through a molecular method, real-time multiplex PCR (FilmArray GI Panel BioFire, Biomerieux). WBC, NEUT-RI, and NEUT-GI were analyzed using the Sysmex XN 2000 hematology analyzer (Sysmex, Kobe, Japan). The Test-1 Alifax instrument was used to determine the ESR, while CRP and PCT were determined on the Beckman DxC AU 700 and Biomerieux VIDAS 3 instruments. Statistical evaluation was conducted employing Jamovi software.

Results

NEUT-RI and NEUT-GI were higher in subjects with intestinal bacterial infection, compared with healthy subjects: p < 0.001 and p = 0.002, respectively; in distinguishing subjects with infection from healthy subjects, NEUT-RI and NEUT-GI achieved both significant but moderate accuracy, with receiver operating characteristic area under the curve of 0.788 for NEUT-RI and 0.669 for NEUT-GI.

Conclusion

The parameters NEUT-RI and NEUT-GI allow us to measure the activation state of neutrophils, which are key actors in the innate immune response. Based on the case series examined, they appear to support the diagnosis of bacterial intestinal infection with moderate efficacy.

Keywords

intestinal bacterial infections - neutrophil-granularity intensity (NEUT-GI) - neutrophil-reactivity intensity (NEUT-RI)

Bacterial infections constitute a predominant factor contributing to morbidity and mortality; effective management of patients necessitates an accurate and timely diagnosis.[1]

Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and procalcitonin (PCT) are the most prevalent biomarkers utilized in laboratory diagnostics, alongside microbiological assessments. Nevertheless, these markers are not devoid of limitations.[2]

The total white blood cell (WBC) count and differential count also yield pertinent information concerning the status of infectious diseases, similarly to the band neutrophil count[3] and immature granulocyte (IG) count.[4] Neutrophils serve as pivotal components of innate immunity, acting as the initial line of nonspecific defense employed by the body against foreign pathogens; thus, it is of considerable interest to direct attention toward these cells to assess their potential as early indicators of infection.[5]

The neutrophil-reactivity intensity (NEUT-RI) and neutrophil-granularity intensity (NEUT-GI) parameters associated with neutrophil granulocytes, available on Sysmex XN automated hematology analyzer, may offer valuable support in diagnosing and monitoring inflammation and infections. NEUT-RI and NEUT-GI are interconnected with the morpho-functional alterations that neutrophils experience when transitioning from a quiescent state to an activated state.[6] NEUT-GI and NEUT-RI possess the potential to predict the emergence of inflammatory markers such as IGs, thereby facilitating the early diagnosis of bacterial infections.[7] The assessment of these parameters is characterized by its expeditiousness, cost-effectiveness, and execution in a singular procedural step. The identical specimen utilized for hematological analysis can serve to evaluate these parameters without incurring supplementary expenses; however, it is noteworthy that, given their nature as morpho-functional parameters reflecting the cellular activation state, they may be influenced by any delays in the execution of the hematological analysis. Consequently, it is imperative to conduct the test promptly, ideally within a 4-hour timeframe if the specimen is maintained at ambient temperature, as any postponement in the procedural timeline could compromise the integrity of the results. Moreover, since these parameters are contingent upon the specific analytical equipment employed, it is unfeasible to draw comparisons between datasets obtained from different laboratories utilizing disparate analyzers.

The aim of our work was to evaluate the quantitative variations in the values of NEUT-RI and NEUT-GI in intestinal bacterial infection–positive patients, diagnosed by molecular investigation and in healthy subjects; we also evaluated the correlations between them and the markers classically used for the diagnosis of inflammation/infection (WBC, ESR, CRP, PCT). The performance of NEUT-RI and NEUT-GI in the early diagnosis of intestinal bacterial infection was also considered.

Methods

This investigation constitutes a retrospective observational study involving individuals who were admitted to the Gastroenterology Unit of Scorrano Hospital (Italy) during the timeframe spanning January 2023 to February 2024.

The study protocol was approved by the Local Ethics Committee (prot. 1840/CEL). Since the study was retrospective in nature and the data were handled anonymously in compliance with current regulations, written informed permission was not required.

Out of the 150 patients who were admitted to the Gastroenterology Unit over the course of approximately 1 year, 57 fulfilled the criteria for inclusion in this study, as patients hospitalized and having a positive molecular diagnostic test for fecal bacterial infections. [Fig. 1] shows the design of the study.

Fig. 1 Study design flow chart.

Data utilized in this study were derived from the laboratory tests at the time of patient hospitalization, specifically on the date of admission or, in the case of the molecular diagnosis of infection, on either the first or second day subsequent to admission to the Gastroenterology Unit. For each patient, demographic information and clinical parameters—CRP, ESR, and PCT values—along with data pertaining to the complete blood count, including NEUT-RI and NEUT-GI, were collected from medical records and anonymized.

As the control group, we collected data obtained from medical diagnostic evaluations (comprehensive blood count integrated with advanced inflammatory indicators, NEUT-RI and NEUT-GI), from a sample of 65 healthy subjects selected from the workforce of a singular hospital institution. Moreover, to ensure that there was no statistically significant age difference between the control group and the patients in the Gastroenterology Unit, we place extra emphasis on older individuals (p >0.05 as determined by the Mann–Whitney U-test), while also ensuring the selection of individuals whose WBC counts conformed to the normative ranges pertinent to their respective age and gender.

In the context of the comprehensive blood count evaluation, a venous blood sample was procured utilizing a collection tube containing K3 EDTA (BD Vacutainer); this specimen was subsequently analyzed within 4 hours of collection utilizing the Sysmex XN 2000 automated analyzer. Alongside traditional hemocytometric parameters, the inflammatory metrics associated with neutrophils, specifically NEUT-RI and NEUT-GI, were rigorously assessed.

The technique applied in Sysmex XN analyzers uses the fluorescence flow cytometry. This method enables the differentiation of reactive cells from resting cells based on the variations in the signals produced. An elevation in neutrophil activity correlates with an increase in metabolic processes, thereby resulting in an augmented quantity of nucleic acids that bind more fluorescent dye, which consequently leads to an increase in the fluorescence signal, denoted by the NEUT-RI value. Furthermore, activated neutrophils are characterized by an enhancement in the number of secretory granules and vacuoles, which is associated with an increase in the intensity of scattered light, represented by the NEUT-GI value. The NEUT-RI parameter encapsulates the intensity of neutrophil reactivity, expressed in units of fluorescence intensity (FI), and is correlated with the nucleic acid content within the cell. In contrast, the NEUT-GI parameter provides insights into the internal cellular structure (granularity) and is contingent upon the complexity of cellular architectures (including the morphology of the nucleus, the shape and size of granules, and vacuoles), expressed in units of scattered light intensity (SI).[8] [9]

The same whole blood tubes were utilized to determine the ESR via the Test-1 apparatus, while CRP and PCT analyses were performed on serum or heparinized plasma samples employing the DxC AU 700 and VIDAS 3 instruments, respectively.

The detection of pathogens within fecal specimens was conducted utilizing a real time multiplex PCR molecular approach, which has the capacity to simultaneously identify a variety of infectious pathogens within fecal samples, including viruses, bacteria, and parasites (BioFire FilmArray GI Panel). [Fig. 1] provides a detailed account of the bacterial species identified through the gastrointestinal panel.

Statistical Evaluation

Statistical evaluation was conducted employing Jamovi software. NEU%, LINF%, RBC, Hb, and PLT had a normal distribution, but the predominance of variables of interest exhibited a nonnormal distribution (p <0.001 as determined by the Shapiro–Wilk test); therefore, the statistical analysis was performed employing nonparametric methodologies. Specifically, differences between the positive group and the control group were assessed by comparing medians rather than means, utilizing the nonparametric Mann–Whitney test. Differences were deemed statistically significant at p <0.05. The relationships between variables under study (NEUT-RI. NEUT-GI, WBC, CRP, ESR, and PCT) were elucidated through the Spearman correlation coefficient r. To ascertain the diagnostic efficacy of the study parameters in the identification of intestinal bacterial infections ascertained through RT-PCR (reverse transcription-polymerase chain reaction), the receiver operating characteristic (ROC) curves and the corresponding areas under the curve (AUCs) were utilized. In each ROC analysis, the diagnostic cutoff value for bacterial infection was established in accordance with the Youden index (sensitivity + specificity – 1), then the diagnostic sensitivity and specificity were calculated.

Results

Of the 57 positive patients, 29 were men and 28 were women (median age 66 years, range 17–89 years), while the healthy control group consisted of 65 subjects, of which 34 were females and 31 males (median age 59 years, range 31–67 years).

Only 12 of the patients developed fever, but nearly all of them exhibited symptoms (50/57) like diarrhea, vomiting, and abdominal pain.

In total, 15 out of 57 positives had a Clostridioides difficile infection (homogeneously larger subgroup). The remaining 42 positive patients had some infections caused by other species of bacteria. We found some single infections by Escherichia coli (14 patients), Salmonella (7 patients), Campylobacter (6 patients), Yersinia (2 patients), and Vibrio cholerae (1 patients), while in 12 patients, we observed multiple infections. In three cases, multiple infection was caused by: C. difficile and enteroaggregative E. coli; in two cases by Campylobacter and shiga-toxin producing E. coli; in three cases by Campylobacter and enteropatogenic E. coli; in two cases by enterotoxigenic E. coli and shiga-toxin–producing E. coli; lastly, in two cases multiple infection was caused by three germs: Campylobacter, enteropatogenic E. coli, and enteroaggregative E. coli.

In the group of 65 healthy subjects, NEUT-RI and NEUT-GI had median values of 47 FI (interquartile range [IQR] = 4) and 150 SI (IQR = 4), respectively. For total WBC count, the median was 6.99 (×10⁹/L) (IQR = 1.95); for the absolute neutrophil count, the median was 3.64 (×10⁹/L) (IQR = 1.35), while for percentage count it was 53.70% (IQR = 10.4).

In the group of 57 patients who tested positive for the gastrointestinal tract bacterial infections, the median of NEUT-RI was 51.0 FI (IQR = 6.05), while NEUT-GI showed a median of 154.0 SI (IQR = 5). The CRP had a median = 1.9 mg/dL (IQR = 8.03); PCT had a median = 0.06 ng/mL (IQR = 0.24). ESR had a median = 11.0 mm/h (IQR = 16.8). WBC total count had a median of 7.78 (×10⁹/L) (IQR = 4.77), absolute neutrophil count had a median of 4.97 (×10⁹/L) (IQR = 3.56), and for neutrophil percentage count, the median was equal to 58.30 (IQR = 20.3; [Table 1]).

Table 1 Baseline characteristics of the study population: patients with bacterial intestinal infection (POS) and healthy subjects (CONTROL)

	POS (n = 57) with infection, median (IQR)	CONTROL (n = 65) healthy subjects, median (IQR)
Age (y)	66 (min 17–max 89)	59 (min 31–max 67)
Female	28 (49 %)	34 (52 %)
Male	29 (51 %)	31 (48 %)
NEUT-RI (FI)	51 (6.05)	47 (4.0)
NEUT-GI (SI)	154 (5.0)	150 (4.0)
WBC	7.78 (4.77)	6.99 (1.95)
N# (109/L)	4.97 (3.56)	3.64 (1.35)
N%	58.30 (20.3)	53.70 (10.4)
PCT (ng/mL)	0.06 (0.24)	Not available
CRP (mg/dL)	1.9 (8.03)	Not available
ESR (mm/h)	11 (16.8)	Not available

Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; NEUT-GI, neutrophil granularity intensity; NEUT-RI, neutrophil reactivity intensity; PCT, procalcitonin; WBC, white blood cell.

In patients positive for intestinal bacterial infection, NEUT-RI and NEUT-GI correlated with each other (p = 0.005); NEUT-RI correlated with CRP (p < 0.001) and PCT (p < 0.001); and NEUT- GI correlated with CRP (p = 0.006).

The Mann–Whitney U-test for independent samples showed significant differences between the two groups (positive/healthy), for all the considered parameters (WBC, N in percentage and absolute value, N/L, IG%, and IG in absolute value) and in particular for NEUT-RI (p < 0.001) and NEUT-GI (p = 0.002; [Fig. 2A, B]).

Fig. 2 (A) Box and whisker diagram of NEUT-RI in positive patients (POS) versus control group (CS); p-value < 0.0001 (Wilcoxon–Mann–Whitney test). (B) Box and whisker diagram of NEUT-GI in positive patients (POS) versus control group (CS); p-value = 0.0015 (Wilcoxon–Mann–Whitney test). NEUT-GI, neutrophil-granularity intensity; NEUT-RI, neutrophil-reactivity intensity.

Concerning the diagnostic performance of NEUT-RI and NEUT-GI for the diagnosis of bacterial infection, considering the positive/healthy group, the ROC curves provided AUC values all >0.6 with statistically significant p-values:

• AUC = 0.788 for NEUT-RI with p < 0.0001 (95% CI: 0.702–0.873) ([Fig. 3A]).

• AUC = 0.669 for NEUT-GI with p = 0.0008 (95% CI: 0.570–0.767) ([Fig. 3B]).

Fig. 3 (A) ROC curve for NEUT-RI (FI) for bacterial intestinal infection; NEUT-RI AUC = 0.788, p < 0.0001, 95% CI = 0.702–0.873. (B) ROC curve for NEUT-GI (SI) for bacterial intestinal infection; NEUT-GI AUC = 0.669, p = 0.0008, 95% CI = 0.570–0.767. AUC, area under the curve; CI, confidence interval; NEUT-GI, neutrophil-granularity intensity; NEUT-RI, neutrophil-reactivity intensity; ROC, receiver operating characteristic; SI, scattered light intensity.

When the cutoff values for NEUT-RI and NEUT-GI were 48.0 and 153.2, the sensitivities were 81.8 and 52.7%, while the specificities were 66.2 and 80.0%, respectively.

Discussion

Given that neutrophil granulocytes are the body's first nonspecific line of defense against external assaults, the study's objective was to assess the value of prolonged inflammatory measures as early indicators of intestinal bacterial infection.[5] The main conclusions of our work are summarized as follows: (1) NEUT-RI and NEUT-GI levels were higher in intestinal bacterial infection subjects than in healthy subjects; (2) for intestinal bacterial infection, NEUT-RI and NEUT-GI achieved both significant but moderate accuracy, with ROC AUC of 0.788 and 0.669, respectively.

In recent years, several research studies have focused on identifying the most effective biomarker of inflammation and infection. One of the things that drove the development of this branch of research was the need to identify the most effective sepsis marker.

In this study, we looked at the quantitative differences in neutrophil functional characteristics, NEUT-RI and NEUT-GI, between patients who tested positive for intestinal bacterial infection and healthy individuals. We also looked at how well NEUT-RI and NEUT-GI performed in the diagnosis of infection. Real-time multiplex PCR was used as a molecular technique to identify the pathogens in fecal samples. Instead of using culture tests to diagnose bacterial infections, a molecular test allowed for a quicker reaction, allowing the illness to be identified as soon as possible.[10] [11] [12] The high sensitivity (>98.5%) and specificity (>99%) of the molecular test as well as the rapid execution times (< 2 hours, from sample preparation to result) mean that this test can be considered by far the most efficient and precise in the early diagnosis of intestinal infections, and not only for these.[13] [14] [15] The speed of execution and the correctness of the laboratory results more than make up for the apparent rise in diagnostic costs, and the hospital company frequently saves money by implementing proper therapy and reducing hospital stays.[16]

The NEUT-RI values, which were statistically significantly different in the group of patients who tested positive for the infection than in the group of healthy subjects, reflect the morpho-functional changes that the neutrophil undergoes in response to the stimulus represented by the bacteria. There is a strong correlation between the rise in mRNA observed in activated neutrophils that are first involved in the protein synthesis of cytokines and NEUT-RI, a measure of the nucleic acid content of the cell. Our findings also suggest that there are significant differences between bacterial infection patients and healthy individuals in terms of NEUT-GI, which is linked to the granule cell content (toxic granulations, vacuolization, and Dohle bodies).[17]

The extended inflammatory parameters NEUT-RI and NEUT-GI showed significantly different values between the two groups (healthy/positive for infection) with p <0.001 for NEUT-RI and p = 0.002 for NEUT-GI. By analyzing the ROC curves, NEUT-RI showed a higher AUC value than NEUT-GI (AUC for NEUT-RI was 0.788 with p <0.0001 and AUC for NEUT-GI was 0.669 with p = 0.0008); these are not optimal values but still clear evidence of statistically significant differences between the two groups.

The usefulness of extended inflammatory measures as potential biomarkers for the early identification of infection or sepsis has been widely investigated in earlier research over the years. According to a 2015 hypothesis by Cornet et al, the structural characteristics of neutrophils NEUT-RI and NEUT-GI can forecast the emergence of infection indicators, like the presence of IGs, which typically manifest later.[7] When comparing the extended inflammatory parameters to traditional indicators of inflammation like WBCs, neutrophils, lymphocytes, and hemoglobin levels, Park et al looked at the new hematological parameters in sepsis patients and found that NEUT-RI and NEUT-GI had similar or higher values in sepsis patients compared with healthy individuals.[18] NEUT-RI was higher in the group with bacterial infection than in the control group in a cohort study conducted on children under 5 years of age.[19] NEUT-RI demonstrated a strong association with CD64, a measure of neutrophil activation, in a group of African patients with bacterial infections, whether or not they had human immunodeficiency virus.[20] Numerous investigations conducted in recent years have demonstrated that patients with sepsis have much greater levels of NEUT-RI than patients without sepsis.[21] [22] [23] [24] The potential relevance of the extended inflammatory parameters NEUT-RI and NEUT-GI in the treatment of chronic inflammatory disorders, such as autoimmune diseases (psoriasis and psoriatic arthritis, type II diabetes mellitus, etc.), has also been the subject of several recent studies. In conjunction with traditional biochemical indicators of inflammation like CRP, these studies demonstrate the value of NEUT-RI and NEUT-GI as indicators of immune system activation in the treatment of chronic inflammatory illnesses.[25] [26]

In our study, although NEUT-RI and NEUT-GI exhibit statistically significant differences between the two groups, when the group of infection-positive patients is compared with that of healthy individuals, there is an overlap in the 95% CI between the two groups. Despite a significant p-value, there is an overlap of values. Furthermore, NEUT-RI and NEUT-GI appear to have only a moderate diagnostic efficacy (AUC = 0.788 and AUC = 0.669 for NEUT-RI and NEUT-GI, respectively). When the cutoff values for NEUT-RI and NEUT-GI were 48.0 and 153.2, the sensitivities were 81.8 and 52.7%, while the specificities were 66.2 and 80.0%, respectively. These cutoff values overlapped with the normal range of NEUT-RI and NEUT-GI. Considering these findings, our study shows that NEUT-RI and NEUT-GI have some limits in supporting the early diagnosis of acute infection. A limitation of our work is represented by the small number of included patients. Furthermore, we did not investigate the variation of NEUT-RI and NEUT-GI values over time (after 24 and 48 hours) to investigate a potential correlation between the variation of NEUT-RI and NEUT-GI over time and the presence of infection. Our work should currently be regarded as preliminary because this element may be the focus of future research.

The use of extended inflammatory parameters in the treatment of viral and inflammatory disorders is often limited as well. To begin, these parameters are dependent on the analyzer, making it impossible to compare data from laboratories using different analyzers. Furthermore, a delay in the blood count test's execution durations could have an impact on these morpho-functional characteristics, which represent the cells' activation state and must be completed promptly.

In our study, the diagnosis of bacterial infection was conducted with a molecular method. From recent literature, we do not know of other authors who have studied the correlations between NEUT-RI and NEUT-GI and an infectious state diagnosed by molecular methods. Therefore, we believe that this aspect makes our work worthy of attention.

In conclusion, the parameters NEUT-RI and NEUT-GI are provided by Sysmex XN analyzers at no extra cost when using the hemochromocytometric test, a frequently used test in the laboratory. They allow us to measure the activation state of neutrophils, which are key actors in the innate immune response. In our investigation, NEUT-RI and NEUT-GI significantly differed between the intestinal bacterial infection patient group and the group of healthy patients.

However, when it came to diagnosing intestinal bacterial infections, NEUT-RI and NEUT-GI had a moderate accuracy.

Despite the limited number of patients examined, the results obtained in this preliminary study seem to provide useful clues to identify subjects with intestinal bacterial infection early. However, it is necessary to study this concept in greater depth on a larger case study.

Conflict of Interest

None declared.

Acknowledgments

None.

Authors Contributions

L.B., L.T., and A.T. contributed to the design of the study and data analysis. L.B., M.C., M.S., and P.P. were responsible for data collection, while M. Licchelli and M. Laneve developed the methodology. G.P. and A.A. handled data curation, and A.A. together with F.D.G. managed the ethical committee documentation. Manuscript writing was carried out by L.B. and F.D.G., with revisions by A.T. and L.T. Study supervision was provided by A.T. and L.T.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Ethical Approval Statement

The study protocol was approved by the Local Ethics Committee (prot. 1840/CEL).

Consent to Participate

Not necessary, as this is a retrospective observational study.

^* These authors contributed equally to this work.

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Publikationsverlauf

Eingereicht: 29. Januar 2025

Angenommen: 30. Juli 2025

Artikel online veröffentlicht:
09. Oktober 2025