Predictive value of the systemic immune inflammation (SII) index for stroke‐associated pneumonia

Abstract Objective To investigate the predictive value of the systemic immune inflammation (SII) index on the occurrence of stroke‐associated pneumonia (SAP) in patients with acute stroke. Methods Data of patients with or without a previous history of pulmonary who visited the First Affiliated Hospital of Kunming Medical University within 24 h of the onset of stroke were collected between January 2017 and December 2019. Patient's demographic data, stroke type, past medical history, National Institutes of Health Stroke Scale score, Glasgow Coma score, and laboratory tests were collected. Logistic regression models and receiver‐operating characteristic (ROC) curves were used to investigate the predictive value of SII for the development of SAP in patients with stroke. Results We included 395 patients with acute stroke, with a mean age of 63.89 ± 13.42 years, of whom 340 (86.1%) had ischemic stroke, and 55 (13.9%) had hemorrhagic stroke. Out of 395, 113 (28.6%) had SAP and 282 (71.4%) did not, and the SII level in the SAP group was higher than that of the non‐SAP group (p < .05). Logistic regression analysis of patients with stroke showed that higher SII was a risk factor for SAP in patients with stroke (per 100 units, HR = 1.081, 95% CI: 1.035–1.130, p < .001), and tertile grouping of SII showed that the risk of SAP was 5.059 times higher in the SIIQ3 group than in the SIIQ1 group (95% CI: 2.061–12.418, p < .001). ROC curve analysis indicated that the SII index had predictive value for the occurrence of SAP in patients with stroke, with an area under the curve of 0.752 (95% CI: 0.698–0.806). When the cutoff value was 861.01, the SII predicted SAP in patients with stroke with a sensitivity of 61.9% and a specificity of 76.2%. Conclusion Higher SII is an independent risk factor for the development of SAP in patients with stroke and has some predictive value for the development of SAP.


INTRODUCTION
Stroke is a type of disease that results from brain damage due to insufficient blood supply to the brain caused by rupture (hemorrhagic stroke) or blockage (ischemic stroke) of blood vessels in the brain and is a common cause of death (Liu et al., 2019;Zhou et al., 2016).The mortality rate of patients with stroke is currently decreasing (He et al., 2014;Li et al., 2016).However, the clinical outcomes of stroke are of widespread concern.Stroke-associated pneumonia (SAP) is one of the most common complications in patients with stroke.It may be due to a combination of poststroke aspiration and changes in immune function (Hoffmann et al., 2017).Aspiration can lead to infections from pathogenic bacteria in patients with stroke, whereas immune suppression creates an environment conducive to the pathogens.SAP increases the length of hospital stay, financial burden, and mortality rate of patients with stroke (Katzan et al., 2007;Suda et al., 2018;Vermeij et al., 2009;Wilson, 2012;Yu et al., 2016).Therefore, accurate and rapid prediction of SAP is crucial in patients with stroke.
The systemic immune inflammation (SII) is one of the most commonly used prognostic indicators of inflammation.It can assess body inflammation and immune function in various cancers, such as esophageal squamous cell carcinoma and gastric cancer (Inoue et al., 2021;Luo et al., 2019;Yang et al., 2018;Ye et al., 2022).Zhao et al. (2020) reported that in patients with stroke, immunosuppression and inflammatory responses decreased the number of lymphocytes and platelets while increasing the number of neutrophils.Kim et al. reported that the SII index, which is based on three cell types, provides a more comprehensive picture of patients' immune and inflammatory responses (Zhao et al., 2020) and is also independently associated with stroke severity at the time of patient admission (Hou et al., 2021).Therefore, we hypothesized that SII, an inflammatory marker composed of neutrophil, lymphocyte, and platelet counts, could predict SAP.Thus, this study aimed to investigate the diagnostic value of SII in predicting the occurrence of SAP in patients with acute stroke.

Study population
In this study, we included 395 patients admitted to the First Affiliated

Statistical analysis
SPSS 24.0 software (IBM Inc) was used for statistical analysis; the measured data were tested for normality using Shapiro-Wilk.Data following normal distribution was expressed as mean ± standard deviation (x ± s), and t-test was used to compare the two groups.Data that did not follow a normal distribution were expressed as median (P25, P75).Categorical data were expressed as frequencies (composition ratio), and the χ 2 test was used to compare categorical data between group.Logistic regression analysis was used to examine the risk factors for SAP in patients with stroke.The SII index was classified into lower quantile Q1, middle quantile Q2, and higher quantile Q3 based on tertiles.The trend relationship between SII and the risk of SAP in patients with stroke was examined.The receiver-operating characteristic (ROC) curve was used to evaluate the predictive value of SII for concurrent SAP in patients with stroke.p < .05 was considered to be statistically significant.

Comparison of general and clinical data between non-SAP and SAP groups
Data were collected from 450 patients with acute stroke, of whom 395 (88%) were eligible patients with a mean age of 63.89 ± 13.42 years.
Out Of them, 340 (86.1%) had ischemic stroke, and 55 (13.9%) had hemorrhagic stroke.Of the eligible patients, 250 (63.3%) were men, and 145 (36.7%) were women.The SAP group consisted of 113 (28.6%) patients, including 68 (60.2%) men and 45 (39.8%) women.There were 282 (71.4%) non-SAP patients, including 182 (64.5%) men and 100 (35.5%) women.Table 1 shows the results of analysis performed between the groups showing that the percentage of age, NIHSS score, presence of heart failure, use of an indwelling gastric tube, neutrophil count, mortality during hospitalization, and SII index were higher in the SAP group than those in the non-SAP group (p < .05).

TA B L E 1
Comparison of general and clinical data between non-stroke-associated pneumonia (SAP) and SAP groups.

Variables
Overall

Predictive value of SII for the development of SAP in patients with stroke
The ROC curve analysis showed that the area under the curve of SII predicting the occurrence of SAP in patients with stroke was 0.752 (95% CI: 0.698-0.806,p < .001),and the optimal cutoff value of SII predicting the occurrence of SAP was 861.01, with a sensitivity of 61.9% and a specificity of 76.2%.This suggested that SII has a certain extent of predictive value for SAP (Figure 1).

DISCUSSION
In this study, we retrospectively collected data from 395 patients with acute stroke from the First Affiliated Hospital of Kunming Medical University between January 2017 and December 2019.The results showed that SII was an independent risk factor for the development of SAP in patients with stroke, and there was a trend of a relationship between SII and the development of acute stroke, suggesting a predictive value of SII for early SAP.
SAP is a severe complication in patients with stroke and can worsen their condition, increasing morbidity and mortality.We found a 28.6% prevalence of SAP with longer hospital stay and a higher mortality rate, which is consistent with the findings of other studies (Cheng et al., 2020;Hilker et al., 2003;Smith et al., 2015).The pathogenesis of SAP in patients with stroke is unclear, but some studies suggest that immunosuppression-induced pathological changes in the body are associated with stroke-induced SAP (Dirnagl et al., 2007).
Most studies have linked SAP to stroke-induced immunodepression The receiver-operating characteristic (ROC) curve was used to evaluate the diagnostic value of SII for stroke-associated pneumonia (SAP) severity.
Patients with SAP have diverse clinical presentations and rapidly changing conditions, and most clinical indicators used to detect SAP lack specificity (Emsley & Hopkins, 2008;Finlayson et al., 2011;Li et al., 2014).The use of simple blood parameters for the early prediction of SAP has gradually gained attention in recent years.Hu et al. (2014) proposed that SII is a novel inflammatory index consisting of three cell counts: neutrophils, lymphocytes, and platelets.Many studies have shown that SII is closely related to various diseases and is a relatively good predictor of stroke prognosis (Wang et al., 2021;Wang et al., 2022;Wu, Yan et al., 2021).However, there are few studies on the relationship between SII and SAP.The results of this study may provide a theoretical basis for predicting and diagnosing SAP using SII.Considering that SII is associated with inflammatory response and immunosuppression in patients with stroke, it is possible that SIDS predicts SAP by decreasing the number of peripheral lymphocytes in the body, increasing the risk of infection in patients with stroke (Chamorro, Amaro et al., 2007;Chamorro, Urra et al., 2007).Second, in patients with stroke, an early inflammatory response occurs after brain injury.Neutrophils infiltrate and accumulate in areas of ischemic injury, secreting the inflammatory factors reactive oxygen species and matrix metalloproteinase 9, which exacerbate brain tissue damage and become a marker of poor prognosis in patients with stroke (Garau et al., 2005;Zhang et al., 2020).Endothelial cells are also damaged in patients with stroke, leading to platelet activation, the expression of adhesion molecules, and the release of inflammatory factors, resulting in atherosclerosis, thrombosis, and a decrease in platelet count (McMorran et al., 2009;Modjeski & Morrell, 2014).In addition, it has been shown that T-lymphocytes and neutrophil-to-lymphocyte ratio have been shown to predict SAP development (Feng et al., 2018;Wu, Zhang et al., 2021).However, SII provides a more stable and objective response to changes in neutrophil, lymphocyte, and platelet counts in patients with stroke and can be used to predict SAP.Our study revealed that the SII level was higher in the SAP group than in the non-SAP group (p < .05),and higher SII was a risk factor for SAP in patients with stroke, whereas the results of ROC curve analysis showed that SII had a predictive value for SAP.
This study has some limitations: First, it is a single-center retrospective study with possible selection bias and information bias, and other inflammatory markers associated with SAP, such as calcitonin, creactive protein, were not collected for comparative studies with SII.
Further validation with a large multicenter sample is needed in the future.In conclusion, our study showed that a high SII was an independent risk factor for the development of SAP in patients with stroke and had some predictive value for the development of SAP.

AUTHOR CONTRIBUTIONS
Zhanhang Cui, Sai Kuang, Xiaorong Yang, Ying Wang, Shanshan Gu, Hongyu Li, and Huibin Chen contributed to the study conception and design.Sai Kuang was responsible for the design methodology.
Xiaorong Yang and Ying Wang were responsible for material preparation.Shanshan Gu, Huibin Chen, and Hongyu Li were responsible for data collection.Zhanhang Cui and Sai Kuang were responsible for data analysis.Haimei Sun and Yanbing Han were responsible for the preparation of the first draft and review.All authors read and approved the final manuscript, and Haimei Sun and Yanbing Han confirmed the authenticity of all original data.

ACKNOWLEDGMENTS
This thesis was completed under the guidance of Sun Haimei and Han Yanbing.The teachers' profound professional knowledge, serious scientific attitude, rigorous academic spirit, and tireless teachings have had a profound impact on me.From the selection of the topic to the final completion of the project, Sun Haimei and Han Yanbing have always given me careful guidance, not only to set ambitious academic goals but also to make me understand many of the principles of the world, as well as to give me unfailing care in spirit and life.I would like to express my most sincere gratitude and thanks to Sun Haimei and Han Yanbing.In addition, the successful completion of this thesis could not have been achieved without the care and assistance of all the teachers, and their help is very appreciated.