Anemia is the most common blood disorder and remains the major global public health problem, which affects more than 30% of the world’s population (1). It is a condition characterized by a lower-than-normal level of red blood cells or hemoglobin in the blood, leading to reduced oxygen-carrying capacity. This can lead to symptoms such as fatigue, weakness, dizziness, and shortness of breath, which can significantly impact an individual’s daily activities, work performance, and overall well-being. It is more common among females and the older population (2). In the United States, anemia is a common condition with multifactorial and complex causes, including nutritional deficiencies, chronic diseases, immune factors and certain medications. Anemia has been associated with an increased risk of a range of health conditions, including cardiovascular diseases, cognitive impairment, and complications during pregnancy. Numerous studies have demonstrated that anemia is associated with an increased risk of mortality, particularly in older adults and individuals with underlying chronic conditions (3). Early identification of anemia provides an opportunity to delay or prevent disease onset and improve treatment outcomes. Jeong-Yeol Park et al. found that the diagnosis and early intervention of anemia in gynecologic cancer patients can decrease the blood transfusion rate within 3 weeks after the operation (4). Therefore, to find a cheap and easy-to-obtain index which is closely related to anemia is very valuable.

Systemic immune-inflammation index (SII) as a stable and accurate indicator of the local or overall immune response and systemic inflammation in the human body, has been confirmed to be related to the prognostic value for tumors and chronic diseases induced by chronic inflammation or immune dysfunction (5–8). This indicator integrated three inflammatory factors, including platelets, neutrophils and lymphocytes (9). In recent years, the application field of SII has been expanding continuously, and more studies have shown that SII can also be used to predict the risk of certain diseases and monitor the effect of treatment.

It is widely recognized that inflammation plays a significant role in the development and persistence of anemia (10). Inflammatory processes can disrupt the body’s normal mechanisms for producing and regulating red blood cells and can contribute to the development of various types of anemia (11). Inflammation can affect the body’s ability to effectively use and regulate iron, which is essential for the production of hemoglobin and red blood cells. Additionally, inflammatory cytokines can suppress the production of erythropoietin, a hormone that stimulates red blood cell production in the bone marrow. At present, the research on the inflammatory factors related to anemia mainly focuses on neutrophil-to-lymphocyte ratio (NLR), cytokines and innate immune cells such as phagocytes and dendritic cells (12, 13). However, it is not yet clear how the inflammatory level indicator SII and anemia are related.

Therefore, to explore the association between SII and anemia among participants in the US National Health and Nutrition Examination Survey (NHANES), we carried out a population-based investigation and assumed that an elevated SII would be associated with a higher risk of anemia.

The role of the inflammatory response in the development and progression of anemia is an increasingly studied area in recent years. In this nationally representative cross-sectional study, we observed that participants with higher SII showed an increased likelihood of anemia. Moreover, we found a nonlinear relationship between SII levels and the risk of anemia after adjusting for all covariates. We further found that when SII is higher than 455, the risk of anemia will increase significantly. Additionally, as anemia becomes more severe, the positive correlation between SII and anemia becomes stronger. Subgroup analyses showed that there were stratification effects in female participants. Sensitivity analyses showed that our results remain robust. As far as we know, this is the first study to investigate the relationship between SII and the risk of anemia by using a representative sample of US adults.

SII was first developed in 2014 and was analyzed for its prognostic value in patients with hepatocellular carcinoma (9). SII was calculated by counting three kinds of circulatory cells: neutrophils, lymphocytes, and platelets. As a novel systemic immune inflammation index, there have been no studies on the association between anemia and SII in the previous literature. However, anemia has been linked in many clinical studies with several traditional inflammatory indicators. Current research on clinical inflammatory factors affecting anemia mainly focuses on NLR, immune cells, cytokines and C-reactive protein (CRP) (10). NLR is emerging as an indicator of systemic inflammation. Yazeed et al. demonstrated that in a large number of Saudi subjects, anemia group exhibited a significant increase in NLR compared to the non-anemic group (18). Another study also showed NLR was significantly higher in anemics (19). A multicenter prospective cohort study of 4955 elderly Chinese cancer patients (aged ≥65 years) suggested that a high NLR was an independent risk factor for anemia in older patients with cancer (20). Inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1 (IL-1), and interferons are signaling molecules that play a key role in the inflammatory response and have been implicated in the development of anemia (21). Macciò et al. reported that IL-6 negatively correlated with Hgb level and was an independent factor for anemia in ovarian cancer (22). CRP is an acute phase protein produced in response to inflammation, and elevated levels of CRP have been associated with anemia and can serve as a marker for inflammation related anemia (23, 24). These anemia-associated inflammatory factors are produced by activated immune cells or other cells stimulated by inflammation and serve as important mediators of the immune and inflammatory processes. Meanwhile, cytokines in the inflammatory response activate immune cells such as lymphocytes, granulocytes and macrophages to participate in the immune response (25). Platelets, while primarily known for their role in blood clotting, also have immune-modulatory functions and can release inflammatory mediators in response to various stimuli (26).

Most study findings about the relationship between above inflammatory parameters and anemia are consistent with our findings. Compared to traditional inflammatory factors, the SII selected in this study included more clinical information than one or two kinds of peripheral blood markers could truly reflect the burden of inflammation. Several studies showed that SII has been confirmed the better prognostic value in many diseases compared with other inflammatory factors (7–9, 27). Ling et al. found that SII had better predictive performance compared with other inflammatory factors in the early prediction of acute kidney injury in severe acute pancreatitis patients (8). Another study reported that SII was more accurate and effective in predicting the outcomes of patients with cervical cancer compared with NLR, platelet/lymphocyte ratio (PLR), and monocyte/lymphocyte ratio (MLR) (7). Similar results were confirmed in some other studies such as esophageal squamous cell carcinoma (27), hepatocellular carcinoma (9). Additionally, SII had been shown to be associated with a wide range of diseases and medical conditions including kidney stones (28), diabetic depression (29), coronary heart disease (30), heart failure (31), asthma (32), rheumatoid arthritis (33), hepatic steatosis (34). For example, Xingpeng et al. showed SII was positively associated with a high risk of kidney stones in US adults aged less than 50 (28). Therefore, as a reliable and minimally invasive biomarker, SII has promising prospects for clinical application.

The exact mechanisms underlying the positive association between inflammation and anemia still remain unclear (35). Inflammation can disrupt the normal processes of red blood cell production, iron metabolism, and erythropoiesis, leading to anemia (11). Inflammation, particularly chronic inflammation, can lead to the release of pro-inflammatory cytokines such IL-6 and tumor necrosis factor alpha (TNF-a). These cytokines can directly inhibit the production and maturation of red blood cells in the bone marrow, disrupting erythropoiesis and leading to reduced red blood cell counts (13). Furthermore, inflammation can alter iron metabolism by promoting the sequestration of iron within cells and reducing its availability for erythropoiesis. This can lead to functional iron deficiency, where iron levels appear normal in the body, but are not effectively utilized for red blood cell production (36). Additionally, inflammatory processes can lead to the dysregulation of erythropoietin, a hormone critical for the production of red blood cells. This can further impair the body’s ability to respond to anemia by producing adequate numbers of red blood cells (37).

In this study, stratified analysis showed that the positive association between SII and anemia was statistically significant only for females and not for males. The observed gender differences could potentially be attributed to the differential immune responses mounted by inflammatory cells in males and females (38). It is well-documented that females generally exhibit stronger and faster innate and adaptive immune responses compared to males. Sex hormones, particularly estrogen, contribute to the development and activity of the immune system. Both innate and adaptive immune systems have receptors for sex hormones and respond to hormonal cues accounting for differences in gender-related immune responses (39). Additionally, females of reproductive age are more susceptible to anemia due to factors such as blood loss during menstruation, childbirth, and hemodilution during pregnancy (40, 41). Compared to postmenopause, females in non-menopausal had lower iron stores (42). Inflammation is associated with anemia by affecting iron metabolism, as described in the above mechanism description. Our study also found a higher likelihood of anemia and a stronger positive association between SII and anemia in non-menopausal and younger female. These gender-specific factors may contribute to the observed disparity in the relationship between SII and anemia.

This research explored the association between SII and anemia and provided several advantages. Firstly, we used a nationally representative and large enough sample of adults in the US. Secondly, we adjusted for known and potential variables, such as WBC counts and chronic medical diseases to produce more reliable results. Additionally, we used restrictive cubic spline and smooth curve fitting to explore their non-linear relationship. Finally, to confirm the robustness of our results, we conducted sensitivity analyses on platelet which was a parameter of SII and had a definite effect on anemia (43).

However, this research also has limitations that should be considered. First, due to the cross-sectional study design, we could not obtain causal inferences and prospective studies are required to elucidate the causality. Second, Hgb values and the cell counts were obtained from one blood test only. Serial testing may be more reliable. Third, although some potential covariates were adjusted, the influence of other possible confounding factors could not be completely excluded.

This cross-sectional study demonstrated that SII was positively associated with the risk of anemia especially among female participants. Further large-scale prospective studies are still needed to analyze the role of SII in anemia.

The original contributions presented in the study are included in the article/ Supplementary Materials , further inquiries can be directed to the corresponding author/s.

The studies involving humans were approved by National Center for Health Statistics (NCHS) Ethics Review Committee. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

SC: Data curation, Writing – original draft. JX: Writing – review & editing, Data curation. WC: Data curation, Writing – review & editing. XL: Writing – review & editing. CL: Writing – review & editing. YD: Writing – original draft. YZ: Writing – original draft. GS: Writing – original draft. QS: Writing – review & editing. HW: Writing – review & editing. ZX: Project administration, Writing – review & editing.