Obesity and its associated comorbidities have become significant global health challenges, with obesity now recognized as the fifth leading cause of mortality worldwide. According to the World Health Organization, childhood obesity ranks among the most critical challenges of the 21st century, affecting over 100 million children globally. Obesity in youth impacts nearly all organ systems, predisposing them to cardiovascular diseases, type 2 diabetes (T2D), endocrine disorders, autoimmune diseases, depression, and cognitive impairments, These conditions significantly elevate the risk of premature death. One of the primary causes is obesity-induced chronic inflammation, characterized as a low-grade, persistent inflammatory response by metabolic cells to excess nutrients and energy, termed metabolic inflammation. This condition has endocrine, paracrine, and metabolic implications that heighten the long-term risk of several severe illnesses. (1–3). Body Mass Index (BMI) is a simple index measured by calculating weight (kg)/height (m²), which helps determine whether a child is overweight or obese because of its close correlation with the amount of body fat, and is widely used as a measure of obesity and obesity prevalence (4, 5), Higher Body Mass Index (BMI) and its increase during childhood and adolescence correlate with a rise in adult and central obesity, it is also an important preventable cause of death and is a major cause of cardiovascular diseases such as heart failure and stroke, as well as other serious diseases stroke and cardiovascular diseases, skeletal system disorders and malignant tumors, are major risk factors (6). Current studies have demonstrated that neutrophils, lymphocytes, platelet count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune inflammation index (SII) are associated with BMI in adults, but there is insufficient information about the use of these markers in childhood obesity (7).

CBC-derived inflammatory biomarkers such as NLR, PLR, inflammatory response index (SIRI) and SII are associated with BMI in adults. SIRI and SII are used as prognostic factors for various diseases (8). unlike traditional inflammation indices such as NLR and PLR, the systemic immune inflammation index (SII) and systemic Inflammatory Response Index (SIRI) are new composite indices that contain three separate leukocyte subpopulations and platelets, reflecting the interplay of thrombocytosis, inflammation, and immunity. A study by Hu et al. (9) demonstrated that the SII reflects the local immune response and the level of systemic inflammation across the entire human body; whereas, the SIRI is a more comprehensive inflammation based on the count of monocytes, neutrophils, and lymphocytes marker (10), which is a good indicator of the chronic inflammatory state of the body (11).

There are few studies on the correlation of BMI with SII and SIRI, so this study used data from a large sample of people aged 6 to 19 years from the National Health and Nutrition Examination Survey (NHANES) to investigate the association between SII and SIRI and BMI in children and adolescents.

It has been discovered that there is positive correlation between increasing BMI levels and increasing SII and SIRI levels, This relationship is even more significant in obese children, and it is worth noting that stratified analyses revealed variability in this relationship in gender, obesity category, and age period. In the fitted curves of BMI and SII, we found that the curves flattened as BMI increased to 48.2 (kg/m²), suggesting that there may be a peak in SII. In the gender subgroup analyses, there were inflection points of 16.4 (kg/m²) and 41.1 (kg/m²) in male children, There was a positive correlation between BMI and SIRI, while there was an inverted U-shaped relationship between BMI and SIRI with an inflection point of 33.3 (kg/m²), suggesting that when the BMI is less than 33.3 (kg/m²), the increase in BMI is a risk factor for the increase in SIRI. But the mechanism of which is unclear.

Metabolic inflammation, the term used to describe obesity-induced inflammation, is a chronic, low-grade inflammatory response that is triggered by excess nutrients in metabolic cells. It has been shown that inflammatory signaling carried out by the metabolic cells ultimately causes obesity activation and that levels of circulating cytokines and acute temporal reactants correlate with these levels. Unlike the classical inflammatory response, adipose tissue is the main organ of control of this inflammation (15). While there is a persistent energy surplus, adipocytes compensate for the excess by multiplying and hypertrophying, which results in obesity and an increase in body mass index (BMI). In the case of obesity, there is initially homeostatic stress induced by a positive energy balance and an overall high anabolic state, particularly in adipocytes. which leads to an adaptive inflammatory response through the release of chemokines that permit a healthy expansion of adipocytes with a concurrent reduction in energy stores. In general, when the pressure from the adipocytes reaches a certain point owing to restricted cell and tissue expansion that is insufficient to support additional anabolic pressure, these cells will eventually reach a threshold that triggers an inflammatory process to initiate (16, 17). Inflammatory substances of intestinal origin, food items, or metabolites are among the substances that might trigger inflammation in adipose tissue. Alternatively, the rapid expansion of adipose tissue in obesity may produce internal signals that can lead to inflammation, which includes adipocyte cell death, hypoxia, and mechanical transduction brought on by cell interactions with the extracellular matrix (ECM) (18).

A greater amount of circulating classical CD14 ^{+ +} CD16 ^- and intermediate CD14 ^{+ +} CD16 ⁺ monocytes is associated with childhood obesity. These monocytes appear to be important in the development and progression of atherosclerosis and to be a key link between obesity and cardiovascular disease. Furthermore, childhood obesity is accompanied by altered obesity-associated gene expression of monocytes and increased complexity of adult coronary atherosclerosis (19). Prabhakara R et al (20) found that in obesity, the inflammatory mediator IL-1 β reaches the bone marrow through IL-1R and stimulates the growth of hematopoietic progenitor cells in vitro through experiments measuring the proliferation of BM progenitor cells in a mouse model, resulting in the production of more monocytes. Additionally, it was discovered that obesity has a feed-forward mechanism wherein inflammatory adipose tissue stimulates the production of more monocytes, resulting in increased inflammation and related disease processes. It is now demonstrated that insulin resistance, pro-inflammatory macrophage accumulation, and adipose tissue inflammation are dependent on CCR2-dependent monocyte recruitment (21). Jongkil Kim et al (22) shown that the involvement of the MCP-1 (monocyte chemotactic protein-1) receptor and CCR2, which are expressed on peripheral monocytes/macrophages, can cause macrophage recruitment to obese adipose tissue (AT). This is one of the main features of adverse metabolic outcomes in dietary obesity. It has been demonstrated that macrophages and other immune cells are the primary inflammatory cells in obesity, releasing the majority of the inflammatory chemicals in the adipose tissue of obese humans and animals (23), such that one of the characteristics of obesity-associated adipose tissue inflammation is an increase in macrophages (24).

Platelets have been shown to play a major role in the inflammatory process and platelet activation is a common feature of inflammatory diseases. Obesity correlates with platelet activation and count. IL-6 is likely to be the main driver, acting synergistically with other interleukins to increase thrombopoietin, of which visceral adipose tissue itself may be an additional source of thrombopoietin, which in turn stimulates megakaryocyte production, leading to thrombocytosis. Mean platelet volume (MPV) is a parameter that reflects platelet activation in vivo. In obese patients MPV levels are increased and BMI and MPV are positively correlated and reversible after weight loss. A recent study on the formation of dinoprost analogues in vivo found that obese patients had elevated levels of MPV and that body mass index was positively correlated with MPV. In addition, the study found that in patients with abdominal obesity, low-grade inflammation may trigger TX-dependent platelet activation through enhanced lipid peroxidation (25, 26). On the contrary, Y. FURUNCUOğLU et al (6) discovered a significant association between BMI and SII, neutrophil, lymphocyte, and leukocyte counts, as well as all platelet indices (MPV excluded). The current study suggests that altered platelet transcriptome in obese patients as well as obesity-induced changes in plasma lipid composition can lead to increased platelet activation (27).

Neutrophils are the most abundant white blood cells in the blood and are the first immune cells to infiltrate in adipose tissue. Neutrophils are activated and release inflammatory factors that recruit macrophages and other immune cells, including B cells, T cells and NK cells. These immune cells in turn perpetuate the inflammatory state by producing cytokines and chemokines that can reach other parts of the body, creating a systemic inflammatory state. In obese patients neutrophils are increased and there is a significant correlation between the level of neutrophil counts and higher BMI, with overweight individuals with neutrophilia exhibiting higher serum C-reactive protein (CRP) concentrations and larger waist circumferences (28). Obese individuals are able to produce higher levels of inflammatory mediators such as TNF - α, IL - 1 β, IL - 6 and IL - 8, which increase bone marrow granulopoiesis and release neutrophils from the bone marrow into the peripheral circulation. In addition, these inflammatory mediators induce neutrophil detachment from the endothelial wall, leading to neutrophilia. High levels of leptin are observed in obesity, leptin significantly stimulates the emergence of granulocyte macrophage colonies and monocyte and granulocyte precursors, and plasma leptin concentrations significantly correlate with leukocyte counts in overweight and obese individuals, leptin additionally stimulates oxidative bursts of neutrophils, induces chemotaxis, and inhibits apoptosis of these cells, obese adipose tissue is responsible for the promotion of systemic inflammation, which leads to neutrophil production, increased numbers and activation (25, 28, 29). Raghavan et al (30) studied hematological indices in obese women and found a progressive increase in absolute neutrophil counts and neutrophil sorting counts with increasing BMI.

SIRI and SII encompass neutrophil and lymphocyte counts, their discriminative attribute resides in including additional cell types for analysis, Specifically, SIRI considers monocyte counts. whereas SII focuses on platelet counts (31). neutrophil-to-lymphocyte ratio (NLR) is a simple and readily available biomarker and NLR appears to recognize persistent systemic inflammation in overweight individuals. NLR has been found to be significantly higher in obese individuals than in healthy lean individuals and the higher NLR in overweight individuals may reflect the subclinical inflammation that already exists in this population (28). Oliver et al (32) found that lymphocyte sorting counts declined progressively with increasing BMI, and that the absolute lymphocyte counts were offset by a greater increase in neutrophils. In conclusion, elevated levels of neutrophils, lymphocytes, platelets, and monocytes were observed in obese children, with elevated neutrophils offsetting elevated absolute lymphocyte counts. This resulted in elevated levels of SII and SIRI.

There are certain advantages to this study. firstly, this study is particularly representative of the child and adolescent population since we used a large nationally representative sample from NHANES sources. Second, this study performed subgroup analyses of different variables. Third, there are more studies on the inflammatory mechanisms of obesity and fewer studies on the associated inflammation levels, and to the best of our knowledge this paper is the first to investigate the indicators of obesity inflammation levels.

There are several restrictions on our investigation. First, the NHANES database is an observational study; weight affects BMI values based on a variety of factors, including physical examination, a child’s nutritional status, and additional weight bearing. Furthermore, we were unable to rule out the influence of additional confounders beyond the covariates in this article, so our findings might not accurately reflect the true situation. Second, due to limitations of the NHANES database, the study did not include the disease profiles of the patients, obesity brought on by medicine, congenital familial disorders, associated disorders, etc. SII and SIRI levels have been demonstrated to be correlated with a number of diseases, including hypertension, cardiovascular disease, insulin resistance, diabetes mellitus, and endocrine disorders. However, as there were so few children in this set of diseases, the relationships between BMI, SII, and SIRI and disease were not investigated further.

The findings suggest that SII and SIRI levels appears to be increasing as body mass index (BMI) increases, indicating that these parameters could be used as possible markers of inflammation in children that have been classified as overweight or obese.