Association between the systemic inflammation response index and iron deficiency anemia in US adults, 2003–2018: A population-based cross-sectional analysis

Systemic inflammation shapes iron homeostasis and can contribute to functional iron deficiency. The systemic inflammation response index (SIRI) – computed from neutrophil, monocyte, and lymphocyte counts – captures the balance between pro-inflammatory and immune-regulatory pathways. Its population-level relationship with iron deficiency anemia (IDA), including potential nonlinearity, is not well characterized. This study aims to examine the association between SIRI and prevalent IDA in US adults using the National Health and Nutrition Examination Survey (NHANES), with a priori interest in nonlinearity. We conducted a cross-sectional analysis of 11,047 adults from NHANES 2003 to 2010 and 2015 to 2018. SIRI was calculated as (Neutrophils × Monocytes)/Lymphocytes and analyzed as lnSIRI and by tertiles. IDA was defined using established hemoglobin and iron-status criteria. Survey-weighted multivariable logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs), with multiple imputation for missing data. Restricted cubic splines (3 knots at the weighted 10, 50, and 90 percentiles of raw SIRI) assessed nonlinearity. Sensitivity analyses excluded participants with C-reactive protein (CRP) > 10 mg/L; severity analyses distinguished mild versus moderate-to-severe IDA. In the fully adjusted model, lnSIRI was positively associated with IDA (OR: 1.38; 95% CI: 1.11–1.72; P = .004). Compared with the lowest tertile, the highest SIRI tertile had higher odds of IDA (OR: 1.55; 95% CI: 1.22–1.97; P for trend < .001). The exposure–response curve was nonlinear ( P for nonlinearity = .012), with a threshold around SIRI ≈ 0.60 ( P for nonlinearity = .012), below which the association was inverse and above which it was positive. Findings were robust after excluding high-CRP individuals and were more pronounced for moderate-to-severe IDA (OR for lnSIRI 1.48; 95% CI: 1.10–2.00), whereas mild IDA showed weaker associations. In this large, nationally representative NHANES sample, higher SIRI is independently associated with the prevalence of IDA, following a nonlinear pattern with a threshold near 0.6. SIRI may serve as an accessible biomarker to help flag individuals at risk of inflammation-related iron deficiency; causal inference is limited by the cross-sectional design.