Given this gap, the present study utilizes data from the nationally representative National Health and Nutrition Examination Survey (NHANES) in the United States to analyze the association between PIV levels and the risk of LTBI.

NHANES, administered by the Centers for Disease Control and Prevention (CDC), is a nationwide study that utilizes personal interviews, physical measurements, and laboratory tests to capture detailed demographic, health, and nutrition data from a representative sample of US residents, providing data critical for research and public health strategies. This study utilized data from participants in the NHANES 2011-2012 cycle. We excluded subjects under 20 years of age, those who were pregnant, reported having active tuberculosis, or lacked data on QuantiFERON-TB Gold In-Tube (QFT-GIT), PIV, and mortality (Fig. 1). After applying these criteria, 4877 participants remained, including 497 individuals identified with LTBI and 4380 without LTBI. Ethical approval for research involving human subjects was obtained from the Ethics Review Board of the National Center for Health Statistics (https://www.cdc.gov/nchs/nhanes/about/erb.html). All methods were performed in accordance with the relevant guidelines and regulations, and the study protocol complies with the principles of the Declaration of Helsinki.

The PIV, utilized as the measure of exposure, was determined using the following equation: PIV = [neutrophil count (10^9/L) × monocyte count (10^9/L) × platelet count (10^9/L)] divided by lymphocyte count (10^9/L). LTBI was assessed using the QFT-GIT test, which was performed according to the manufacturer's instructions. Peripheral blood samples were incubated with Mycobacterium tuberculosis-specific antigens at 37 °C for a duration of 16 to 24 h, after which interferon-gamma (IFN-γ) concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Interpretation of results followed the CDC recommendations for interferon-gamma release assays (IGRAs). Participants with a positive QFT-GIT were identified as having LTBI, and those with negative results were considered LTBI negative. If QFT-GIT results were indeterminate, a positive purified protein derivative (PPD) test-defined as an induration of 10 mm or greater-was used to classify the individual as LTBI positive, irrespective of risk factors.

Given that LTBI is a non-infectious, asymptomatic immunological state that does not itself cause death, the mortality analysis was prespecified as exploratory and descriptive, intended to assess whether baseline systemic inflammation (indexed by PIV) correlates with overall health status among individuals with LTBI. We analyzed all-cause mortality outcomes for LTBI patients using the NHANES Public-Use Linked Mortality File, which provides follow-up data on participants through probabilistic linkage to the National Death Index until December 31, 2019. The follow-up period began at the baseline examination at the mobile examination center and continued until death or the end of the observation period.

Data on several covariates were collected and included in the analysis. These potential covariates comprised age (years), gender (female/male), and race (Mexican American/Non-Hispanic Black/Non-Hispanic White/Other Hispanic/Other Races), marital status (married or not), poverty income ratio (PIR), education level (above high school or not), smoking history (yes/no), body mass index (BMI, kg/m), Hemoglobin A1c (HbA1c, %), diabetes (yes/no), hypertension (yes/no), cardiovascular disease (yes/no), serum uric acid (SUA, µmol/L), and the estimated glomerular filtration rate (eGFR, mL/min/1.73m). Calculation of eGFR was based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, integrating variables such as age, gender, race, and serum creatinine. Diabetes and hypertension were based on self-reported medical histories. Cardiovascular diseases (CVDs) status was determined based on self-reported history of heart attack, stroke, heart failure, coronary artery disease, or angina.

Statistical analyses followed CDC recommendations and accounted for NHANES's sampling weights. For continuous variables, median and interquartile range was reported, while categorical variables were summarized as counts and weighted proportions. Group differences were analyzed using the Kruskal-Wallis test and the chi-square test. The association between PIV and LTBI risk was evaluated using logistic regression models (Model 1: without covariate adjustment; Model 2: adjusted for age, gender, and race; Model 3: adjusted for age, gender, race, marital status, PIR, education, smoking, BMI, HbA1c, diabetes, hypertension, CVDs, SUA, and eGFR). Potential nonlinear patterns were explored with Restricted Cubic Spline (RCS). Subgroup analyses assessed potential effect modifiers, stratifying by age, gender, BMI, diabetes, hypertension, cardiovascular disease, and eGFR. Multivariate Cox regression examined the association of PIV with all-cause mortality among LTBI patients. Sensitivity analyses were conducted by excluding participants with major noncommunicable diseases (diabetes, hypertension, CVDs) and CKD (eGFR < 60 mL/min/1.73 m²) to assess the robustness of the results. PIV levels were also compared between individuals with LTBI and those who self-reported active TB in NHANES. All analyses were conducted with R version 4.2.1, and a two-sided P value < 0.05 denoted statistical significance.