Infection with Mycobacterium tuberculosis (M.tb) is traditionally thought to lead to three different outcomes in the human body: the eradication of M.tb, the development of active tuberculosis (TB), and the establishment of latent tuberculosis infection (LTBI). However, recent work by Coussens et al. (1) in The Lancet Respiratory Medicine proposes a more nuanced classification of outcomes following M.tb infection, highlighting the complexity of the disease spectrum (1). The term LTBI signifies the presence of M.tb within the host, albeit in a “dormant state” without any corresponding clinical manifestations. Once the immune system is compromised, M.tb has the opportunity to proliferate and cause disease (2). It is imperative not to underestimate the significance of LTBI, as approximately one-fifth of the global population is affected by it (3). Although LTBI is asymptomatic, it represents a potential reservoir for the transmission and progression of TB. The immune system plays a pivotal role in controlling the infection. In the majority of individuals, M.tb is controlled through the formation of granulomas, thereby preventing the proliferation of bacteria (4, 5).

The systemic immune-inflammation index (SIRI), calculated from the counts of neutrophils, monocytes, and lymphocytes in peripheral blood (6), has emerged as a promising tool for understanding the inflammatory processes underlying various diseases (7, 8). A clinical study involving 256 patients demonstrated that SIRI (>1.22) is a pivotal indicator for predicting the onset of coronary artery disease (9). A prospective study of 737 patients at Wuhan Jinyintan Hospital demonstrated that SIRI is a straightforward and effective inflammatory marker for predicting tuberculosis-related obstructive lung disease (10). A meta-analysis demonstrated that elevated SIRI was significantly associated with unfavorable prognosis in individuals diagnosed with colorectal cancer (hazard ratio [HR] = 2.65, 95% CI: 1.42-4.93). This suggests that SIRI may serve as an independent prognostic marker (11). Qian Zhou and colleagues observed that pretreatment SIRI may serve as a promising universal prognostic indicator in cancer (12). Tian Ren and colleagues demonstrated a statistically significant correlation between SIRI and all-cause mortality (HR = 2.18) as well as cardiovascular mortality (HR = 2.32) in patients with hyperuricemia (13).

SIRI is a newly developed composite measure that evaluates the overall level of inflammation in the body and has demonstrated significant promise as a prognostic indicator across various disease contexts. In the U.S. population, there was no known correlation between all-cause mortality and SIRI and LTBI. The present study, therefore, aimed to investigate the association between the SIRI and the risk of developing LTBI in U.S. adults through a population-based survey and to clarify the relationship between SIRI and all-cause mortality in patients with LTBI.

This study, based on the NHANES 2011-2012 database, provides the first comprehensive insight into the complex associations of the SIRI with LTBI and all-cause mortality. During the mean follow-up period of 92.35 months, a significant inverse association was identified between SIRI and LTBI (adjusted OR=0.76, 95% CI: 0.66-0.89). The observed association was consistent across gender, age group, BMI group, smoking status, alcohol consumption, and the presence of diabetes, hypertension, hyperlipidaemia, and CHD. Conversely, a significant positive association was observed between SIRI and all-cause mortality. Among patients with LTBI, each unit increase in SIRI was associated with a 48% higher risk of mortality (adjusted HR=1.48, 95% CI:1.01-2.15). The linear dose-response relationship was confirmed by RCS. The time-dependent ROC curve demonstrated that SIRI exhibited moderate predictive capacity for all-cause mortality. In the LTBI population, SIRI demonstrated AUCs of 0.731, 0.640, and 0.634 for predicting all-cause mortality at 1, 3, and 5 years, respectively.

The present study found that the mean age of participants in the highest SIRI tertile (T3) was significantly greater than that of those in the lower tertiles (T1 and T2). This finding is consistent with the report by Accardi G. et al. (19), which indicated that elevated SIRI levels correlate with advancing age (19). This phenomenon may reflect age-related immune dysregulation and the progressive accumulation of chronic low-grade inflammation, commonly referred to as “inflammaging” (20). However, when grouping participants by age at 60, the proportion of T3 was higher among individuals younger than 60, while the proportion of T1/T2 was greater among those aged 60 and older. This seemingly paradoxical phenomenon may reflect the varied inflammatory regulatory mechanisms present in different age groups. In the context of global aging, the number of individuals aged 60 and older is increasing rapidly, leading to a sharp rise in the prevalence of chronic diseases among the elderly and a growing number of individuals facing multiple coexisting diseases (21). Therefore, it is possible that the elderly population received anti-inflammatory or immunomodulatory therapies for multiple comorbidities, which may have contributed to the reduced proportion of T3 in the SIRI group. Additionally, the sample of the elderly population may have been underestimated due to survival bias; that is, individuals with high SIRI may have died from complications (22) and were not included in the cross-sectional study. Chronic low-grade inflammation is associated with increased rates of various age-related diseases and all-cause mortality (23–25). According to a study based on the NHANES, elevated systemic immune inflammation index (SII) and SIRI were significantly associated with all-cause mortality risk in the general population aged 60 and older. This suggests that as SII or SIRI levels increase, the risk of all-cause mortality in the elderly correspondingly rises (26). Additionally, a meta-analysis showed that high SIRI was significantly associated with both short-term and long-term mortality in stroke patients (27).

In recent years, the potential value of routine blood indicators for disease prediction has gradually attracted attention alongside the development of precision medicine. A study published in Nature in 2025 demonstrated that long-term stable set points of individual routine blood indicators can serve as biomarkers to predict the risk of various diseases, including cardiovascular disease, diabetes, and atrial fibrillation, thereby providing a new approach for early screening and personalized health management (28). An increased SIRI level indicates an intensified inflammatory state, which may result from an augmented neutrophil and monocyte count and/or a decreased lymphocyte count. LTBI is characterized by a latent immune response to M.tb, in which T-cell-mediated immunity plays a core role in controlling bacterial replication (29). Intriguingly, in the present study, we observed that lower SIRI levels were associated with the prevalence of LTBI in U.S. adults, even after adjusting for confounding variables. Similar to our study, previous research has found an inverse association between the neutrophil-to-lymphocyte ratio and the likelihood of LTBI (30). The underlying mechanisms linking SIRI to LTBI remain unclear. The association between the two may be due to the fact that the occurrence of M.tb infection is related to an individual’s low-grade inflammatory state. We speculate that this is primarily because the low-grade inflammatory state may weaken the immune function, making it easier for M.tb to invade and multiply. Evidence suggests that low-grade inflammation is associated with chronic diseases and metabolic disorders (31, 32). For example, patients with diabetes mellitus often experience chronic low-grade inflammation, which affects immune cell function, particularly the reduced activity of alveolar macrophages, thereby increasing the risk of infection (33).

The immune system is fundamental to human health, as most diseases and health conditions are closely linked to immune status. Routine blood parameters, including lymphocyte, monocyte, neutrophil, eosinophil, and basophil counts, are commonly used to assess immune cell status. This study further investigated the association between peripheral blood immune cell counts and the occurrence of LTBI (see Supplementary Tables 4 , 5 ). Our analysis revealed significantly lower monocyte and neutrophil counts in individuals with LTBI compared to non-LTBI controls (P < 0.05), with monocyte depletion showing a particularly strong association with LTBI development. This finding aligns with the critical role of monocytes in the immunoregulation of TB. Monocytes serve as precursors to macrophages, the primary phagocytic cells responsible for engulfing and restricting the growth of M.tb. Additionally, monocytes modulate inflammatory responses that influence disease progression. Reduced monocyte counts may compromise the host’s capacity for bacterial clearance. Notably, certain medications, such as glyburide, may exacerbate this vulnerability by suppressing monocyte activity (34). Recent transcriptomic analyses of monocyte-related genes revealed increased monocyte abundance in patients with active TB, while individuals with LTBI exhibited 165 differentially expressed monocyte-associated genes. These genes were enriched in pathways related to the inflammatory response and immune regulation, potentially influencing the establishment of latent infection through metabolic reprogramming or modulation of complement system activity (35). M.tb infection significantly alters the monocyte-to-lymphocyte ratio (MLR) in peripheral blood, with extreme MLR (<9% or >25%) serving as critical predictors of active TB (36).

However, since this part of the study is based on cross-sectional data, we cannot assess the causal relationship between low SIRI levels and M.tb infection. The association between the two may also be related to dynamic changes in the immune and inflammatory states associated with LTBI. Previous studies have indicated that LTBI is typically accompanied by a sustained, long-term low-grade inflammatory state, rather than a notable systemic inflammatory response (37). Moreover, long-term immune activation in individuals with LTBI might increase the risk of hypertension and atherosclerotic cardiovascular diseases (CVD) (38, 39). High SIRI values might be more related to other acute or chronic inflammatory diseases (such as CVD, chronic kidney disease, acute gout attacks, etc.) rather than LTBI (40–42). Additionally, SIRI values might not only be associated with the risk of LTBI but also predict the risk of LTBI progressing to active TB (43). Xiaoshan He et al. research found that the SIRI is an important inflammatory indicator for predicting cavitary lesions in pulmonary TB. A SIRI value higher than 2.095 is significantly associated with cavitary pulmonary tuberculosis, and the combination of CRP and PLR can significantly enhance the diagnostic sensitivity for cavitary pulmonary tuberculosis (44). This suggests that SIRI, as an inflammatory marker, may play an important role in immune monitoring and in predicting disease progression in LTBI. In the future, prospective cohort studies could be conducted to monitor changes in SIRI at different stages of TB (incubation, progressive, and active) and to verify its value as a predictor.

In the present study, no significant associations were observed between monocyte count, lymphocyte count, and neutrophil count and all-cause mortality in patients with LTBI (see Supplementary Tables 11 , 12 ). However, a composite measure of these three cell types, the SIRI, demonstrated a significant association with all-cause mortality. This finding suggests that the relationship between cell counts alone and mortality may be obscured by other factors, and that SIRI, as a composite indicator, can more effectively reflect the overall health status of patients.

SIRI has emerged as a novel and cost-effective serum biomarker for predicting all-cause mortality. The observed positive association between elevated SIRI levels and increased mortality aligns with findings from previous research. Numerous studies have demonstrated that higher SIRI levels are linked to an increased risk of all-cause mortality across various conditions, including asthma (45), chronic kidney disease (46), hypertension (47), and heart failure (48). Our findings further support this association, showing that elevated SIRI levels are significantly correlated with increased all-cause mortality risk in patients with LTBI. As an integrative marker of inflammation and immune function, SIRI reflects the dynamic interplay between neutrophils, monocytes, and lymphocytes. Elevated SIRI levels indicate a heightened inflammatory state and may serve as a potential predictor of cardiovascular disease (38–41). In patients with LTBI and high SIRI levels, persistent inflammation could exacerbate comorbidities such as cardiovascular disease and diabetes, ultimately increasing mortality risk (49, 50). Research has indicated that diminished monocyte counts and elevated lymphocyte-to-monocyte ratios are significantly associated with unfavorable outcomes in TB (51). Estevez O. et al. conducted a retrospective analysis of 52 patients with tuberculosis and found that a lower monocyte count and a higher lymphocyte-to-monocyte ratio were significantly associated with an increased risk of death within 3 months (52). They also found that longitudinal changes in monocyte counts serve as prognostic indicators.

Despite the absence of direct data from patients with active TB in the present study, a comprehensive review of the existing literature revealed the significant potential value of inflammatory markers such as the SIRI, MLR, neutrophil-to-lymphocyte ratio (NLR), and CD64 expression in distinguishing between different types of TB and its active state. For instance, SIRI levels were found to be significantly higher in patients with cavitary pulmonary TB than in those with non-cavitary pulmonary TB, suggesting that SIRI may serve as a potential biomarker to distinguish between these two types of pulmonary TB (44). Chai et al. demonstrated that SIRI levels were elevated in patients with pulmonary TB compared to those with non-TB pulmonary infections (53). Furthermore, MLR has been shown to be significantly higher in patients with active TB than in those with LTBI and healthy donors. The MLR and CD64 expression have been identified as effective biomarkers that can help distinguish active TB from other states (54). Single-cell RNA sequencing and flow cytometry have revealed an increased proportion of monocytes in patients with active TB (55). The study by Fritschi N et al. demonstrated that elevated MLR and NLR were significantly associated with M.tb infection compared with healthy controls (56). Furthermore, studies have demonstrated that SIRI can be utilized as a biomarker for expedited screening of multidrug-resistant TB when combined with the cardiometabolic index, yielding an AUC value of 0.910 in patients with new-onset TB (57). These findings underscore the significance of inflammatory markers such as SIRI in the diagnosis and prognostic assessment of TB.

This study has several significant advantages. Firstly, the nationally representative sample based on the NHANES database ensures the external validity of the research findings. Secondly, the research employs rigorous statistical methods, including multivariate adjustment, subgroup analysis, and restricted cubic spline analysis, thereby enhancing the reliability of the findings. Thirdly, this is the inaugural study to investigate the correlation between SIRI and LTBI, thereby offering a novel perspective for comprehending the function of inflammatory responses in tuberculosis infection. Furthermore, the relatively long follow-up period (with an average of 92.35 months) allows for the reliable assessment of the relationship between SIRI and long-term prognosis.

There are certain limitations to our study. Firstly, it is not possible to determine the causal relationship between SIRI and LTBI. Secondly, SIRI was derived from a single complete blood count rather than multiple measurements over time, which may have introduced bias. Thirdly, although multivariate adjustment was conducted, there may still be unidentified confounding factors. Fourthly, the study was unable to obtain comprehensive medication data from the participants, which may have influenced the observed levels of inflammatory markers. In addition, the use of Mtb sensitization (as measured by TST or QFT) as a proxy for LTBI is a limitation in TB research and clinical practice. In conclusion, due to the nature of the NHANES database, the study results are primarily applicable to the U.S. population. Further verification is required to evaluate the generalizability of the findings in other populations.

Our findings reveal an inverse correlation between SIRI and LTBI in the U.S. adult population, with higher SIRI levels associated with a lower risk of LTBI. However, in individuals with LTBI, a higher SIRI was associated with an elevated risk of all-cause mortality.