The primary classifications of chronic respiratory disease (CRPD) encompass COPD and asthma (1). The condition is primarily characterized by airflow limitation (AL). The global incidence of CRPD is notably high and demonstrates an upward trend annually (1, 2). CRPD prevalence and severity are silent plagues that erode society’s health (3). In 2019, there were more than 400 million CRPD cases and more than 4 million deaths globally, an increase of 28.5 % and 39.8 % from 1990, respectively (3). Deaths from COPD, the leading cause of mortality among CRPDs, surpassed 3 million. In addition, there are more than 200 million cases of asthma, which has the highest prevalence among CRPD (3). All of this indicates the current grim situation of CRPD. Therefore, screening for CRPD at an early stage, before it becomes symptomatic and progresses, is crucial.

At an early stage of CRPD, lung function assessment has advantages (4–6). However, lung function is only tested at the onset of respiratory symptoms. Furthermore, lung function testing is not widely used as part of health screening or primary care (7, 8). A United States study indicates that despite improvements in spirometer use for COPD detection and management in primary care following the National Lung Health Education Program (NLHEP), 70% of COPD patients remain undiagnosed through spirometry (9). In epidemiology, a straightforward biomarker for early-stage lung dysfunction could aid in the disease’s assessment, management, and treatment.

Inflammation holds a vital position in lung dysfunction, with various biomarkers such as C-reactive protein (CRP), lymphocytes, neutrophil-to-lymphocyte ratio (NLR), and platelets being indicative of its severity and progression. These markers are cost-effective, stable, and reproducible (10, 11). A relatively new nutritional indicator of inflammation is the CALLY index. The CALLY index was initially identified as a quick and straightforward biomarker for evaluating the anticipated progression of patients with non-small cell lung cancer (12). CALLY is a novel, comprehensive inflammatory index that integrates serum albumin, lymphocyte count, and CRP. These interrelated components serve as indicators of an individual’s nutritional status, immune function, and level of inflammation, respectively (13). The CALLY score’s clinically accessible parameters have garnered increasing attention. CLR, a composite biomarker combining neutrophils and CRP, is also a cost-effective and accessible option. CLR is linked to poor prognosis in non-small cell patients, aiding in predicting postoperative outcomes (14).

Currently, there is a lack of academic findings on the relationship between two inflammatory markers, the CALLY index and CLR, and COPD. In the past, most of the research on the CALLY index and CLR in pulmonary diseases was confined to lung cancer (12, 14). There were few studies on COPD, which is closely associated with inflammation. Recently, the team led by Yu Ding explored the influence of the CALLY index on the survival prognosis of COPD patients (15). However, the database used in this study had relatively old data and only focused on this single CALLY index. In contrast, the data our team used in this study is more recent and can better represent the current clinical situation. Moreover, we combined multiple inflammatory indicators to compare their impacts on COPD patients comprehensively and investigated the predictive performance among them. This study was like a detective seeking to evaluate the connection between blood inflammatory biomarkers and the risk of COPD and to explore whether these biomarkers could act as early warning beacons for COPD using data from the 2017 to March 2020 NHANES in the United States.

In addition, existing studies have shown that inflammatory markers are of great significance in cardiovascular diseases and other aspects. For example, the research team led by Karakayali et al. (16) found that the systemic immune-inflammation index (SII), as a new inflammatory marker, is associated with coronary artery disease. Similarly, the C-reactive protein to albumin ratio (CAR) has also been proven to be related to the severity of coronary artery disease (17). These studies suggest that inflammatory markers may play a crucial role in various diseases and also provide a reference for exploring the relationship between the CALLY index, CLR, and COPD.

No academic studies in the United States have examined the correlation between the CALLY Index, CLR, and COPD in middle-aged and older adults. Researchers sampled 15,560 people between 2017 and March 2020, with a final 2,300 enrolled after multiple screenings to determine if the inflammatory index was associated with COPD. Multifactorial logistic regression analyses revealed a strong negative association between the CALLY index and COPD prevalence, while CLR exhibited a positive relationship with COPD. Additional subgroup analyses were performed to assess the precision and robustness of this association. Figure 2 presents the results. The inverse relationship between the CALLY index and COPD was stronger among participants aged 60 and above, as well as non-Hispanic whites. The opposite conclusion can be affirmed by subgroup analyses of the CLR. Furthermore, this phenomenon was consistent across the entire population sample. An RCS curve-fitting model was constructed to further assess the reliability of the results.

The study reveals a substantial finding that the CALLY index is negatively correlated with COPD, with a P-non-linearity value of 0.604, indicating that a lower CALLY Index may increase COPD incidence. Consistent with previous descriptions, the positive association of CLR with COPD was also confirmed here. After adjusting for relevant variables, ROC curve analysis revealed that the CALLY index and CLR are more predictive of COPD risk compared to other hematological inflammation indicators.

The prevalence of COPD among individuals with obesity is exhibiting a year-on-year increase (20). COPD involves ongoing airflow restriction linked to an increased chronic inflammatory response in the respiratory system. Patients with COPD often experience pulmonary alterations accompanied by changes in the composition of their body (21, 22), dysfunction of the skeletal musculature (23), diseases related to the cardiovascular and circulatory systems (24), mood disorder (25), inflammatory bone disease, decreased physiological tolerance of exercise (26), and inflammation throughout the body (27). Inflammatory responses could constitute a significant risk factor for additional complications associated with COPD (28). COPD patients face a heightened risk of extrapulmonary manifestations and comorbidities, including cardiovascular disease and pulmonary carcinoma, which substantially assist in the transmission of diseases (29–31). The assessment of lung function is presently regarded as the primary diagnostic approach for COPD. However, lung function testing is only performed when respiratory symptoms occur (7, 8). A United States study indicates that despite improvements in spirometry use for COPD detection and management in primary care following the NLHEP implementation, 70% of COPD patients have not received spirometry testing (9). A straightforward biological marker for early-stage COPD screening could aid in its evaluation, management, and treatment.

As one of the most widely studied biomarkers in COPD, CRP occurs during pathological changes (32–34), severe destruction of lung parenchyma, and the onset of inflammatory response in this disease (35). A previous study elucidated that immediate detection of CRP can reduce the unnecessary use of antibiotics for patients with acute exacerbations of COPD and help improve antibiotic management to reduce overtreatment (36). In addition to identifying better COPD prevention and treatment strategies, aggressive or supportive treatment for COPD can also be facilitated through the pursuit of novel markers (37–40). Wang’s team investigated the link between NLR and lung function decline, indicating COPD risk. The study indicates that the NLR is a significant biomarker linked to impaired lung function and increased COPD risk, based on its correlation with DNA methylation profiles, by examining the clinical features of patients with acute COPD exacerbations and the NLR’s prognostic value. The NLR is acknowledged as an effective prognostic biomarker for severe acute COPD exacerbation due to its proven performance in various studies and its accessibility (41).

The CALLY index is an innovative measure that integrates various aspects of nutritional status, immune function, and inflammation levels (42–45). Acknowledging the TNM staging system’s limitations, including tumor heterogeneity, molecular traits, and immune status, Liu’s team developed and validated the CALLY index for predicting non-small cell lung cancer prognosis. They also created a CALLY-based nomogram model to forecast long-term outcomes for NSCLC patients. The study demonstrated that compared to high scores, low CALLY index scores were associated with much poorer overall survival, aligning with our findings in COPD. The new predictive model surpasses the traditional TNM staging system by simultaneously integrating multiple independent variables to numerically estimate the likelihood of clinical events. In addition, based on the morphometric map of the CALLY index, clinicians can risk-stratify each lung cancer patient according to different risk factors and thus develop personalized treatment strategies as early as possible (12). A recent study by Nagano et al. (14) assessed the prognostic significance of preoperative inflammatory markers, the findings of this study indicate that, among the inflammatory markers analyzed, the CLR demonstrates highly significant predictive advantages in forecasting surgical outcomes for those diagnosed with non-small cell lung cancer. This marker can serve as a critical reference for healthcare professionals in assessing postoperative recovery and the risk of disease progression, thereby facilitating the development of more personalized treatment and follow-up plans.

No research has explored the association between the CALLY index and CLR, both indicators of inflammation, and COPD. This survey is the first cross-sectional study to examine their relationship with COPD. The survey used NHANES data from 2017 to March 2020, with 15,560 participants taking part in the 2017–2020/3 survey cycle. A final sample size of 2,300 was achieved by applying strict inclusion and exclusion criteria to ensure comprehensive and accurate results. In this study, we confirmed that both the CALLY index and CLR predicted the risk of developing COPD, and both performed slightly better than the NLR.

This study has multiple advantages. The study utilized a sample that is representative of middle-aged and older Americans, balanced for age and gender, to evaluate the relationship between the CALLY Index, CLR, and COPD, ensuring standardized and high-quality measurements reflective of the general United States population. This study uniquely explores the association between these two novel inflammatory indices and COPD. Second, we adjusted for potential confounders by adjusting for covariates such as sociodemographic factors and lifestyle variables. Third, we performed subgroup analyses to elucidate their respective differential effects on COPD in different subgroups. Through fully adjusted models and RCS curve fitting, we identified a linear negative association between the CALLY index and COPD in middle-aged and older Americans, contrasting with the positive correlation observed between CLR and COPD, thereby minimizing potential confounding bias. After adjusting for all relevant variables, the CALLY index and CLR were found to be more effective in predicting the risk of developing COPD, with an improved AUC of 0.831. These findings suggest that, among other markers of hematological inflammation, the CALLY index and CLR may be better indicators for estimating the probability of the risk of developing COPD in such patients. The team led by Karakayali et al. (46) found that the HALP (hemoglobin, albumin, lymphocyte, and platelet) score, as an indicator reflecting nutritional status and systemic inflammation, is associated with the in-hospital mortality of patients with ST-segment elevation myocardial infarction. This is similar to the conclusion of our study, in which the CALLY index and CLR reflect the body’s inflammatory and nutritional status and thus affect the disease risk, further supporting the importance of inflammation - and nutrition-related indicators in the assessment of disease prognosis.

The CALLY index integrates serum albumin, lymphocyte count, and CRP, enabling it to comprehensively reflect an individual’s nutritional status, immune function, and inflammation level (12). A higher CALLY index implies a better nutritional status (normal albumin level), stronger immune function (adequate lymphocyte count), and a lower inflammation level (low CRP level). These factors may act together to reduce the risk of COPD, thus giving it good predictive ability for COPD risk (36, 47).

An elevated CRP level indicates the presence of an inflammatory response in the body. When the lymphocyte count is relatively low, the CLR value increases, suggesting a relatively strong inflammatory response and a relatively weak immune defense (14). This makes it difficult for the body to effectively deal with inflammation, further exacerbating the pathological damage in the lungs and increasing the risk of COPD, making it an effective predictor of COPD risk.

During the development of COPD, there is a disorder in the immune function, with abnormalities in the number or function of lymphocytes. When the CALLY index is high, the number of lymphocytes is sufficient, and the immune function is relatively normal, which can better regulate the immune response, resist pathogen infections, reduce lung inflammation, and lower the risk of COPD. Conversely, when the CLR increases, the number of lymphocytes is relatively insufficient, the immune-regulatory function is impaired, and the inflammatory response cannot be effectively controlled, thus promoting the development of COPD.

The pathogenesis of COPD is closely related to multiple inflammatory signaling pathways, such as the nuclear factor - κB (NF - κB) pathway (37, 48). Under normal circumstances, NF - κB is in an inhibitory state. When stimulated by inflammation, NF - κB is activated, translocates into the nucleus, and initiates the expression of a series of inflammation-related genes, including pro-inflammatory cytokines (such as tumor necrosis factor - α, interleukin - 6, etc.,) and chemokines, leading to an exacerbation of the inflammatory response (49). CRP can promote the inflammatory response by activating the NF - κB pathway. Albumin in the CALLY index may have antioxidant and anti-inflammatory effects, which can inhibit the activation of the NF - κB pathway and reduce the production of inflammatory factors (50). Therefore, when the CALLY index is high, the activation of the inflammatory signaling pathway is inhibited, which helps to reduce the risk of COPD. When the CLR increases, it means that the relative amount of CRP to lymphocytes increases, which may further activate the NF - κB pathway, aggravate lung inflammation, and increase the risk of COPD (51).

Oxidative stress also plays an important role in the pathogenesis of COPD. A large number of reactive oxygen species (ROS) generated by oxidative stress can damage airway epithelial cells, lung parenchymal cells, etc., leading to cell dysfunction, aggravated inflammation, and tissue damage (52). Lymphocytes have a certain antioxidant capacity and can scavenge ROS by producing antioxidant enzymes (such as superoxide dismutase, glutathione peroxidase, etc.) (53). When the CALLY index is high, the number of lymphocytes is sufficient, and the antioxidant capacity is strong, which can effectively reduce the damage of oxidative stress to lung tissues and lower the risk of COPD (54). When the CLR increases, the number of lymphocytes is relatively insufficient, the oxidative stress damage cannot be effectively repaired, the inflammatory response persists, and thus promoting the development of COPD (55).

A significant limitation of our study was its cross-sectional design, which restricted the ability to determine causal and temporal relationships between the CALLY index, CLR, and COPD. Even though multiple covariates such as age, gender, race, education level, marital status, smoking history, drinking history, and diabetes were included in the analysis, there may still be other unmeasured factors influencing the relationship between COPD risk and inflammatory markers. For example, environmental factors such as long-term exposure to air pollution and occupational dust may simultaneously affect the occurrence of COPD and the levels of inflammatory markers, but these were not measured and adjusted for in this study. Individual genetic susceptibility may also play an important role in the development of COPD and is related to the inflammatory response. However, this information is missing from the study. These unmeasured factors may interfere with the observed association between inflammatory markers and COPD risk in the study. In addition, the association between these two inflammatory indices and COPD needs to be further validated by larger cohort studies and more prospective studies. Even after additional covariates are screened and employed to control for detection bias, unexplained confounding factors may persist. Although these factors might contribute to COPD etiology, they are not explicitly documented in the NHANES database. As our research primarily targeted middle-aged and elderly individuals, we excluded COPD results for younger participants.

In conclusion, our study identified a linear negative relationship between the CALLY index and COPD, independent of potential confounders. A higher CLR is linked to an elevated risk of COPD development. Both the CALLY index and CLR were superior in predicting the risk of developing COPD. Our findings emphasize that the CALLY index with CLR may be a new inflammatory early warning biomarker for COPD. The inherent limitations of studies using cross-sectional methods necessitate further prospective studies to verify the causality of this association.