Inflammatory score, intrinsic capacity and the risk of new-onset chronic lung disease: a cohort study from the China Health and Retirement Longitudinal Study

Abstract

Background

Chronic lung disease (CLD) presents a substantial health challenge among aging populations. Currently, the roles of intrinsic capacity (IC) and inflammatory score (IS) in the development of CLD remain to be fully elucidated. This study aimed to investigate the associations of IC and IS with the risk of CLD in older adults.

Methods

This study analyzed data from 5,425 participants aged 45 years and older without CLD at baseline, drawn from the nationally representative China Health and Retirement Longitudinal Study (CHARLS). Participants were followed from 2011 to 2015. Assessment of IC covered six domains according to standardized guidelines. An IS was derived by summing standardized C-reactive protein (CRP) and white blood cell (WBC) values from fasting samples. The associations of IC and IS with new-onset CLD were analyzed using generalized linear models (GLMs), adjusting for demographic, socioeconomic, and behavioral covariates.

Results

Among 5,425 participants (mean age 57.8 years; 49.9% women), 316 (5.8%) developed CLD during follow-up. An elevated IS was significantly associated with a higher risk of new-onset CLD, with participants in the highest quartile exhibiting 38% greater odds compared to the lowest quartile after full adjustment [odds ratio (OR) =1.38, 95% confidence interval (CI): 1.01–1.90]. Conversely, IC showed a strong protective effect, with each unit increase linked to a 20% reduction in CLD risk (OR =0.80, 95% CI: 0.73–0.88) in fully adjusted models. Dose-response analyses confirmed linear associations for both markers.

Conclusions

The results indicate that greater IC corresponds to a reduced likelihood of developing new-onset CLD, whereas elevated systemic inflammation is linked to an increased risk of new-onset CLD.

Highlight box.

Key findings

• The greater intrinsic capacity (IC) corresponds to a reduced likelihood of developing new-onset chronic lung disease (CLD), whereas elevated systemic inflammation is linked to an increased risk of new-onset CLD.

What is known and what is new?

• CLD is prevalent in aging populations, and systemic inflammation plays a role in its pathogenesis. IC has been proposed as a key indicator of healthy aging, but evidence linking IC to respiratory outcomes is limited.

• This study provides prospective evidence that IC is a strong protective factor against incident CLD, while systemic inflammation increases CLD risk. It is among the first studies to jointly examine IC and inflammation in relation to CLD development in a large population-based cohort.

What is the implication, and what should change now?

• Incorporating IC assessment and IS into routine evaluations may improve early identification of individuals at risk for CLD. Interventions aimed at maintaining functional capacity and reducing systemic inflammation may represent promising strategies for the prevention of CLD in aging populations.

Introduction

Chronic lung disease (CLD), primarily comprising chronic obstructive pulmonary disease (COPD) and asthma, represents a serious global health problem, characterized by persistent airflow obstruction and progressive loss of respiratory performance, with substantial heterogeneity in clinical phenotypes and disease progression (1). Globally, CLD-related deaths have increased by 18% over the past three decades, with the highest mortality and disability-adjusted life years (DALYs) observed in low sociodemographic index (SDI) regions—notably Africa, the Middle East, Central and Southeast Asia, and South America. These disparities disproportionately affect low- and middle-income countries (LMIC) (2-4). In China, CLD imposes a significant dual health and economic burden, posing particular challenges for LMIC populations (5). The predominant risk factors for CLD include tobacco smoking, ambient and household air pollution, and occupational exposures (6-8).

Persistent systemic inflammation critically contributes to CLD pathogenesis and advancement through induction of tissue remodeling and rapid loss of function. Leukocytes, well-established markers of inflammation, also act as surrogate indicators of cardio-metabolic risk factors predictive of cardiovascular disease (CVD). Beyond their individual roles, combining leukocyte counts with C-reactive protein (CRP) into an inflammatory score (IS) provides a more robust measure of systemic inflammation. This composite approach reduces the influence of short-term biological variability and daily fluctuations that may affect single markers, thereby better reflecting cumulative inflammatory burden over time. The IS enables longitudinal assessment of cardio-metabolic health trajectories, offering dual clinical utility for both CVD risk stratification and therapeutic response evaluation (9). Concurrent elevations of fibrinogen (>14 µmol/L), white blood cell (WBC) count (>9×10⁹/L), and CRP (>3 mg/L) have been linked to a 3.7-fold increased risk of frequent acute exacerbations within one year. Moreover, advanced cardiovascular-kidney-metabolic syndrome (stages 3–4) is strongly associated with elevated CLD risk, with high-sensitivity CRP (hsCRP) identified as a key mediator of this relationship (10). Elevated CRP levels are also significantly correlated with both absolute and relative declines in forced expiratory volume in one second (FEV1) among COPD patients (11). Thus, the IS represents a valuable tool for quantifying systemic inflammation and predicting disease risk and clinical outcomes across diverse populations (9). Although this inflammation index has been validated primarily in CVD populations (12), its application in CLD remains largely unexplored.

Intrinsic capacity (IC), as defined by the World Health Organization (WHO), refers to the totality of an individual’s physical and psychological functions, has recently gained attention as an important factor influencing health trajectories in chronic diseases (13,14). The IC framework encompasses five domains: cognition, mobility, psychological well-being, vitality, and sensory function. In support of this framework, the WHO issued two key guidelines—Integrated Care for Older People (ICOPE) in 2017, and the Handbook: Person-centred Assessment and Pathways in Primary Care in 2019-offering recommendations for community-based interventions and clinical practice, respectively (15,16). Tracking IC trajectories in older adults may inform strategies to prevent, delay, or mitigate adverse health outcomes such as chronic disease progression, functional decline, disability, frailty, falls, and mortality. Longitudinal studies on IC can elucidate its temporal dynamics and determine whether continuous IC monitoring predicts these adverse outcomes (17). Prospective data from the UK Biobank identify the IC deficit score as a significant predictor of both functional decline and cardiovascular risk trajectories, highlighting its potential as a clinical screening tool for early preventive interventions (18). Furthermore, a meta-analysis has demonstrated that IC is negatively correlated with the risk of functional decline and mortality in the elderly population, these findings underscore the potential of IC as a hallmark metric of healthy ageing (19). Consequently, IC has been proposed as a biomarker for monitoring implementation progress and evaluating intervention effectiveness within the United Nations Decade of Healthy Ageing (20).

Although both IS and IC have been independently linked to respiratory health, their interplay in relation to the risk of new-onset CLD remains poorly understood. Elucidating their combined and interactive effects is essential for advancing our understanding of new-onset CLD pathophysiology and may offer novel opportunities for early detection and intervention. This study sought to explore the relationships of IS and IC with the risk of developing CLD, thereby filling an important gap in current respiratory and gerontological research. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2075/rc).

Methods

The data utilized in this study were obtained from the China Health and Retirement Longitudinal Study (CHARLS), a comprehensive longitudinal survey that is nationally representative and focuses on individuals in China who are aged 45 years and older (21). CHARLS was designed to investigate the aging process in China and to support research on health, socioeconomic status, and retirement among adults. The present study utilized data from the 2011 baseline survey, which collected detailed information on demographics, health status, physical measurements, and other relevant variables, along with follow-up data from the 2015 wave (21,22). Venous blood biomarkers were obtained from biospecimen data collected in the CHARLS (23). CHARLS data are publicly available at http://charls.pku.edu.cn/en. The CHARLS study received approval from the Institutional Review Board of Peking University in 2008, under the identification number IRB00001052-11015, and all participants provided written informed consent. The current study complied with all relevant CHARLS protocols and ethical guidelines.

A total of 17,708 participants were recruited at baseline in 2011, and after applying exclusion criteria, 5,425 individuals were included in the final analysis. The flow of participant inclusion is presented in Figure 1. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Figure 1.

Flowchart of study participants. CLD, chronic lung disease.

Assessment of CLD

CLD status was determined through structured interviews, during which participants were asked, “Have you been diagnosed with CLD by a doctor?”. A response of “yes” indicated a self-reported physician diagnosis of CLD, while a response of “no” indicated no such diagnosis. Participants reporting asthma were excluded. This standardized approach aligns with previously validated methods and facilitates reliable identification of self-reported CLD (24). IC and inflammation score were assessed at baseline before the onset of CLD, and only incident CLD cases occurring during follow-up were included in the analysis.

Assessment of IC

In accordance with WHO guidelines, IC assessment covered six dimensions: locomotion, vitality, hearing, vision, cognition, and psychological function, using standardized operational definitions (25-28). Each domain received a score of 1 for normal function or 0 for functional impairment, yielding a total IC score ranging from 0 to 6, where higher scores indicate superior capacity (29).

1. Locomotion was evaluated using the five-times sit-to-stand test. Participants who completed five repetitions independently within 14 seconds were scored 1, while those requiring more than 14 seconds were scored 0 (26).

2. Vitality was assessed by calculating the body mass index (BMI). Based on the Malnutrition Universal Screening Tool (MUST), individuals with BMI >18.5 kg/m² received a score of 1, while those with BMI ≤18.5 kg/m² were scored 0 (30).

3. Hearing was evaluated via the question “What is your level of auditory function?”. Participants who responded “poor” were scored 0, participants indicating “good”, “very good”, “excellent”, or “fair” were given a score of 1.

4. Vision was assessed based on responses to two questions: “How well do you see distant things?” and “How well do you see near things?”. Participants were scored 1 if both answers were “fair”, “good”, “very good”, or “excellent”. A response of “poor” to either question resulted in a score of 0.

5. Cognition was assessed using the Telephone Interview of Cognitive Status (TICS), comprising memory and mental status components (31). (i) Memory was assessed using immediate and delayed recall of 10 unrelated words. A total of 20 points could be achieved. Mental status included correct orientation (5 points: day, month, year, day of week, and season), serial subtraction of 7 from 100 (5 points), and visuoconstruction ability assessed by replicating two overlapping pentagons (1 point), totaling 11 points. (ii) Participants were classified as having intact cognitive function (score =1) if both memory and mental status scores were above the threshold defined as one standard deviation (SD) below the mean; otherwise, a score of 0 was assigned.

6. The psychological condition was evaluated using the Center for Epidemiologic Studies Depression Scale (CES-D). A score <12 was considered intact and scored 1; a score ≥12 indicated impairment and was scored 0 (32).

Assessment of IS

Blood samples from the venous system were obtained from the participants following a night of fasting at the initial assessment. Plasma concentrations of CRP were measured from frozen specimens using an immunoturbidimetric assay. Automated hematology analyzers in certified clinical laboratories were employed to determine WBC counts (21). For each biomarker, Z-scores were computed using the formula: Z-score = (X − M)/SD, where X denotes the individual measurement, M the cohort mean, and SD the standard deviation. An inflammation score was subsequently derived by summing the z-scores of CRP and WBC (9,33).

Assessment of covariates

A range of potential confounders was included in the analysis, encompassing sociodemographic, socioeconomic, and health-related behavioral factors. Sociodemographic variables consisted of age, gender, BMI, marital status (married vs. single), residential location (city/town vs. village), and education status (elementary school or below vs. middle school or above). Health-related behaviors included smoking status (smoker vs. non-smoker) and drinking status (drinker vs. non-drinker) (34-38).

Statistical analysis

Continuous variables following a normal distribution were presented as mean ± SD, while those with skewed distribution were presented as median and interquartile range (IQR). Categorical variables were expressed as counts and percentages. Baseline characteristics were compared between participants with and without new-onset CLD using the Chi-squared test for categorical variables and independent-sample t-tests for continuous variables, as appropriate. To evaluate inflammation index and IC as potential risk factors for new-onset CLD, regression analyses were subsequently performed.

To evaluate the associations of IS and IC with the risk of CLD, generalized linear models (GLMs) specifying a binomial distribution and logit link function were utilized. IS was analyzed both as a continuous variable (per IQR increment) and as a categorical variable based on quartiles (Q1–Q4). Three logistic regression models were sequentially constructed: crude model (Model 1), without any adjustments; Model 2 was adjusted for sociodemographic and socioeconomic factors including age, gender, marital status, educational attainment, and place of residence; and Model 3 was further adjusted for health-related behavioral factors and physical condition, including smoking status, drinking status, and BMI, to account for potential confounding effects. Results were reported as odds ratios (ORs) with corresponding 95% confidence intervals (CIs).

Restricted cubic spline (RCS) regression was applied to examine potential non-linear associations between IS, IC, and the risk of CLD. Non-linearity was evaluated using likelihood ratio tests that compared models with and without spline terms. To explore potential effect modification, multiplicative interaction terms [e.g., CLD × (interaction term)] were incorporated into the fully adjusted model. Stratified analyses were further performed to evaluate the consistency of associations across key subgroups (39). Statistical analyses were performed using R software (version 4.2; http://www.R-project.org), with RCS implemented via the “rms” package. All statistical tests were conducted as two-sided, with a significance level set at P<0.05.

Results

Baseline characteristics of the study population

Table 1 presents a summary of the initial demographic and clinical characteristics of participants, categorized according to the occurrence of incident CLD. A total of 5,425 individuals were involved, with a mean age of 57.8 years (SD: 8.5 years); 2,707 (49.9%) were women. During follow-up, 316 participants (5.8%) developed CLD. Participants who developed CLD were significantly older (59.3 vs. 57.7 years, p=0.001), had lower IC scores (4.5 vs. 4.9, P<0.001), and lower BMI (23.2 vs. 23.8 kg/m², P=0.006) compared to those without CLD. The proportion of males was higher in the CLD group (59.81% vs. 49.50%, P<0.001), and a greater percentage were current smokers (50.95% vs. 40.05%, P<0.001).

Table 1. Baseline characteristics of the study population with and without CLD.

Characteristic	Without new-onset CLD	With new-onset CLD	P value
Age (years)	57.7±8.5	59.3±8.8	0.001
Gender			<0.001
Female	2,580 (50.50)	127 (40.19)
Male	2,529 (49.50)	189 (59.81)
Marital status			0.58
Married	4,616 (90.35)	282 (89.24)
Single	493 (9.65)	34 (10.76)
Education status			0.07
Elementary school or below	3,291 (64.42)	220 (69.62)
Middle school or above	1,818 (35.58)	96 (30.38)
Residence status			0.71
City/town	1,856 (36.33)	111 (35.13)
Village	3,253 (63.67)	205 (64.87)
Smoking status			<0.001
Non-smoker	3,063 (59.95)	155 (49.05)
Smoker	2,046 (40.05)	161 (50.95)
Drinking status			0.20
Non-drinker	3,008 (58.88)	174 (55.06)
Drinker	2,101 (41.12)	142 (44.94)
BMI (kg/m2)	23.8±3.8	23.2±3.7	0.006
Intrinsic capacity	4.9±1.1	4.5±1.3	<0.001
Inflammatory score	−0.1±1.3	0.2±1.4	0.001
Quartiles of IS			0.009
Q1	1,274 (24.94)	72 (22.78)
Q2	1,292 (25.29)	63 (19.94)
Q3	1,285 (25.15)	78 (24.68)
Q4	1,258 (24.62)	103 (32.59)

Data are presented as mean ± standard deviation or n (%). BMI, body mass index; CLD, chronic lung disease; IS, inflammatory score; Q, quartile.

Regarding inflammatory status, participants with CLD had significantly higher IS levels (mean: 0.2 vs. −0.1, P=0.001). When categorized into quartiles, the distribution also differed significantly between groups (P=0.009), with a higher proportion of individuals in the highest quartile (Q4) among those with CLD (32.6% vs. 24.6%). No significant differences were observed in marital status, drinking status, educational level, or residential location between the two groups (P>0.05).

Association between IS quartiles and the risk of new-onset CLD

The association between the IS quartiles and the risk of incident CLD is summarized in Table 2. When individuals were divided into quartiles, those in the uppermost quartile of IS (Q4) exhibited a markedly higher likelihood of experiencing newly diagnosed CLD in comparison to participants in the lowest quartile (Q1). In Model 1, the OR for new-onset CLD in Q4 was 1.45 (95% CI: 1.06–1.98; P for trend <0.05). This association remained robust after adjusting for age, gender, education, residence, marital status, and BMI in Model 2 (OR =1.42; 95% CI: 1.04–1.95; P for trend <0.05). In the Model 3, which further accounted for smoking and drinking status, the association persisted (OR =1.38; 95% CI: 1.01–1.90; P for trend <0.05). A significant linear trend was observed across IS quartiles (P for trend <0.05), indicating a dose-response relationship between systemic inflammation and CLD risk. Sensitivity analyses treating IS as a continuous variable yielded consistent results, further confirming an independent and positive association between elevated IS and increased risk of new-onset CLD across all models (Table S1).

Table 2. Association between IS quartiles and the risk of new-onset CLD.

Model	Quartile of IS, OR (95% CI)				P for trend*
	Q1	Q2	Q3	Q4
Model 1	1.00 (Ref)	0.86 (0.61–1.22)	1.07 (0.77–1.50)	1.45 (1.06–1.98)*	<0.05
Model 2	1.00 (Ref)	0.85 (0.60–1.20)	1.07 (0.77–1.50)	1.42 (1.04–1.95)*	<0.05
Model 3	1.00 (Ref)	0.84 (0.59–1.20)	1.06 (0.76–1.47)	1.38 (1.01–1.90)*	<0.05

Model 1: crude model; Model 2: adjusted for age, gender, educational level, residence, marital status, BMI; Model 3: adjusted for age, gender, educational level, residence, marital status, BMI, smoking status, drinking status. *, P value for linear trend calculated from category median values (P<0.05). BMI, body mass index; CI, confidence interval; CLD, chronic lung disease; IS, inflammatory score; OR, odds ratio; Q, quartile; Ref, reference.

Association between IC and risk of new-onset CLD

As shown in Table 3, Inversely correlated with the likelihood of developing new-onset CLD, IC demonstrated a significant association. In Model 1, each unit increase in IC was associated with a 20% reduction in the risk of CLD (OR =0.80; 95% CI: 0.73–0.87; P<0.001). After adjusting for age, gender, education, residence, marital status, and BMI (Model 2), the association remained significant and slightly stronger (OR =0.79; 95% CI: 0.72–0.87; P<0.001). This inverse relationship persisted in Model 3, which additionally accounted for smoking and drinking status (OR =0.80; 95% CI: 0.73–0.88; P<0.001). These findings indicate that greater IC is independently associated with a lower risk of developing new-onset CLD, regardless of sociodemographic factors, physical health status, and lifestyle behaviors.

Table 3. Association between the IC and new-onset CLD.

Model	IC, OR (95% CI)	P
Model 1	0.80 (0.73–0.87)*	<0.001
Model 2	0.79 (0.72–0.87)*	<0.001
Model 3	0.80 (0.73–0.88)*	<0.001

Model 1: crude model; Model 2: adjusted for age, gender, educational level, residence, marital status, BMI; Model 3: adjusted for age, gender, educational level, residence, marital status, BMI, smoking status, drinking status. *, P value for linear trend calculated from category median values (P<0.05). BMI, body mass index; CI, confidence interval; CLD, chronic lung disease; IC, intrinsic capacity; OR, odds ratio; Ref, reference.

Dose-response relationship between IS, IC and risk of new-onset CLD

RCS regression was employed to investigate the dose-response associations between IS, IC, and the risk of new-onset CLD. For IS, the overall association with new-onset CLD was statistically significant (Chi-squared =10.06, P=0.02). However, the non-linear component was not significant (Chi-squared =2.67, P=0.26), suggesting a primarily linear relationship (Figure 2A). For IC, a significant inverse association with new-onset CLD risk was observed (Chi-squared =20.26, P<0.001). Similarly, the test for non-linearity was not significant (Chi-squared =0.71, P=0.40), indicating a linear dose-response relationship (Figure 2B).

Figure 2.

RCS curves showing the association between (A) IS and the risk of incident new-onset CLD, and (B) IC and the risk of incident new-onset CLD. Models were adjusted for all covariates listed in the Methods section. CI, confidence interval; CLD, chronic lung disease; IC, intrinsic capacity; IS, inflammatory score; RCS, restricted cubic spline.

Subgroup analyses

Subgroup analyses revealed that the association between elevated IS (Q4 vs. Q1) and increased risk of new-onset CLD remained consistent across stratified populations (Figure 3A), with borderline significant interactions observed for marital status (P=0.054). In contrast, higher IC consistently exhibited a strong protective association with the risk of new-onset CLD across all examined subgroups (Figure 3B), with residential location significantly modifying this relationship (P=0.04). Notably, married individuals with high IS had a significantly elevated new-onset CLD risk (OR 1.40; 95% CI: 1.11–1.78), while no significant association was found among singles. The predicted probability curves further illustrated univariate interaction effects between IS levels and new-onset CLD risk with respect to marital status (Figure 4A). Specifically, the inverse association between IC and new-onset CLD risk was more evident among urban residents (OR =0.70; 95% CI: 0.59–0.83) than among their rural counterparts (OR =0.85; 95% CI: 0.76–0.96). The predicted probability curves further illustrated univariate interaction effects between IC levels and new-onset CLD risk with respect to urban-rural settings (Figure 4B).

Figure 3.

Subgroup analysis. Subgroup analyses of the associations between (A) IS quartiles and the risk of incident new-onset CLD, and (B) IC and the risk of incident new-onset CLD. Models were adjusted for all covariates listed in the Methods section. BMI, body mass index; CI, confidence interval; CLD, chronic lung disease; IC, intrinsic capacity; IS, inflammatory score; OR, odds ratio.

Figure 4.

Logistic regression interaction. Logistic regression interaction analysis revealed distinct associations stratified by marital status and geographic location. A positive correlation was observed between IS and new-onset CLD risk among married individuals (A), whereas a negative correlation emerged between IC and new-onset CLD risk in urban settings compared to rural areas (B). Solid lines depict the predicted probability of new-onset CLD risk across IS quartiles and IC, with shaded areas representing 95% confidence intervals. Models were adjusted for all covariates listed in the Methods section. CLD, chronic lung disease; IC, intrinsic capacity; IS, inflammatory score.

Discussion

Our findings identified IS as a significant and independent risk factor for the development of CLD. Individuals in the uppermost quartile of IS exhibited a significantly elevated risk of CLD when contrasted with those in the lowest quartile, with the association persisting across all adjustment models. The linear trend observed in both categorical and continuous analyses supports a dose-response relationship, indicating that higher levels of low-grade systemic inflammation are associated with greater susceptibility to chronic respiratory conditions. Persistent inflammation has emerged as a central contributor to age-associated conditions, encompassing CLD like COPD, asthma, and pulmonary fibrosis (40,41). In COPD, for example, fluctuations in CRP levels correlate with airway inflammation and clinical outcomes during exacerbations (42). Moreover, COPD’s inflammatory profile involves diverse immune cells, including lymphocytes and neutrophils, which contribute to respiratory tissue damage (43). Collectively, these findings suggest that sustained systemic inflammatory burden promotes airway remodeling, immune dysregulation, and progressive lung function decline in chronic respiratory diseases (44,45).

CRP is widely recognized as a conventional biomarker for distinguishing infection-driven progression of acute exacerbations in COPD (AE-COPD) (46,47). A systematic review reported that individuals with COPD exhibit significantly elevated CRP levels, with an average increase of 1.86 mg/L compared to controls, a difference deemed clinically meaningful (48). Supporting this, Stolz et al. demonstrated markedly elevated CRP concentrations during AE-COPD episodes (49). Collectively, these findings underscore CRP’s role as a sensitive marker of systemic inflammation and disease activity in COPD. Beyond its diagnostic value, CRP serves as a marker of airway inflammation across various respiratory disorders. Being an acute-phase protein, elevated CRP indicates systemic inflammation and potentially (50), oxidative stress (51), and protease-antiprotease imbalance (52). In asthma, particularly among corticosteroid-treated patients, higher CRP levels have been associated with increased airway wall thickness and eosinophilic inflammation (53). While traditional asthma biomarkers primarily focus on eosinophilic inflammation, emerging evidence highlights a critical role for neutrophilic inflammation in acute exacerbations of asthma (AAE) (54,55), suggesting therapeutic implications for targeting neutrophilic inflammation in AAE management (56,57). These findings collectively emphasize CRP as a valuable indicator of systemic inflammation and disease progression in chronic airway conditions.

Blood leukocyte counts, especially eosinophil levels, serve as important biomarkers for COPD onset, classification, and exacerbation (58). Increased leukocyte counts are independently linked to reduced predicted forced vital capacity (FVC) and FEV1, as well as diminished quality of life in COPD patients (58). Observational and Mendelian randomization (MR) studies further suggest that increased neutrophil counts may causally contribute to lung function impairment (59). Specifically, elevated eosinophil counts have been identified as causal contributors to COPD onset, exacerbation, and lung function decline, underscoring their potential as therapeutic targets. Conversely, the increase in neutrophil levels seems to be a result of disease progression rather than a factor contributing to it, highlighting the need for eosinophil-focused treatment strategies (60). Given these associations with lung function, quality of life, exacerbation risk, and mortality, leukocyte count is a robust biomarker in COPD management (58).

Recent studies have also validated emerging inflammatory biomarkers, such as the systemic immune-inflammation index (SII), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and neutrophil-to-lymphocyte ratio (NLR), as potential predictors of COPD risk (61-63). The CALLY index, which is a newly developed biomarker that combines serum albumin levels, lymphocyte counts, and CRP concentrations, has been found to be independently linked to a decreased likelihood of asthma-COPD overlap (ACO), highlighting its potential for clinical risk stratification (64,65). Furthermore, a higher inflammatory burden index (IBI) is significantly linked to increased mortality in chronic inflammatory airway disease (CIAD) patients; participants in the highest IBI quartile showed markedly increased risks of all-cause and respiratory disease-related mortality relative to those in the lowest quartile (66). In our study, we incorporated WBC counts and CRP levels, confirming their independent associations with the risk of new-onset CLD, thereby supporting their utility as inflammatory indicators in the early detection of respiratory diseases. We acknowledge that participants with acute infections at baseline may have had temporarily elevated inflammatory markers, which could affect the inflammation score. However, such cases are expected to be rare and are unlikely to materially influence the associations observed.

Our study provides compelling evidence that IC, a composite measure of physical and psychological reserves, is inversely associated with the risk of CLD. Across all models, higher IC scores were significantly linked to lower CLD risk, with each unit increase in IC corresponding to an approximate 20% reduction in risk, indicating that IC independently predicts disease susceptibility. The observed linear dose–response relationship further suggests that declines in IC may precede the onset of respiratory disease, positioning IC as a potential early marker of physiological vulnerability. Given that IC reflects the integrated functioning of cognitive, psychological, locomotor, sensory, and vitality domains, it may capture early physiological dysregulation not detectable by conventional clinical biomarkers (28). These findings reinforce the WHO’s emphasis on IC as a cornerstone of healthy aging and imply that routine assessment of IC could facilitate early identification of individuals at elevated risk of CLD before clinical symptoms manifest.

Patients with COPD often exhibit impaired lung function alongside cognitive deficits, particularly in memory performance (67). Emerging research suggests that reductions in lung function are linked to an elevated risk of dementia and mild cognitive impairment (MCI), with middle-aged individuals suffering from lung disease showing a modestly elevated risk of cognitive decline later in life. Notably, restrictive lung impairment demonstrates a stronger association with cognitive decline than obstructive disease (68). However, the mechanisms by which cognitive abilities influence physical performance in COPD patients remain insufficiently understood. A recent scoping review suggests that cognitive impairment in COPD is more closely associated with deficits in balance, manual dexterity, and dual-task performance than with overall exercise capacity (69).

A MR study demonstrated a bidirectional causal relationship between typical walking pace (WP) and the risk of COPD, whereas reduced right-hand grip strength (HGS) showed a unidirectional association with increased COPD risk (70). The results indicate that WP could function as a predictive variable for COPD onset and as a simple, objective marker for disease prognosis (70). Complementing this, the five-repetition sit-to-stand test (5-STS) has been identified as an objective measure with good discriminative ability for predicting mortality in COPD patients (71-73). Sensory dysfunction has been shown to play a key role in chronic pulmonary disease risk. In middle-aged and older individuals, initial deficits in visual, auditory, or dual sensory function were associated with an increased likelihood of developing chronic pulmonary disease (P=0.042; HR =1.53, 95% CI: 1.02–2.31) (74), underscoring the need for continuous monitoring and timely intervention to manage chronic disease risk in aging populations. Psychological factors likewise influence respiratory health. Higher subjective well-being was associated with lower COPD risk, particularly among men, as shown in a study of 12,246 Europeans aged 50+ years where well-being measured by CASP-12 predicted reduced COPD incidence over 9 years (75). Depressive symptoms have complex associations with CLD. A study employing the CHARLS found that depressive symptoms were associated with an increased risk of all-cause mortality in individuals diagnosed with hypertension, diabetes, and arthritis. However, this relationship was not observed in participants suffering from CLD (76). In contrast, another prospective CHARLS analysis revealed a bidirectional association between elevated depressive symptoms and CLD incidence: baseline depression increased CLD risk by 68% [hazard ratio (HR) =1.68, 95% CI: 1.46–1.93], while baseline CLD status increased the risk of subsequent depressive symptoms by 17% (HR =1.17, 95% CI: 1.01–1.35) (77). These associations were consistent across most subgroups, although no significant biological or behavioral mediators were identified. This suggests that while depression may not increase mortality in CLD patients, it critically influences disease onset and progression, highlighting the importance of early psychological assessment and intervention. Obesity and body weight status are also implicated in respiratory disease risk. A recent MR study found that obesity increases the risk of most respiratory diseases, including asthma and chronic diseases of the tonsils and adenoids (78). Both individuals classified with low and high BMI exhibited an increased susceptibility to chronic inflammatory-associated disease (CIAD). Furthermore, within the cohort of CIAD patients, the association between all-cause mortality and BMI demonstrated a non-linear pattern, attaining its lowest point at a BMI of 32.4 kg/m² (79). Consistent with these findings, underweight and severe obesity have been linked to reduced lung function, whereas mild obesity appears to exert a protective effect among individuals at risk of COPD and those with preserved ratio impaired spirometry (PRISm) (80). These insights may inform the refinement of early screening and management strategies for COPD. Although BMI is included in the IC score, it was modeled separately in our regression analyses to account for its potential independent association with CLD.

Building on the established links between physical, cognitive, and psychological factors and CLD, IC, which refers to the combined physical and mental capacities of an individual, has emerged as a key indicator of healthy aging. Accumulating evidence suggests that higher levels of IC are inversely associated with functional decline and mortality risk among older adults (19). For instance, a longitudinal aging study in Beijing reported that lower IC was significantly associated with poorer physical performance, frailty, social vulnerability, chronic diseases, fractures, and falls (81). These findings underscore IC as a promising biomarker for identifying older adults at elevated risk of adverse outcomes, affirming its role in healthy aging assessment (18,19,82). Lower literacy, middle income, lack of social engagement, marital disruption (divorced, widowed, never married), smoking, low physical activity, rural residence, non-age-friendly family environments, and absence of health insurance were all associated with a higher likelihood of belonging to the low-decline IC trajectory (83). In parallel, a trajectory characterized by low IC with slow decline is associated with an increased risk of CVD, highlighting the importance of monitoring IC over time for early identification of older adults at elevated cardiovascular risk (84). These findings provide evidence for early identification of heterogeneous IC trajectories and support the implementation of stratified intervention strategies to preserve IC.

Determinants of IC trajectories include age, sex, education, ethnicity, number of chronic conditions, marital status, perceived financial adequacy, economic support, self-rated health, and inflammatory biomarkers such as IL-6, TNFR-1, and GDF-15. Adverse IC trajectory patterns are associated with increased risk of mortality, lower quality of life, disability, frailty, and falls (85). These findings underscore the multidimensional nature of IC and its value as an early marker for identifying older adults at elevated risk of multiple health outcomes. In subgroup analyses, the positive association between elevated IS and incident CLD was observed among married participants but not among singles. While intriguing, this finding should be interpreted with caution. Possible explanations include psychosocial stress associated with marital life or detection bias, whereby married individuals may be more likely to undergo medical evaluation due to spousal encouragement. Despite these advances, evidence linking IC specifically to CLD remains scarce. Our study addresses this gap by demonstrating the predictive value of IC for CLD risk, thereby expanding its application to the early identification of respiratory vulnerability. A deeper understanding of IC could facilitate novel strategies for CLD risk prediction and prevention. From a public health perspective, routine assessment of IC in older adults could serve as a preventive strategy to identify individuals at elevated risk of CLD and CVD before clinical symptoms manifest. Policymakers may consider integrating IC screening into primary care or community health programs to guide early interventions, such as targeted physical, cognitive, or lifestyle interventions, aimed at preserving IC and reducing the burden of chronic diseases in aging populations.

This research employs information derived from a substantial cohort that is representative of older adults across China on a national scale, enhancing the generalizability of our findings. IC was assessed across five WHO-defined domains, and IS was concurrently examined, offering a comprehensive perspective on biological and functional aging. Rigorous adjustment for demographic, lifestyle, and clinical variables strengthens the robustness of our results. Notably, we provide novel evidence linking IC decline to CLD, extending its utility as a predictive marker in respiratory health.

Nonetheless, several limitations merit consideration. First, the longitudinal design does not allow for definitive causal inference regarding IC, IS, and CLD. Second, certain components of IC and IS relied on self-reported or proxy measures, which may be susceptible to recall bias or measurement inaccuracies. Third, both IC and IS were measured only at baseline, preventing assessment of their time-varying effects on CLD risk, which may have led to residual bias. Fourth, the vitality domain of IC was assessed using BMI with a lower cutoff of 18.5 kg/m², without consideration of upper thresholds for obesity, potentially overlooking the adverse impact of obesity on respiratory outcomes. Fifth, smoking was recorded categorically (smoker vs. non-smoker) without quantitative measures such as pack-years, which may limit precision in capturing dose-response relationships. Sixth, participants with overt acute infections at baseline were not specifically excluded, potentially causing transient elevations in inflammatory markers. Finally, comorbidities such as CVD and diabetes, which may influence both IS and CLD risk, were not adjusted for, and residual confounding by these conditions cannot be ruled out. Future prospective studies incorporating repeated measures of IC and IS, detailed comorbidity profiles, and more nuanced assessments of vitality and smoking exposure are warranted to validate our findings and elucidate temporal interactions among IC, IS, and respiratory outcomes.

Conclusions

In this cohort of older Chinese adults, which is representative on a national scale, we found that reductions in IC and elevated IS were independently linked to higher risk of CLD. These results underscore the potential utility of IC as a functional biomarker for early detection of individuals at risk of respiratory decline. Incorporating both IC and IS into geriatric assessments may provide novel strategies for prevention and risk stratification of CLD in aging populations.

Supplementary

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Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.