Introduction

Chronic obstructive pulmonary disease (COPD) is a heterogeneous pulmonary condition characterized by progressively worsening airflow limitation.1 In 2019, the number of prevalent cases of COPD worldwide reached 212.3 million, leading to 3.3 million deaths, with an age-standardized mortality rate of 42.5 per 100,000.2 COPD has emerged as the third primary cause of death worldwide, the sixth foremost cause of death in the United States, and the third most common cause of death in China.3–5 Therefore, it is crucial to identify an easy and effective biomarker for COPD survival risk and prognosis prediction, which will assist pulmonologists in early intervention.

Inflammation, nutrition, and immune response play key roles in the occurrence and progression of COPD. The novel biomarker that combines CRP, serum albumin, and lymphocyte count is the C-reactive protein (CRP)–albumin–lymphocyte (CALLY) index. It can provide a comprehensive overview of a patient’s immunological function, nutritional status, and level of inflammation.6 Previous studies have shown that the CALLY index has significant predictive value in the prognosis of various cancers.7–10 However, there is no research on applying the CALLY index in COPD.

Previous literature has proposed and confirmed various blood inflammation indices that can be used to predict the occurrence and development of COPD. For example, the neutrophil-to-lymphocyte ratio (NLR), the neutrophil-percentage-to-albumin ratio (NPAR), the CRP-to-albumin ratio (CAR), and the systemic immune-inflammation index (SII, platelet count×neutrophil count/lymphocyte count) have all been demonstrated to be strongly associated with the risk of death in COPD patients.11–14 However, these indices only combine information on inflammation and immunity, or inflammation and nutrition, and are not as comprehensive as the CALLY index.

The objective of this study is to assess the relationship between the CALLY index and all-cause mortality in patients with COPD in the United States through a cohort study, aiming to provide a new biomarker for clinical practice.

Materials and Methods Data Source

Launched in the early 1960s, the National Center for Health Statistics (NCHS) is responsible for the extensive and ongoing National Health and Nutrition Examination Survey (NHANES). Utilizing a multistage probability sampling approach, NHANES evaluates the health and nutritional status of the ambulatory population in the United States. The survey includes questionnaire interviews, laboratory tests, and physical examinations. The NCHS Ethical Review Board has approved the NHANES study protocol, and all participants have given written informed consent. The NHANES website provides access to all publicly available data and research studies.

Study Population

The selection of participants was based on the NHANES database, which covered two survey cycles (2007–2008 and 2009–2010). Our study excluded the following: (1) individuals under 20 years old; (2) individuals with missing COPD data; (3) individuals with missing albumin, lymphocyte, or CRP data; (4) individuals without COPD. Ultimately, 1048 individuals were part of the research. Since the study involves hematological variables, we utilized the weights from the Mobile Examination Center (MEC). Figure 1 summarizes the precise inclusion and exclusion criteria.

Figure 1 Flowchart of participants selection.

Definition of the CALLY Index

Blood tests were conducted utilizing automated hematology analyzers in every survey round. The objective of this study is to analyze the CALLY index. The index formula is as follows.7,9

Assessment of COPD

According to previous studies,15,16 we define COPD as the presence of any one of the following conditions: 1. FEV1/FVC < 0.7 post-bronchodilation. 2. A positive answer to any of these questions: (1) “Ever told you that you have emphysema?” (2) “Ever told you had chronic bronchitis?”

Covariates Definition

The covariates of this study include age, gender, race (Mexican American, non-Hispanic white, non-Hispanic black, other Hispanic, other race), body mass index (BMI) (< 25, 25–30, ≥ 30), education level (< high school, high school, > high school), marital status (marriage/living with a partner, widowed/divorced/separated, never married), poverty-income ratio (PIR) (≤ 1.30,1.30–3.50, > 3.50), drinking, smoking, hypertension, cardiovascular diseases (CVDs) and cancer. Drinking at least 12 drinks a year is defined as a drinker. Smokers were defined as those who had smoked more than 100 cigarettes during their lifetime.17 Hypertension was defined as having a systolic blood pressure ≥ 130 mmHg, or diastolic blood pressure  ≥ 80 mmHg. The definition of CVDs is being informed by a doctor or other health professional of having congestive heart failure (CHF), coronary heart disease (CHD), angina, myocardial infarction, or stroke. Cancer was defined by a positive answer to the question: “Have you ever been told by a doctor or other health professional that you had cancer or a malignancy of any kind?”

Study Outcome

The main outcome assessed was all-cause mortality among COPD patients. Survival information for the cohort was extracted from the NHANES public-use linked mortality file until December 31, 2019. The follow-up period for mortality was computed from the survey participation date to either the date of death or December 31, 2019.

Statistical Analysis

Continuous variables were expressed as median (interquartile range [IQR]), while categorical variables were displayed as counts (percentages, %). Demographic characteristics were analyzed using the Pearson’s Chi-squared test for categorical variables and the Wilcoxon rank-sum test for continuous variables. To evaluate the associations between the CALLY index and all-cause mortality in COPD patients, weighted Cox regression analyses were conducted univariately and multivariately. Model 1 was the unadjusted crude model. Model 2 included adjustments for age, gender, race, BMI, marital status, PIR, smoking, and drinking. Model 3, the fully adjusted model, included additional covariates such as hypertension, CVDs, and cancer. Meanwhile, Kaplan-Meier (KM) curves were used to show varying survival probabilities in COPD patients across various CALLY levels. Restricted cubic splines (RCS) with four knots were utilized to assess potential non-linear associations between the CALLY index and all-cause mortality in COPD patients, capturing the risk variation across the continuum of relationships. To balance data completeness and reduce biases from imputation, the random forest method was used to handle variables with missing data.18 The accuracy of the CALLY index in predicting survival outcomes was assessed using receiver operating characteristic (ROC) curve analysis.

All statistical analyses were conducted with R software (version 4.3.3). A p-value < 0.05 (two-tailed) was regarded as statistically significant.

Results Baseline Information of the Participants with COPD

1048 participants were included in this study during the two cycles of surveys (2007–2010). The baseline characteristics of the research participants, stratified by final mortality status, are shown in Table 1. The median (IQR) age of participants was 59 (46–68) years, with non-survivors being older than survivors [68 (61–74) vs 54 (43–65), p < 0.001]. A marginally higher number of males than females (539 cases vs 509). Non-Hispanic Whites comprised over half of the participants, amounting to 66% (687 cases). 41% of the participants hold an educational level beyond high school. Only 10% of the population was never married. Over 70% of the participants smoked or drank. 65% of the participants had a history of hypertension. Compared to those who survived during the follow-up period, non-survivors were characterized by being older, male, smokers, with a lower education level and a lower PIR. In terms of comorbidities, non-survivors had higher prevalence rates of hypertension, CVDs, and cancer compared to survivors. Additionally, non-survivors showed lower levels of albumin and lymphocyte but higher levels of CRP. The median (IQR) value of the CALLY index was 3.15 (1.26–8.04). Non-survivors showed significantly lower CALLY [1.84 (0.72–4.91) vs 3.70 (1.49–9.56), p < 0.001]. The distribution of the CALLY index in different final mortality statuses is shown in the violin plot (Figure 2).

Table 1 Baseline Information of the Participants with COPD

Figure 2 The violin plot shows the distribution of the CALLY index in different final mortality statuses.

Abbreviation: CALLY, C-reactive protein (CRP)–albumin–lymphocyte.

Kaplan-Meier (KM) Survival Curve of the CALLY Index

The CALLY index was calculated as four categorical variables. The weighted Kaplan-Meier (KM) curves revealed markedly different survival outcomes among various groups (Log-rank p < 0.001), as shown in Figure 3. In comparison to the lowest quartile (Q1), it was observed that the survival probabilities increased as the CALLY index quartile increased.

Figure 3 The weighted Kaplan-Meier (KM) curves show the association between the CALLY index and survival in patients with COPD.

Abbreviation: CALLY, C-reactive protein (CRP)–albumin–lymphocyte.

Multivariable-Adjusted Restricted Cubic Spline (RCS) Curves of the CALLY Index

As illustrated in Figure 4, the weighted multivariable-adjusted RCS analyses were employed to visualize the association between the CALLY index and all-cause mortality in COPD patients. The RCS analysis indicated a non-linear association of the CALLY index with the all-cause mortality of COPD patients (P for non-linear < 0.001).

Figure 4 The weighted multivariable-adjusted restricted cubic spline (RCS) curves show dose-effect relationships between the CALLY index and COPD patients’ survival.

Abbreviations: CALLY, C-reactive protein (CRP)–albumin–lymphocyte; BMI, body mass index; PIR, family income-poverty ratio; CVDs, cardiovascular diseases.

Notes: Adjusted for the effects of age, gender, race, BMI, educational level, marital status, PIR, smoking, drinking, hypertension, CVDs, and cancer.

Cox Regression Analysis of the Association Between the CALLY Index and the All-Cause Mortality in Patients with COPD

In addition, multivariate weighted Cox regression analyses were performed to assess the association between the COPD patients’ all-cause mortality and the CALLY index. The CALLY index was found to be an important predictor of COPD patients’ all-cause mortality, as shown in Figure 5 [model 1: hazard ratio (HR) = 1.69, 95% confidence interval (CI): 1.05–2.72 in 3rd quartile, p = 0.031; HR = 2.54, 95% CI: 1.52–4.24 in 2nd quartile, p < 0.001; HR = 4.02, 95% CI: 2.64–6.13 in 1st quartile, p< 0.001. Model 2: HR = 1.54, 95% CI: 0.97–2.44 in 3rd quartile, p = 0.069; HR = 2.07, 95% CI: 1.19–3.60 in 2nd quartile, p = 0.010; HR = 2.99, 95% CI: 1.90–4.69 in 1st quartile, p < 0.001. Model 3: HR = 1.61, 95% CI: 1.02–2.52 in 3rd quartile, p = 0.039; HR = 2.11, 95% CI: 1.22–3.65 in 2nd quartile, p = 0.008; HR = 3.12, 95% CI: 2.00–4.85 in 1st quartile, p < 0.001].

Figure 5 The forest plots show the relationship between the CALLY index and the risk of all-cause mortality in COPD patients.

Abbreviations: CALLY, C-reactive protein (CRP)–albumin–lymphocyte; BMI, body mass index; PIR, family income-poverty ratio; CVDs, cardiovascular diseases.

Notes: Bold values indicate p-value < 0.05. Model 1: unadjusted; Model 2: adjusted for age, gender, race, BMI, educational level, marital status, PIR, smoking, and drinking; Model 3: adjusted for age, gender, race, BMI, educational level, marital status, PIR, smoking, drinking, hypertension, CVDs, and cancer.

Predictive Performance of the CALLY Index, CRP, Albumin, and Lymphocyte in Predicting All-Cause Mortality in COPD Patients

Time-dependent receiver operating characteristic (ROC) curve analysis illustrates the area under the curves (AUCs) of the CALLY index, CRP, albumin, and lymphocyte to establish their predictive power for all-cause mortality (Figure 6). The results demonstrated that the AUCs for CALLY, CRP, albumin, and lymphocyte at 5-year were 0.693, 0.653, 0.637, and 0.650, while at 10-year, the AUCs were 0.656, 0.627, 0.627, and 0.603. These findings indicate that, at both 5- and 10-year, the CALLY index exhibits superior predictive accuracy for survival risk compared to CRP, albumin, and lymphocyte.

Figure 6 The time-dependent receiver operating characteristic (ROC) curves show the predictive power of the CALLY index, CRP, albumin, and lymphocyte for mortality among COPD patients.

Abbreviations: ROC, receiver operating characteristic; AUC, area under the curve; CALLY, C-reactive protein (CRP)–albumin–lymphocyte.

Discussion

This study assessed the association between the CALLY index and all-cause mortality in patients with COPD. We determined negative associations between the CALLY index and the all-cause mortality among individuals with COPD. Furthermore, the ROC curves showed that the CALLY index holds certain predictive value for clinical outcomes of this population.

In the occurrence and development of COPD, inflammation, nutrition, and immune response play a key role. Airway inflammation is a crucial factor in the progression and exacerbation of COPD, and its severity is related to the degree of airflow obstruction.19,20 The immune system is a key player in the pathogenesis of COPD, and the progression of COPD is associated with changes in the immune system.21 Nutritional status is also a crucial determinant of COPD prognosis, with insufficient protein intake linked to a higher risk of exacerbations in mild to moderate COPD.22,23 The hypothesis related to autoimmunity suggests that the inflammatory response can promote immune responses that further stimulate the inflammatory response to exacerbate lung damage.24 Due to the chronic systemic inflammatory state in patients with COPD, elevated levels of inflammatory markers can lead to malnutrition, manifesting as muscle wasting, weight loss, decreased appetite and so on.25,26 In addition, these inflammatory characteristics may accelerate the rate of muscle wasting, further reducing exercise tolerance in patients with COPD, and leading to a vicious cycle of disease progression.27

Our study found that the RCS curves revealed a non-linear association between the CALLY index and mortality risk in COPD patients (P for non-linear < 0.001). The relationship exhibited a trend of first decreasing and then increasing. Notably, lower CALLY levels are associated with higher mortality risk, while higher CALLY levels show only a minimal increase in risk. An extremely low level of the CALLY index may be influenced by higher CRP, lower albumin, and lower lymphocyte counts, which could increase the risk of all-cause mortality. C-reactive protein (CRP) is an acute-phase protein that not only reflects the level of inflammation in the body but also regulates innate immunity and the course of inflammation.28 Previous meta-analyses have shown that elevated CRP levels are associated with acute exacerbations and hospitalization in patients with COPD and that those with higher CRP levels are linked to an increased risk of early mortality.29 Lymphocytes are integral to the immune system and play a pivotal role in the body’s defense mechanisms, reflecting the level of the immune response.30 Studies have shown that low blood lymphocyte counts and lymphocyte decline are important prognostic factors in COPD.31 Serum albumin levels are one of the assessments for malnutrition in COPD, with hypoalbuminemia being a risk factor for acute respiratory failure and associated with increased mortality in patients with COPD.32,33 Our study shows that a decrease in the CALLY index (elevated CRP levels, reduced lymphocyte count, and decreased serum albumin) is linked to an increased risk of all-cause mortality in patients with COPD, consistent with the findings of the aforementioned studies.

The ROC curve demonstrated that the CALLY index exhibited good predictive ability for mortality risk in COPD patients, surpassing the performance of its components (CRP, albumin, and lymphocyte count). As a composite inflammatory index, the CALLY index not only reflects the inflammation, nutritional, and immune status of COPD patients but also can be used to identify high-risk patients and help clinicians develop more personalized and effective intervention strategies.

Some of the strengths of this study should be acknowledged. Firstly, this study is the first to assess the predictive role of the CALLY index in COPD patients. Secondly, to evaluate the clinical superiority of the CALLY index, we compared its prognostic value with other indices, including CRP, albumin, and lymphocyte. Furthermore, this study utilized a broad, nationally representative sample of COPD patients in the United States, which lends broad generalizability and applicability to our findings. However, there are some limitations to this study. Firstly, due to the differing data collected in each survey cycle, we included only 1,048 COPD patients, which is a relatively small number and may introduce bias into the study results. Secondly, due to the lack of relevant data on some risk factors for COPD, such as shortness of breath and history of exacerbations, these factors were not included in the analysis of this study. In future studies, we plan to include more patients and collect more comprehensive data to validate the clinical utility of the CALLY index.

Conclusion

In summary, this study found that the CALLY index is substantially associated with all-cause mortality among COPD patients in the United States and has good predictive value for their survival risk. Our findings would help pulmonologists to intervene early with dynamic monitoring of patients with COPD using the CALLY index. Moreover, to validate our findings, further large-scale prospective studies are needed.

Data Sharing Statement

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

Ethics Approval and Informed Consent

All study protocols were approved by the National Center for Health Statistics Research Ethics Review Board. All participants provided written informed consent prior to their health examinations. According to Article 32, Items 1 and 2, of the Measures for the Ethical Review of Life Science and Medical Research Involving Human Subjects (China, February 18, 2023), studies that use legally obtained publicly available data, data generated through non-intrusive observation of public behavior, or anonymized data are exempt from ethical review (https://www.gov.cn/zhengce/zhengceku/2023-02/28/content_5743658.htm).

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The study was funded by the Shandong Medical and Health Technology Project (202303021034), the Ministry of Science and Technology of the National Administration of Traditional Chinese Medicine and the Shandong Provincial Health Commission Collaborative Project (GZY-KJS-SD-2023-048), and the Shandong Province Traditional Chinese Medicine Science and Technology Project (Q-2023041).

Disclosure

The authors report no conflicts of interest in this work.

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