Three key factors predicting the severity of exacerbations of chronic obstructive pulmonary disease: T lymphocytes, lactate, and prealbumin

Introduction

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) describe the acute worsening of the underlying symptoms of patients with chronic obstructive pulmonary disease (COPD). AECOPD is usually caused by smoking but may also be linked with other factors such as air pollution and genetic factors (1). AECOPD is now the fourth leading cause of death worldwide, and as many as 600 million people suffer from AECOPD annually, which is the leading cause of hospitalization and death in patients with COPD, and has a mortality rate as high as 11% (2-4). Thus, AECOPD is a significant problem, and is a major human health and economic burden worldwide.

The diagnosis of COPD is clinical, and that it would be useful to have biomarkers for diagnosis and to identify severity (5). Further, patient compliance is essential for pulmonary function testing. A study has shown that serum pre-albumin and C-reactive protein (CRP) have a certain effect on AECOPD (6). T lymphocytes play a crucial role in AECOPD. When AECOPD occurs, T lymphocytes are activated. Subpopulations of T lymphocytes, such as Th1, Th2, Th17 and CD8+ T cells, trigger and exacerbate airway inflammation and tissue damage by releasing cytokines and cytotoxic substances (7).

AECOPD is linked to abnormal airway inflammation and airflow limitation, with pre-albumin levels in patients indicating malnutrition and being affected by inflammation, while the relationship between pre-albumin and respiratory diseases needs further study (8,9). Blood lactic acid, a product of glucose anaerobic metabolism, is normally low (10). In patients with ventilation dysfunction, reduced oxygen supply inhibits mitochondrial processes, leading to increased lactic acid production due to pyruvate and NADH deposition (11). This study explored the correlations among peripheral blood T cell subtype levels, serum albumin levels, and serum lactic acid levels and the severity of AECOPD to identify valuable biomarkers for the clinical diagnosis of AECOPD. We present this article in accordance with the TRIPOD reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-416/rc).

Methods

Participants

The patients diagnosed with AECOPD and admitted to the Dongyang People’s Hospital between January 2020 and December 2021 were recruited. The inclusion criteria for patient selection were strictly based on the clinical diagnostic criteria for AECOPD (12); none of the patients had taken oral corticosteroids, immunosuppressants, or immunomodulators within six weeks before their admission to hospital. Further, the patients had to be able to tolerate the pulmonary function tests and have complete lung function data. Inclusion criteria must comply with AECOPD diagnostic criteria. AECOPD is defined as acute exacerbation of respiratory symptoms in COPD patients that require additional treatment. Patients were excluded from the study if they had severe cardiovascular, hepatic, or renal diseases, with concomitant bronchial asthma, active pulmonary tuberculosis, interstitial lung disease, malignancy, autoimmune diseases, or allergies. Bronchial asthma, active pulmonary tuberculosis, interstitial lung disease, severe patients with liver and kidney diseases, malignant tumors, autoimmune diseases, allergic diseases, and those who have taken oral steroids, immunosuppressants, and immunomodulators 6 weeks before admission need to be excluded.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.The study was approved by ethics board of Dongyang People’s Hospital (No. 2023-YX-269). Individual consent for this retrospective analysis was waived.

Diagnostic criteria for AECOPD

All participants must meet the criteria of GOLD guide in 2021 (13). Under the Diagnosis and Treatment Guidelines for Chronic Obstructive Pulmonary Disease (Revised in 2021), the severity of hospitalized AECOPD patients is graded as follows: Grade I: non-respiratory failure: (I) respiratory rate 20–30 times/min. (II) no application of auxiliary respiratory muscle groups. (III) no change in mental consciousness state. (IV) no increase in PaCO₂. Grade II: non-life-threatening acute respiratory failure: (I) respiratory rate >30 times/min. (II) application of auxiliary respiratory muscle groups. (III) no change in mental consciousness state. (IV) hypoxemia can be improved by inhaling 24–35% actual oxygen concentration. hypercapnia with an increase or decrease in the basal value of PaCO₂ to 50–60 mmHg. Grade III: life-threatening acute respiratory failure: (I) respiratory rate >30 beats/min. (II) application of auxiliary respiratory muscle groups. (III) a sharp change in the state of mental consciousness. (IV) hypoxemia cannot be improved by inhaling oxygen at concentrations greater than 40%. (V) hypercapnia with an increase of >60 mmHg of PaCO₂ compared to the baseline, or acidosis (pH ≤7.25).

Data collection

Detection of T lymphocytes, B lymphocytes, and natural killer (NK) cells subgroups

Cluster of differentiation (CD)3, CD4, and CD8 are markers for T lymphocytes; CD19 is a marker for B lymphocytes; and CD56 is a marker for NK cells. The FC500 flow cytometer (Beckman Coulter, USA) was used to determine the T lymphocytes, B lymphocytes, and NK cells subgroups. The peripheral venous blood samples (2 mL) were collected from fasting subjects within 24 hours of hospital admission. The blood samples were collected into vacuum blood collection tubes containing ethylenediaminetetraacetic acid as an anticoagulant, and thoroughly mixed. A suspension of individual cells was obtained after centrifugation and washing. The selected monoclonal antibodies were added to the T lymphocytes, B lymphocytes, and NK cell suspension, followed by appropriate incubation and antibody staining. The cell samples were then analyzed using the FC500 flow cytometer. The subgroups were identified and analyzed using laser irradiation and measuring light signals by setting appropriate parameters and gating strategies. Finally, the obtained data and corresponding analysis software were applied for the quantitative and qualitative analyses of the subgroups.

Detection of serum pre-albumin and CRP

Peripheral venous blood (8 mL) was collected within 24 hours of the admission, and the serum was obtained after centrifugation. A COBAS8000 analyzer (Roche Diagnostics, Indianapolis, IN, USA) was used to determine the serum pre-albumin content via immunoturbidimetry. An enzyme-linked immunosorbent assay (ELISA) was used to quantify the levels of CRP in the serum, and the ELISA (TIANGEN, Beijing, China) involved coating a microplate with specific anti-CRP antibodies and creating an antigen-antibody complex. The optical density values were measured using a microplate reader, and the CRP concentration in the serum was determined by calculating it based on a standard curve.

Detection of serum lactic acid

Serum lactic acid levels were determined using the ELISA method (Mlbio, China). Venous blood samples (8 mL) were collected within 24 hours of the admission. Diluted serum (ratio =1:1) was loaded into the wells and incubated with 50 µL of biotin-labeled antibody for 60 minutes at 37 ℃. After clearing the solution, 80 µL of horseradish peroxidase-loaded secondary antibody was added, followed by a 30-minute incubation at 37 ℃. Subsequently, 50 µL of substrates were added and incubated at 37 ℃ for 10 minutes. The reaction was stopped by adding 50 µL of the stop solution, and the optical density value was measured using a microplate reader (MD, USA). This method quantified serum lactate levels, providing valuable insights into the metabolic status and clinical implications in the study’s context.

Statistical analysis

Distribution of data was assessed with GradPad Prism (USA, California). Descriptive statistics are presented as the mean ± standard deviation for the normally distributed continuous variables. The t-test was used for comparisons between two groups, while the one-way analysis of variance was used for comparisons among multiple groups. A Pearson correlation analysis was conducted to examine the associations between variables. A P value less than 0.05 was considered statistically significant, indicating a significant difference or correlation. The statistical analysis was performed using SPSS 29.0 statistical software (IBM, New York, USA).

An ordinal multinomial logistic regression model was established using AECOPD grading as the dependent variable, and T cells, pre-albumin and lactic acid individually as the independent variables.

Results

Comparison of T lymphocyte, B lymphocyte and NK cell among the three groups

Cluster of differentiation (CD)3, CD4, and CD8 are markers for T lymphocytes; CD19 is a marker for B lymphocytes; and CD56 is a marker for NK cells. As Table 1 shows, no statistically significant differences (P>0.05) were found in the levels of the CD8⁺, CD19⁺, and CD56⁺ cells between the Grade I and Grade II groups. However, the Grade I group exhibited significantly higher levels of CD3⁺, CD4⁺, and CD8⁺ cells, and had a significantly higher CD4⁺/CD8⁺ ratio than the Grade II group (P<0.05). The Grade II group had significantly higher levels of CD3⁺ and CD8⁺ cells, significantly lower levels of CD19⁺ cells, and a significantly lower CD4⁺/CD8⁺ ratio than the Grade III group (P<0.05). Further, the Grade I group had significantly higher levels of CD4⁺/CD8⁺, CD3⁺, CD4⁺, CD8⁺, and CD56⁺ cells than the Grade III group (P<0.05). The Grade I group exhibited significantly lower levels of CD19⁺ cells than the Grade III group.

Comparison of serum pre-albumin, CRP, and lactic acid among the three groups

Compared to the Grade I group, both the Grade II and Grade III groups exhibited a significant decrease in serum procalcitonin levels and a significant increase in serum lactate levels (P<0.05) (Table 2). In contrast, there was no significant differences in the serum procalcitonin levels and serum lactate levels between the Grade II and Grade III groups (P>0.05). The Grade II group had significantly higher levels of CRP than the Grade I and Grade III groups (P<0.05). However, there were no statistically significant differences between Grade I and Grade III groups in terms of CRP.

Discussion

AECOPD is a leading cause of mortality and morbidity worldwide. It is characterized by partially reversible airflow limitation, chronic inflammation, and emphysema. COPD is also a major public health concern (12). A study has shown the crucial roles of various inflammatory cells in the development and progression of AECOPD (14).

T cells are an essential component of the immune system, and T cell subsets play important roles in the development and inflammatory processes of AECOPD (15). CD4⁺ helper T (Th) cells can be classified into different subtypes, such as Th1, Th2, Th17, and regulatory T cells. In AECOPD, the increase and activation of Th1 and Th17 cells have been found to be associated with inflammatory responses and airway remodeling (16). The cytokines produced by these cells, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-17 (IL-17), can contribute to airway inflammation and damage (17). CD8⁺ cells are cytotoxic T cells that are crucial in clearing infected cells. In AECOPD, the activation and infiltration of CD8⁺ cells are increased, leading to the release of inflammatory mediators and cytotoxins, which result in lung tissue damage and airway narrowing (18). Overall, the development and inflammatory processes of AECOPD involve the dysregulation and dysfunction of various T cell subsets. These abnormal T cell subsets can promote airway inflammation, lung tissue destruction, and airway remodeling, exacerbating the pathological progression of AECOPD. Understanding the roles of T cell subsets in the development of AECOPD could help elucidate the pathogenesis of the disease, and provide potential targets for the development of novel treatment strategies.

This study observed a gradual decrease in CD3⁺ T cells, CD4⁺ T cells, and CD8⁺ T cells among Grades I, II, and III, suggesting that the reduction of these cells may be associated with disease progression. B cells are an essential type of white blood cell in the immune system, primarily responsible for humoral immune responses, including antibody production and immune regulation (19). B cells might play a role in the onset and progression of AECOPD (20). B cells in patients with AECOPD may be overactivated, leading to an increased production of autoantibodies (21). These autoantibodies produced by B cells may be associated with lung tissue inflammation and airway obstruction. B cells can participate in regulating lung inflammation by secreting inflammatory cytokines and chemokines such as IL-6 and TNF-α (22). B cells in AECOPD may have immunoregulatory functions, and participate in the activation and function of T cells (23). B cells can suppress the production of inflammatory cytokines, thus alleviating inflammatory responses. Although the relationship between B cells and AECOPD has been discovered, further research is needed to confirm their specific roles in the pathogenesis of AECOPD and their therapeutic potential. Further research may extend the understanding of the role of B cells in AECOPD, and provide a theoretical foundation for the development of new treatment strategies. The study results suggest that CD19⁺ B cells gradually increase as disease severity increases, which suggests that these cells are associated with lung tissue inflammation and airway obstruction.

NK cells are important immune cells responsible for killing infected and tumor cells. Research on the relationship between NK cells and AECOPD has been relatively limited (24-26). Further, NK cells are thought to participate in the development and progression of AECOPD by regulating inflammatory responses (27). Therefore, impaired or reduced NK cell functions may result in decreased infection resistance, affecting the course and prognosis of patients with AECOPD. Our results revealed that the number of CD56⁺ cells gradually decreased as disease severity increased, which may be due to the weakened capabilities of NK cells, which in turn leads to disease progression.

Pre-albumin, also known as transthyretin, is a serum protein that plays a major role in the body by transporting thyroid hormones and vitamin A, and by participating in the body’s nutritional metabolism (28). However, the relationship between pre-albumin and AECOPD is not yet fully understood. The pre-albumin levels may be affected by the inflammatory response, and the release of inflammatory factors may increase or decrease the pre-albumin levels (29). Further, patients with AECOPD may experience respiratory difficulties and declining lung function symptoms due to airway obstruction and lung tissue damage. These factors may be associated with the pre-albumin levels, but further research is needed to determine the specific relationship. Our results revealed higher levels of pre-albumin in the early stages of the disease, followed by a decrease in the advanced stages.

Lactate is a metabolic byproduct, and its generation and clearance in the body are regulated via normal energy metabolism processes (30). Several aspects may be involved in changes in lactate levels associated with AECOPD (31). First, patients with AECOPD show an increase in lactate production. Patients with AECOPD often experience progressive lung function impairment, particularly airflow limitation and abnormal gas exchange. This may lead to muscle fatigue, hypoxia, and acidosis, promoting increased lactate production. Lactate is produced under hypoxia conditions through lactate dehydrogenase, which can elevate lactate levels. Second, patients with AECOPD show a decrease in lactate clearance. In patients with AECOPD, the clearance capacity of lactate may decrease due to limited lung function and inadequate ventilation. Abnormal gas exchange in the lungs can restrict lactate clearance from the blood, causing elevated lactate levels. This is consistent with our finding that lactate levels increase as disease severity increases.

T, B, and NK cells are critical cellular components of the immune system, and play crucial roles in the management and prognosis assessment of AECOPD. This study showed that T cell subtype imbalance, such as the CD4⁺/CD8⁺ ratio imbalance, and reductions in D3⁺ T cells, CD4⁺ T cells, and CD8⁺ T cells are associated with disease severity. B cells play significant roles in the pathogenesis and inflammatory processes of AECOPD, participating in the regulation of inflammatory cytokine release and immune response modulation. Increased CD19⁺ B cells may worsen AECOPD. Conversely, NK cells play an essential immunoregulatory role in pathogen clearance and the control of inflammatory responses. Reductions in CD56⁺ cells may worsen AECOPD.

In addition to the above, there are many other markers for the severity and predictability of AECOPD. Procalcitonin (PCT) is crucial in AECOPD caused by bacterial infections. It can reflect the severity of the infection and help determine whether antibiotics are necessary. An increase in white blood cell count and the proportion of neutrophils indicates a severe inflammatory condition, and their changes can also predict the disease course (32). Fractional exhaled nitric oxide (FeNO) reflects airway inflammation and is related to the disease condition (33). Blood gas analysis indicators such as pH, PaO₂, and PaO₂ can evaluate the severity of the condition and have important predictive value for the prognosis.

Retrospective studies rely on data recorded in the past, which may be incomplete due to negligence, omissions, or other factors during the recording process. This study, as a retrospective study, does not have the above-mentioned issues. The results shown that Cluster of differentiation (CD)3+ T cells, CD4+ T cells, and the CD4+/CD8+ ratio were significantly higher in the Grade I group, while CD19+ B cells were significantly lower in the Grade II group compared to Grade I. The Grade I group also had higher levels of CD56+ cells than the Grade III group. Serum pre-albumin levels were significantly lower in the Grade II and III groups, while serum lactate levels were significantly higher in the Grade III group. CRP levels were also higher in the Grade II group. The study suggested that Serum pre-albumin, lactate, and lymphocyte levels were found to be closely related to the severity of AECOPD, and could be potential biomarkers for clinical diagnosis.

Conclusions

In summary, Serum pre-albumin, lactate, and lymphocyte levels were found to be closely related to the severity of AECOPD. Monitoring these indicators can help assess disease severity, guide treatment decisions, and provide a reference for prognosis assessment. However, further research needs to be conducted to explore the underlying mechanisms linking these indicators to AECOPD and to determine their value in clinical practice.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-416/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-416/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-416/prf

Funding: This work was supported by the grants from the Jinhua Public Welfare Technology Application Research Project (2022-4-275).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-416/coif). P.S.P.C. reports grants from Merck ISP and EPSRC, and consultancy with Strados, outside of the submitters work. The other authors have no conflicts of interest to declare.

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. The study was approved by ethics board of Dongyang People’s Hospital (No. 2023-YX-269). Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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