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Predictive biomarkers in chronic obstructive pulmonary disease
*Corresponding author: Ashish Sharma, Department of Biochemistry, Geetanjali Medical College and Hospitals, Udaipur, Rajasthan, India. dr.ashishsharma@geetanjaliuniversity.com
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Received: ,
Accepted: ,
How to cite this article: Patidar P, Sharma A, Kurmi N, Takodara S, Syed A. Predictive biomarkers in chronic obstructive pulmonary disease. J Lab Physicians. 2025;17:328-32. doi: 10.25259/JLP_186_2024
Abstract
Objectives:
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized low-grade inflammation and variable disease progression, though currently available approach (pulmonary and radiological analysis) to diagnose subtype and severity of disease are beneficial yet potential inflammatory biomarkers can aid in precise prediction of severity of disease which can help to categorize patients for interventions and can lead to better utilization of resources and improve outcome. Our study investigates that biomarkers, when combined with clinical variables, may be useful to predict subtypes, disease severity, disease progression, and morbidity in COPD patients.
Materials and Methods:
Serum inflammatory markers (interleukin-6 [IL-6], C-reactive protein [CRP], ferritin) were analyzed in COPD patients, and they were categorized into four groups based on disease severity (Global Initiative for Chronic Obstructive Lung Disease standard guidelines).
Statistical analysis:
One-way analysis of variance and Tukey honestly significant difference post hoc test were applied to determine whether these biomarkers were predictive of disease severity, disease progression, or morbidity.
Results:
A total of 115 COPD patients were recruited and categorized into mild (16), moderate (23), severe (42), and very severe (34), based on forced expiratory volume in 1 s (FEV1%). Serum levels of inflammatory markers IL-6, CRP, and ferritin showed potential differentiating ability between stages and severity of COPD. Levels of inflammatory markers are strongly correlated with FEV1%.
Conclusions:
Patients with increasing severity of COPD had a significantly higher serum inflammatory marker level. A negative correlation was observed between various serum inflammatory markers and FEV1%.
Keywords
Chronic obstructive pulmonary disease
C-reactive protein
Ferritin
Forced expiratory volume interleukin-6
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disorder characterized by airflow limitation due to abnormalities in the airways or alveoli. It impairs breathing and is both preventable and treatable. The airflow obstruction in COPD is progressive and only partially reversible, linked to an abnormal inflammatory response of the lungs to inhaled irritants or toxic gases.[1] Over time, the disease worsens, making daily activities such as walking and climbing stairs increasingly difficult. Common symptoms at onset include shortness of breath during physical exertion and a persistent cough. Long-term exposure to irritants such as cigarette smoke, air pollution, and occupational chemicals is the primary cause of COPD.[2] The World Health Organization reports that approximately 384 million people worldwide are affected by COPD, highlighting its significant public health impact.[3] The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has updated its staging system, traditionally relying exclusively on the percentage of predicted forced expiratory volume in 1 s (FEV1).[4,5] Inflammatory markers such as ferritin, C-reactive protein (CRP), and interleukin-6 (IL-6) are potential indicators used to assess disease severity and progression.[5-7] These markers have been associated with factors such as quality of life, exercise capacity, treatment response, and disease severity.[8]
Therefore, this research aimed to evaluate the association between inflammatory markers – CRP, IL-6, and ferritin – and disease severity in patients with COPD. Our study offers a pragmatic and scalable approach to integrating biochemical markers into routine COPD assessment. It bridges the gap between clinical observation and molecular diagnosis, offering a path toward personalized treatment protocols and potentially reducing healthcare burdens associated with disease exacerbations and hospital readmissions. There is a need for more precise biomarkers to predict the severity and progression of COPD. This is especially valuable in low-resource settings where optimal use of clinical tools can significantly improve patient outcomes.
MATERIALS AND METHODS
Study Design
This is a cross-sectional observational study.
Study Setting and Population
This study included 115 patients with a confirmed diagnosis of COPD who attended the inpatient and outpatient departments of respiratory medicine at a tertiary healthcare center in southern Rajasthan, India. Written informed consent was obtained from all participants, and the study was approved by the Institutional Ethics Committee (Ref: GU/ HREC/EC/2022/2150 dated 03/10/2022).
Inclusion Criteria
Patients were diagnosed and classified according to the severity of COPD based on the recommendations of the GOLD.[6]
Exclusion Criteria
Patients were assessed for any signs of acute exacerbation, recent infections (within the past 4 weeks), recent hospitalizations, trauma, or surgery. Patients with fever, elevated WBC counts, or radiological evidence of infection were excluded. Those under antibiotic or corticosteroid treatment at the time of sampling were also not included. This ensured that elevated inflammatory markers were representative of chronic systemic inflammation associated with COPD, rather than acute events. Above exclusion criteria will remove the confounder of acute inflammatory response.
Sample Collection and Analysis
Using aseptic techniques, 5 mL of venous blood was drawn from each patient into a plain vial. The samples were incubated at 37°C for 15 min and then centrifuged at approximately 3,500 rpm for 10 min. The serum was separated for the estimation of inflammatory markers – IL-6, CRP, and ferritin. IL-6 and ferritin levels were measured using electrochemiluminescence immunoassay, while CRP levels were determined using a particle-enhanced immunoturbidimetric assay on a COBAS-6000 fully automated machine. All tests were performed in a National Accreditation Board for Testing and Calibration Laboratories-accredited laboratory with high quality assurance.
Statistical Analysis
Data were entered and analyzed using the Statistical Package for the Social Sciences software version 20. Quantitative data (biochemical biomarkers) were analyzed using one-way analysis of variance to calculate P-values. The Tukey honestly significant difference post hoc test was applied to determine significance between groups. Pearson’s correlation coefficient was used to assess the relationship between different variables. A P < 0.05 was considered statistically significant.
RESULTS
The study aimed to determine the correlation between inflammatory markers and disease severity in COPD patients. A total of 115 patients were enrolled, categorized according to the GOLD guidelines into mild (n = 16), moderate (n = 23), severe (n = 42), and very severe (n = 34) stages of COPD. The overall mean age was 61.94 ± 11.99 years, with 73 males and 42 females. The mean age for females was 60.78 ± 11.40 years, and for males, it was 62.61 ± 12.34 years. The mean mid-upper arm circumference was 25.80 ± 3.05 cm, and the mean body mass index was 18.05 ± 1.57 kg/m2 [Table 1].
| Variables | Mild (n=16) | Moderate (n=23) | Severe (n=42) | Very severe (n=34) | P-value |
|---|---|---|---|---|---|
| Age (year) | 59.93±14.7 | 60.17±11.91 | 60.35±12.78 | 66.05±8.72 | 0.127 |
| Male (%) | 8 (50) | 15 (65.21) | 29 (69.04) | 21 (61.76) | 0.605 |
| Female (%) | 8 (50) | 8 (34.78) | 13 (30.95) | 13 (38.23) | 0.453 |
| MUAC (cm) | 28.18±3.88 | 27.17±4.063 | 25.02±1.918 | 24.73±1.95 | 0.001** |
| BMI (Kg/m2) |
19.2±1.30 | 19.06±1.58 | 17.76±1.41 | 17.19±1.18 | 0.001** |
As shown in Table 2, there was a significant difference (P = 0.001) in the levels of inflammatory markers among the COPD groups. The mean IL-6 levels (pg/mL) (mean ± standard deviation [SD]) for mild, moderate, severe, and very severe COPD patients were 29.9 ± 11.4, 58.5 ± 20.9, 72.6 ± 24.3, and 71.6 ± 17.3, respectively. Table 3 indicates a significant difference in IL-6 levels between mild and moderate COPD (P = 0.001) and between moderate and severe COPD (P = 0.042) but not between severe and very severe COPD (P = 0.997). Serum IL-6 levels were elevated across all groups, with the highest levels observed in patients with severe COPD. There was a negative correlation between FEV1% and IL-6 levels (r = −0.477, P = 0.001) among the COPD groups [Table 4].
| Variable | Mean±SD | P-value | |||
|---|---|---|---|---|---|
| Mild COPD (n=16) | Moderate COPD (n=23) | Severe COPD (n=42) | Very severe COPD (n=34) | ||
| IL-6 (pg/mL) | 29.9±11.4 | 58.5±20.9 | 72.6±24.3 | 73.6±17.3 | 0.001** |
| CRP (mg/L) | 24.9±10.4 | 33.5±8.87 | 48.2±18.7 | 64.8±22.7 | 0.001** |
| Ferritin (ng/mL) | 248.1±4 7.1 | 216.9±61.3 | 327.8±125.6 | 399.1±173.3 | 0.001** |
| FEV1% | 80.5±2.91 | 61.65±6.87 | 39.9±4.5 | 47±4.36 | 0.001** |
| P-value | |||
|---|---|---|---|
| Variables | Mild with moderate | Moderate with severe | Severe with very severe |
| IL-6 (pg/mL) | 0.001** | 0.042* | 0.997 |
| CRP (mg/L) | 0.441 | 0.010* | 0.001** |
| Ferritin (ng/mL) | 0.872 | 0.005* | 0.073 |
| Variables | r-value | P-value |
|---|---|---|
| IL- 6 (pg/mL) | −0.477** | 0.001** |
| CRP (mg/L) | −0.590** | 0.001** |
| Ferritin (ng/mL) | −0.433** | 0.001** |
The mean CRP levels (mg/L) (mean ± SD) for mild, moderate, severe, and very severe COPD patients were 24.9 ± 10.4, 33.5 ± 8.87, 48.2 ± 18.7, and 64.8 ± 22.7, respectively. As shown in Table 2, there was a significant difference (P = 0.001) among the groups. Table 3 demonstrates a significant difference in CRP levels between moderate and severe COPD (P = 0.01) and between severe and very severe COPD (P = 0.001). Serum CRP levels were elevated across all groups, with the highest levels in very severe COPD patients. A negative correlation was found between FEV1% and CRP levels (r = −0.59, P = 0.001) across all COPD groups [Table 4].
The mean ferritin levels (ng/mL) (mean ± SD) for mild, moderate, severe, and very severe COPD patients were 248.1 ± 47.1, 216.9 ± 61.3, 327.8 ± 125.6, and 399.1 ± 173.3, respectively. As shown in Table 2, there was a significant difference (P = 0.001) among the COPD groups. Table 3 reveals a significant difference in ferritin levels between moderate and severe COPD patients (P = 0.005). Serum ferritin levels were elevated across all groups, and a negative correlation was observed between FEV1% and ferritin levels (r = −0.43, P = 0.001) [Table 4].
DISCUSSION
This study focused on serum inflammatory markers – IL-6, CRP, and ferritin – in COPD patients. The findings indicate that levels of these markers were significantly elevated in COPD patients and increased with disease severity. Significant differences (P = 0.001) in inflammatory markers were observed between mild and moderate stages (IL-6), moderate and severe stages (IL-6, CRP, and ferritin), and severe and very severe stages (CRP) among COPD patients.
However, Harting et al. (2012) reported lower IL-6 levels in COPD patients, which do not correlate with our findings.[9] Several retrospective studies have associated elevated serum levels of IL-6 and CRP with the progression of COPD.[10] However, some studies did not support these findings, reporting no correlation between CRP levels and the risk of COPD.[9,11]
Research by Kwon (2018) found that IL-6 levels were significantly higher in COPD patients compared to healthy controls and were associated with systemic inflammation markers.[12] Pinto-Plata (2018) reported that patients with higher IL-6 levels were more likely to experience COPD exacerbations.[13] Su et al. (2016) indicated that COPD was linked to increased serum IL-6 without an association with TNF-a; TNF levels did not significantly differ between COPD patients and controls.[14] Kim et al. (2021) demonstrated that high IL-6 levels correlated with poorer outcomes in COPD patients undergoing pulmonary rehabilitation.[15] Villar et al. (2020) emphasized the importance of measuring IL-6 in COPD patients to assess their elevated risk of lung cancer.[16]
Our results are consistent with earlier studies. De Torres et al. (2006) reported that serum CRP levels significantly increased with COPD severity.[17] In contrast, Pinto-Plata (2018) found no significant difference in serum CRP levels between patients with mild-to-moderate COPD.[18]
Most studies have shown that COPD patients have increased CRP levels. Agustí et al. (2012) proposed a unique COPD phenotype characterized by persistent systemic inflammation, based on elevated levels of circulating inflammatory biomarkers CRP and IL-6.[19] Abdelsadek et al. (2012) found that COPD patients had significantly higher CRP levels than healthy controls (P = 0.05). Moreover, CRP levels were significantly correlated with disease stage, increasing with COPD severity.[20]
Similarly, Karadag (2020) compared 35 male patients with stable COPD to 30 age- and sex-matched individuals with normal lung function. They found that serum CRP levels were significantly higher in COPD patients than in controls (P < 0.001).[21] Studies by Joo (2014) indicated that elevated CRP levels are associated with a higher risk of developing COPD and may be used alongside other biomarkers for more accurate diagnosis. Elevated CRP levels have consistently been associated with more severe COPD.[22]
Kim et al. (2018) found iron deficiency in COPD patients despite elevated ferritin levels, increased production of acute-phase proteins like ferritin, and impaired mobilization of iron from endothelial reserves.[23] Other studies by Ghio and Hilborn (2017), Lee et al. (2020), and Brigham et al. (2015) examined the association between ferritin and lung function in the general population, showing no correlation between lung function and ferritin levels.[24-26] A study published in the European Respiratory Journal reported that individuals with COPD had significantly higher ferritin levels than those without the disease.[27]
Kim et al. (2018) compared serum ferritin levels and airflow limitation severity in COPD patients, finding that higher ferritin levels were associated with more severe airflow limitation.[23] Sprooten et al. (2016) found that higher ferritin levels were associated with increased mortality in COPD patients.[28]
Limitations
This study has certain limitations: First, the cross-sectional design restricts our ability to infer causality or assess longitudinal trends in inflammatory markers; second, being a single-center study with a limited sample size may affect the external validity of the results; and third, the exclusion of other systemic inflammatory biomarkers may overlook their potential contributions. Moreover, the absence of a healthy control group limits our ability to benchmark the elevation in biomarkers specifically to COPD.
CONCLUSIONS
Our study indicates that systemic inflammatory markers play a crucial role in the pathogenesis of COPD. There was a progressive elevation of inflammatory markers across the sequential stages of COPD. The serum levels of IL-6, CRP, and ferritin showed statistically significant differences among the various COPD groups. A negative correlation was observed between these inflammatory markers and FEV1% as the disease progressed through its stages. Emphasizes the potential of these biomarkers as indicators of pulmonary function decline and overall disease burden.
Author contributions:
PP: Investigation, resources, data collection, methodology, writing; AS: Supervision, methodology, review and editing; NK: Data analysis, review & editing; ST: Review and editing; AS: Data collection.
Ethical approval:
The research/study was approved by the Institutional Review Board at Geetanjali Medical College & Hospitals, Udaipur, Rajasthan, approval number GU/HREC/ EC/2022/2150, dated 3rd October 2022.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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