Neutrophil-Lymphocyte Ratio as a Predictor of COPD Exacerbations: A Cross-sectional Study
Correspondence Address :
Dr. Kranti Garg,
Associate Professor, Department of Pulmonary Medicine, Government Medical College, Patiala, Punjab, India.
E-mail: drkrantigarg@yahoo.com
Introduction: Chronic Obstructive Pulmonary Disease (COPD) is characterised by a modified inflammatory response to chronic irritants, which is often associated with some degree of systemic inflammation. Exacerbations in COPD are characterised by exaggeration of the ongoing inflammation. A number of inflammatory mediators are found to be raised in COPD exacerbations, but most of them are expensive and not readily available. The Neutrophil-lymphocyte Ratio (NLR) is a rapid, easy and cheap biomarker, that has been shown to be raised in patients of COPD.
Aim: To evaluate the role of NLR in patients of stable and acute exacerbation of COPD.
Materials and Methods: This cross-sectional observational study was conducted in Department of Pulmonary Medicine at Government Medical College, Patiala, Punjab, India. Study included 150 patients of stable COPD, 150 patients of Acute Exacerbation COPD (AECOPD) and 100 subjects as controls. NLR was calculated from a peripheral blood sample of the study participants. Continuous variables were summarised as mean with standard deviation and compared between groups using Unpaired t-test. A p-value <0.05 was considered statistically significant.
Results: The mean age in AECOPD group was 61.7±10.4 years, in stable COPD group was 63.1±8.9 years and 63.2±7.8 years in controls. Mean NLR was found to be highest in AECOPD group (4.0±1.7) followed by stable COPD (2.9±0.8) and then control (1.8±0.4). NLR showed good predictive value for predicting exacerbations in stable COPD patients with sensitivity and specificity of 75.3% and 70.7%, respectively (cut-off=3.4 and AUC=0.806).
Conclusion: The NLR is an easily available biomarker of inflammation and can be used as a predictor of exacerbation in patients of COPD.
Biomarker, Chronic obstructive pulmonary disease, Inflammation
Chronic Obstructive Pulmonary Disease (COPD) is characterised by a modified inflammatory response to chronic irritants. There is an increase in the number of macrophages, activated neutrophils, and lymphocytes in peripheral airways, lung parenchyma, and vessels (1). The role of the neutrophils in the pathogenesis of COPD is only partially known. The imbalance between proteases and their inhibitors cause parenchymal destruction and emphysematous changes, while the production of cytokines, enzymes, adhesion molecules, and growth factors from activated neutrophils promote infiltration of the airways by inflammatory cells and further production of proinflammatory factors, creating a vicious circle, which maintains and enhances the local and systemic effects of the disease (2),(3).
Along with pulmonary inflammation, some degree of systemic inflammation is also seen in COPD, although the mechanism of this systemic inflammation remains unclear. Several pathways have been suggested that may lead to systemic inflammation in COPD, these include; overflow of inflammatory mediators from pulmonary compartment; proinflammatory reaction to bacterial products; inflammatory reaction to tissue hypoxia, and inflammation induced due to smoking (4). During exacerbations of COPD, pulmonary as well as systemic inflammation is accentuated characterised by cellular activation, cytokine production and tissue injury. The infective (bacterial or viral (5)) and non infective triggers of exacerbations accentuate the ongoing inflammation in patients of COPD (6).
Increased inflammation in lungs is associated with raised inflammatory markers in circulation leading to an increase in systemic inflammation as well (4). Several biomarkers of inflammation which are found to be raised in COPD are C-Reactive Protein (CRP), Interleukin-8 (IL-8), Tumour Necrosis Factor (TNF-α), leptin, endothelin-1, fibrinogen, IL-6, Leukotriene (LT) B4 and E4 (7). Although some of these novel biomarkers can identify the severity of disease and acute exacerbation in COPD, most of them are time-consuming, expensive, and not readily available (8). The Neutrophil-Lymphocyte Ratio (NLR) is a rapid, easy and cheap biomarker that is calculated from Complete Blood Count (CBC). Blood NLR has been demonstrated to be an indicator of inflammatory states and is utilised for risk stratification of several disorders, including acute coronary syndrome (9), pancreatitis (10), sepsis, and infectious conditions (11). NLR is also been used as a prognostic indicator in several diseases like breast cancer (12), sepsis (13), and most recently in Coronavirus Disease 2019 (COVID-19) (14).
There has been extensive research on the role of NLR in COPD. Multiple studies have corroborated that NLR increases during exacerbations of COPD [8,15-24] and other studies have explored its role as a predictor of exacerbations (8),(15),(16),(18),(25),(26) and mortality (17),(24),(25),(27),(28),(29),(30). However, data in the Indian population is scarce. Prasannan G et al., and Sharma K et al., found that NLR was raised in COPD exacerbations when compared to stable patients (21),(22). Prasannan G et al., also found that NLR has a positive correlation with mMRC and BODE score of the patients (21). While Arya V et al., found no correlation between NLR and severity of COPD exacerbation (31). Hence, the present study was conducted to evaluate the role of NLR in patients of COPD, especially as a predictor of exacerbations.
This cross-sectional observational study was conducted from June 2019 to November 2020, in Department of Pulmonary Medicine at Government Medical College, Patiala, Punjab, India. Institutional Ethical Committee approval was obtained for the study (BFUHS/2K19p-TH/2073).
Inclusion criteria: All patients attending the study Institute with diagnosis of COPD {as per GOLD 2018 report criteria (1)} were included in the study.
Exclusion criteria: Pregnant and lactating females, and patients with bronchiectasis, active tuberculosis, malignancy, or other inflammatory diseases such as arthritis, inflammatory bowel diseases, or connective tissue disorders were excluded from the study.
Patients of COPD were divided into two groups of 150 patients each.
COPD group (n=150): One group was of stable patients of COPD, defined as those with no significant change in symptoms and no need for additional therapy for the past three months (32).
AECOPD group (n=150): All patients with Acute Exacerbation of COPD (AECOPD) which was defined as an acute worsening of symptoms in COPD patient that requires additional therapy (1).
Controls (n=100): Healthy subjects with no history of smoking or biomass exposure, no co-morbidities, and no clinical symptoms.
Data Collection
Baseline demographic data and clinical history was noted. Blood samples were collected from participants and subjected to total and differential leucocyte count, absolute eosinophil and neutrophil counts. Neutrophil-lymphocyte ratio was calculated by dividing neutrophil count with lymphocyte counts.
Statistical Analysis
Categorical variables were summarised as proportions. Continuous variables were summarised as mean with Standard Deviation (SD) and compared between groups using Unpaired t-test. A p-value <0.05 was considered statistically significant. Data was analysed using R software version 4.0.1.
The mean age in AECOPD group was 61.7±10.4 years, in stable COPD group was 63.1±8.9 years and 63.2±7.8 years in controls. Male predominance was seen in all three groups studied. The mean BMI of participants was significantly lower in stable COPD patients, as compared to AECOPD and controls. Only 82% patients of AECOPD and 77.3% of stable COPD patients were smokers, biomass fuel exposure was present in 23.3% and 26.7% of patients of AECOPD and stable COPD respectively. Current smokers were significantly higher in AECOPD group, as compared to stable COPD group (Table/Fig 1).
When comparing haematological parameters between AECOPD and stable COPD groups, total leucocyte count, neutrophil percentage, absolute neutrophil count, and absolute eosinophil count were significantly higher in the AECOPD group compared to stable COPD group. Mean NLR was significantly higher in AECOPD group (4.0±1.7) compared to stable COPD group (2.9±0.8). However, there was no significant difference in haemoglobin levels or eosinophil percentage between the two groups.
Comparative evaluation of haematological parameters between stable COPD patients and controls showed that the total leucocyte count, neutrophil and eosinophil percentage, and absolute eosinophil and neutrophil counts were significantly lower in control group compared to stable COPD group. The mean NLR was significantly higher in stable COPD group compared to control group. Comparison of haematological parameters between AECOPD and controls revealed that the total leucocyte count, neutrophil and eosinophil percentage, absolute eosinophil count, and absolute neutrophil count were significantly higher in the AECOPD patients, compared to controls group. NLR was significantly higher in AECOPD group compared to control group (Table/Fig 2).
Receiver-Operating Characteristic (ROC) analysis revealed a good predictive value of NLR for predicting an exacerbation of COPD. At a cut-off of 3.4, the sensitivity, specificity and Area Under Curve (AUC) were 75.3%, 70.7% and 0.806, respectively (Table/Fig 3).
Study participants were characterised, based on blood eosinophil percentage into two groups i.e., blood eosinophils <2% and ≥2%. In patients of AECOPD, NLR was found to be significantly higher in non eosinophilic group (blood eosinophils <2%) and in those, with blood eosinophils ≥2%. NLR was similar in two groups in patients of stable COPD and controls (Table/Fig 4).
In the present study, the Total Leucocyte Counts (TLC) in patients of stable COPD were significantly higher than controls, a finding that was present consistently in previous studies (8),(15),(19),(20),(24). COPD is characterised by an altered inflammatory response to airway irritants leading to parenchymal and airway destruction which further causes persistent symptoms and airflow limitation. Apart from airway inflammation, an abnormal systemic inflammation is also seen in COPD, which in turn is responsible for most of the systemic manifestations of the disease. Several mechanisms have been proposed in order to explain systemic inflammation in COPD, like systemic spread of inflammatory mediators from pulmonary compartment, an inflammatory response to tissue hypoxia or bacterial components, smoking induced inflammation, pulmonary hyperinflation (4). Furthermore, exacerbation of COPD is characterised by increased inflammation as a result of infective aetiology in most cases and hence, leads to higher TLC, which is seen in the present study, as well as, in previous literature (8),(15),(19),(20),(24), when compared to controls or stable COPD patients.
In the present study, it was found that NLR was significantly higher in stable COPD, when compared to controls and even higher in AECOPD when compared to stable COPD and controls. Similar findings have been reported by a number of studies (Table/Fig 4). NLR is an established marker of inflammation and has been shown to increase in several inflammatory conditions (9),(10),(11),(12),(13),(14). Exacerbations in COPD are characterised by flaring of the chronic inflammatory process of COPD at pulmonary and systemic level. Bacterial, viral as well as non infectious causes of exacerbations lead to increased inflammation in airways and release of proinflammatory cytokines and chemokines (6). These markers of inflammations are often increased in AECOPD and lead to heightened systemic inflammation in form of neutrophil recruitment and activation. These result in a higher NLR in AECOPD, when compared to stable COPD and controls.
Since, NLR is significantly higher in AECOPD, it could be used as a biomarker of exacerbation in patients of COPD. In the present study a cut-off value of 3.4 showed a sensitivity and specificity of 75.3%, and 70.7%, for predicting an exacerbation. Several previous studies have also found a good predictive value of NLR in predicting an exacerbation of COPD (Table/Fig 5) (8),(15),(17),(18),(20),(21),(22),(23),(24),(26).
A significantly higher NLR was found in patients of AECOPD with blood eosinophil percentage <2%, when compared to those with eosinophils ≥2% but no significant difference was found when categorising controls and stable COPD patients into these categories. Moreover, the number of AECOPD patients showing this trend was very less, hence, no conclusion could be drawn from this finding.
Limitation(s)
The NLR was not evaluated with respect to other variables like severity of underlying COPD, severity of exacerbations, frequency of previous exacerbations. Since, it was a cross-sectional study and no follow-up was done, prognostic role of NLR was not studied.
Frequent and severe exacerbations of COPD adversely affect the health status of the patient and also, contribute to progression of disease and mortality (1). Predicting exacerbations early can help in early detection and management. Current study shows that, NLR is an inflammatory biomarker that raises significantly during COPD exacerbations and can be used to predict COPD exacerbations, and help in detecting exacerbations early.
DOI: 10.7860/JCDR/2023/59293.17337
Date of Submission: Aug 26, 2022
Date of Peer Review: Oct 06, 2022
Date of Acceptance: Nov 03, 2022
Date of Publishing: Jan 01, 2023
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. NA
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