ORIGINAL ARTICLE |
https://doi.org/10.5005/jp-journals-11010-1142 |
Association of Interleukin-6 Levels with Body Mass Index in Chronic Obstructive Pulmonary Disease Patients
1,3–6Department of Biochemistry, Government Medical College and Hospital, Chandigarh, India
2Department of Pulmonary Medicine, Government Medical College and Hospital, Chandigarh, India
Corresponding Author: Seema Gupta, Department of Biochemistry, Government Medical College and Hospital, Chandigarh, India, Phone: +91 9646121661, e-mail: dr.seemasingla@yahoo.com
Received: 04 April 2024; Accepted: 04 December 2024; Published on: 17 February 2025
ABSTRACT
Background: Chronic obstructive pulmonary disease (COPD) is considered to be a systemic inflammatory state. There is an increase in the circulating markers of inflammation like interleukin-6 (IL-6), tumor necrosis factor-alpha, and C-reactive protein (CRP) in COPD patients, which are reported to be associated with disease severity. IL-6 levels are found to be increased in overweight/obesity as well. However, increased body mass index (BMI) has been documented to show a protective effect on COPD. The current study was planned to explore the association of IL-6 with BMI and grades of disease severity.
Materials and methods: The study design was observational and cross-sectional and included 70 diagnosed cases of COPD. The patients were divided into underweight, normal weight, and overweight/obese groups by Asian criteria based on BMI. The circulating IL-6 and CRP levels were measured. The disease severity was assessed by the Global Initiative for COPD criteria.
Results: No significant difference was found in IL-6 and CRP levels among different subgroups based on BMI (p > 0.05). However, a statistically significant difference was found in IL-6 and CRP levels among patients with mild, moderate, and severe disease (p < 0.001). A significant correlation was found between IL-6 and CRP, but no significant correlation was found between these and BMI.
Conclusion: The present study does not support the obesity paradox in COPD, as no significant association of BMI with disease severity was found, whereas IL-6 and CRP showed a significant difference among patients with different severity grades.
Keywords: Body mass index, Chronic obstructive pulmonary disease, Interleukin-6
How to cite this article: Gupta S, Saini V, Jaswal S, et al. Association of Interleukin-6 Levels with Body Mass Index in Chronic Obstructive Pulmonary Disease Patients. Indian J Respir Care 2024;13(4):221–225.
Source of support: Nil
Conflict of interest: None
INTRODUCTION
The prevalence of noncommunicable diseases has shown a tremendous increase in India, particularly in the last few decades. Out of the foremost causes of death in India, three are due to noncommunicable diseases, and chronic obstructive pulmonary diseases (COPD) are in second position on this list.1 As the name suggests, it is a pulmonary disease causing chronic obstruction of airflow in the lungs, which is not fully reversible. Various population-based studies have found the prevalence of COPD to range between 2–22% in males and 1.2–19% in females in different states of India.2 The treatment of COPD and associated comorbidities requires frequent hospitalizations, and the mean length of stay in the hospital can vary from 4.5 to 16 days,3 which adversely affects quality of life and adds to the huge burden in resource-poor settings.
Chronic obstructive pulmonary disease is considered to be a systemic inflammatory state, and complications like anorexia, atherosclerosis, and cachexia may contribute to disease outcomes. IL-6 is a proinflammatory cytokine and induces the synthesis of various acute phase reactants like C-reactive protein (CRP), fibrinogen, and serum amyloid A.4 Many studies have found its positive association with COPD severity and the number of episodes of acute exacerbations.5
The main goal of COPD management is to modify the risk factors for better clinical outcomes. The presence of various comorbidities and nutritional status also has an impact on the disease course in these patients. An association has been observed between body mass index (BMI) and lung function decline in recent studies. In one such study, it has been documented that the average BMI of bronchial asthma patients was higher than that of COPD patients (p < 0.001), and the mean BMI in COPD patients reduced significantly with progression in severity.6 COPD is a hypermetabolic state with increased cost of breathing due to airflow obstruction, so negative energy balance is reported to be the cause of weight loss in these patients. However, some studies reported resting energy expenditure to be independent of disease severity and oxygen cost of breathing.7
Circulating levels of IL-6 have been found to be significantly lower in normal weight controls as compared to overweight and obese subjects.8 However, some studies have emphasized the protective effects of obesity and overweight, termed as the “obesity paradox,” on certain chronic conditions, including COPD.9 It has been reported that obese COPD patients have a lower frequency of exacerbations compared to the lean ones.10 IL-6 levels are reported to be increased in obesity but are also found to be positively associated with COPD severity.5 These findings are contradictory, and there is a conundrum regarding the association of BMI with IL-6 in these patients. The present study aims to find the relation of BMI with IL-6 levels in COPD patients, if any, and their association with disease severity.
MATERIALS AND METHODS
The study design was cross-sectional. Seventy physician-diagnosed COPD patients visiting the pulmonary medicine OPD were enrolled after obtaining their consent. The study approval was obtained from the Institutional Research and Ethics Committees. Patients with recent pulmonary infections, cardiac diseases, those on immunosuppressant therapy, and patients under 18 years of age were excluded from the study.
A detailed history was obtained, and the height and weight of the patients were recorded to calculate the BMI using the following formula:
BMI = weight in kg/(height in m)2
The study group was divided into following categories according to Asian BMI criteria11:
<18.5 kg/m2 underweight
18.5–22.9 kg/m2 normal weight
23–24.9 kg/m2 overweight
>25 kg/m2 obese
The severity of the disease was assessed based on the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) criteria.12 Under aseptic conditions, a 5 mL venous blood sample was drawn for the estimation of IL-6 along with routine investigations. Serum was separated by centrifugation, and IL-6 levels were estimated using a chemiluminescence-based direct immunoassay (ADVIA Centaur XPT) with the Siemens IL-6 kit. Serum CRP was estimated by immunoturbidimetric assay, while total protein and albumin were estimated using colorimetric assays on a general chemistry autoanalyzer (Beckman Coulter AU 5800).
Data were entered into Microsoft Excel and analyzed by Statistical Package for the Social Sciences version 25 (IBM Technologies, Chicago, USA). Continuous variables were expressed as the mean and standard deviation in normally distributed data and as the median and interquartile range in nonnormal distribution. Categorical variables were expressed as numbers and proportions. Comparison of quantitative data among different groups was done by ANOVA in normal distribution, and those with skewed distribution were analyzed using the Kruskal–Wallis test. Nonquantitative data were compared using the Chi-square or Fisher’s exact test, as applicable. Pearson or Spearman correlation was calculated as appropriate. A p-value of <0.05 was taken as significant.
RESULTS
The study group comprised 70 COPD patients, of which 82.8% were males and 17.2% were females. Table 1 shows the demographic details and baseline investigations in the study group. Five patients in the study group were underweight (BMI <18.5 kg/m2), 42 were of normal weight (BMI 18.5–22.9 kg/m2), six were overweight (BMI 23–24.9 kg/m2), and 17 were obese (BMI ≥25 kg/m2). For statistical analysis, the overweight and obese groups were combined, and the data were analyzed accordingly.
| n = 70 | |
|---|---|
| Mean age (years) | 55.28 ± 12.57 |
| Gender | Female—12 Male—58 |
| Smoking status | Smokers—50 Nonsmokers—20 |
| BMI (kg/m2) | <18.5 (5) 18.5–22.9 (42) 23–24.9 (6) >25 (17) |
| Total serum proteins (gm/dL) | 7.10 ± 0.756 |
| Serum albumin (gm/dL) | 3.66 ± 0.637 |
| CRP (mg/L) | 10.0 ± 5.26 |
Normality of the data was checked by the Shapiro–Wilk test, and the distribution of BMI, IL-6, and CRP was found to be skewed (p < 0.05). Median ± SEM levels of IL-6 and CRP were calculated and found to be 7.3 ± 3.97 pg/mL and 10.0 ± 5.26 mg/L, respectively. Table 2 shows the median levels of IL-6 and CRP in different BMI subgroups, but no statistically significant difference was found between them. Also, no significant difference was found in total protein and albumin levels (p > 0.05) among the subgroups based on BMI.
| Median | IQR | p-value | ||
|---|---|---|---|---|
| IL-6 (pg/mL) | BMI <18.5 (kg/m2) n = 5 |
13.1 | 4.8 | p = 0.171a |
| BMI 18.5–22.9 (kg/m2) n = 42 |
8.1 | 21.76 | ||
| BMI ≥23 (kg/m2) n = 23 |
2.4 | 11.9 | ||
| CRP (mg/L) | BMI <18.5 (kg/m2) n = 5 |
6.0 | 29.5 | p = 0.074a |
| BMI 18.5–22.9 (kg/m2) n = 42 |
11.5 | 20.6 | ||
| BMI ≥23 (kg/m2) n = 23 |
8.0 | 8.9 |
aKruskal–Wallis
According to the disease severity (GOLD criteria), patients were divided into stage 1 (mild, n = 23), stage 2 (moderate, n = 33), and stage 3 (severe, n = 14). None of the patients had stage 4 or very severe COPD. Figure 1 shows the median levels of IL-6 and CRP in these severity groups, and a statistically significant difference was found between them (p < 0.001 each). However, Table 3 shows that no statistically significant difference was found in BMI among the different severity groups.
| Severity grade (GOLD) | Median | IQR | Range | p-value | |
|---|---|---|---|---|---|
| BMI (kg/m2) |
Mild (n = 23) |
22.5 | 20.7–25.7 | 16.5–30 | p = 0.125a |
| Moderate (n = 33) |
21.1 | 20.0–23.15 | 16.3–31.2 | ||
| Severe (n = 14) |
20.8 | 20.0–23.05 | 18.7–28.7 |
aKruskal–Wallis
Fig. 1: Box plots showing levels of IL-6 and CRP in patients having mild, moderate, and severe disease according to GOLD criteria
The Spearman correlation analysis was done (Table 4), and a significant correlation of IL-6 was found between CRP, total serum proteins, and albumin. However, no significant association was found between IL-6 levels and BMI. CRP showed a significant correlation with albumin but not with BMI or total serum proteins.
| Correlation coefficient (r) | p-value | |
|---|---|---|
| IL-6 | ||
| BMI | –0.168 | 0.165 |
| CRP | 0.585 | 0.000 |
| Total protein | –0.281 | 0.016 |
| Albumin | –0.274 | 0.022 |
| CRP | ||
| BMI | –0.204 | 0.090 |
| Total protein | –0.056 | 0.647 |
| Albumin | –0.056 | 0.025 |
DISCUSSION
Chronic obstructive pulmonary disease is a significant health issue with high prevalence, morbidity, and mortality. It shows male preponderance, and similar findings were observed in the present study also. The median BMI levels in the present study were 21.7 kg/m2, which were close to 21.5 kg/m reported in an earlier study.13 It was observed that the BMI levels decreased with an increase in the severity grade of the disease in the present study, but the difference was not statistically significant. However, in a meta-analysis, it has been documented that low BMI is associated with more severe disease and worse outcomes.14 In a post hoc analysis of TIOSPIR (Tiotropium Safety and Performance in Respimat) and UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) studies, the risk of severe exacerbation and mortality due to respiratory diseases was found to be increased in underweight patients compared to those in other BMI categories.15 It was suggested that less risky lower body obesity and favorable body composition could be the reason behind this observation, as many obese patients also have increased muscle mass in addition to increased fat mass. It was also suggested that poor lung functions and likely current smoker status could be the cause of adverse outcomes in underweight patients.15 Air trapping, emphysema, hyperinflation, and loss of diaphragmatic curvature are said to be the other causes of poor FEV1/FVC in underweight patients.15 However, no muscle mass assessment was done, and no significant difference in BMI levels was found among smokers and nonsmokers in the present study. Also, no significant difference in the FEV1/FVC ratio was found in the three subgroups based on BMI in the present study (p > 0.05). This contradictory finding could be attributed to the cross-sectional study design, as no follow-up was done to observe the frequency of exacerbations in the present study. The different BMI cutoffs taken in various studies might also contribute to discordant findings.15
In another COPDGene (Genetic Epidemiology of COPD) study carried out on 3,631 patients, it was seen that obesity was related to worse COPD outcomes compared to normal weight or overweight individuals.15 So, the research conclusions on the effect of BMI on disease outcomes have been inconsistent. BMI may not always depict fat/lean mass distribution of the body. More accurate indicators of visceral fat, like waist circumference and waist-hip ratio, may be used as markers of obesity in future studies. It was observed that BMI misclassified body fat status in 41% of heart failure patients compared to dual-energy X-ray absorptiometry.9
The median IL-6 and CRP levels were found to be raised in COPD patients. The results are in line with the findings of a previous study, which reported median IL-6 as 8.8 pg/mL and high-sensitivity C-reactive protein (hsCRP) as 5.50 mg/L,16 suggesting that systemic inflammation is present in COPD patients. Bolton et al. also reported increased IL-6 levels in COPD patients, which further led to increased CRP synthesis and secretion.17 Many studies have reported that increased IL-6 levels were associated with a higher frequency of acute exacerbations in COPD patients.16,18 Since the present study was cross-sectional in design, no follow-up was done to explore the frequency of exacerbations. Significant differences in median IL-6 and CRP levels were observed among different subgroups in the present study. Similar findings were reported in a case-control study, where significantly higher IL-6 levels were found in severe COPD patients compared to mild and moderate COPD patients.18
However, both CRP and IL-6 levels did not show any significant difference when compared between underweight, normal weight, and overweight or obese patients, and no significant correlation was found between BMI and IL-6 or CRP levels in COPD patients in the present study. On the contrary, in a cross-sectional study carried out in Egyptian overweight and obese adults, IL-6 levels correlated positively with BMI. In obese individuals, there is adipose tissue expansion causing cellular hypoxia, which may lead to inflammation found in obesity. There is also increased adipocytokine production and upregulation of proinflammatory genes, which is said to be the cause of increased IL-6 levels.8 On the contrary, it is also reported that IL-6 has pleiotropic effects, including a role in lipolysis and skeletal muscle atrophy, and obesity has been observed in IL-6 knockout mice.19
Another important finding of the present study is the significant negative correlation of IL-6 with total serum protein and albumin, which underscores the need for managing nutritional status in these COPD patients. Proinflammatory cytokines decrease albumin production, which can be the cause of low albumin concentration seen in these patients.20
Cross-sectional study design and small sample size are the limitations of the present study. Longitudinal studies with a larger sample size may be planned to elucidate the cause-effect relationship of obesity with COPD outcomes.
CONCLUSION
The present study asserts the association of IL-6 with disease severity but could not address the same for BMI. It is also pertinent to mention here that BMI is not always a reliable indicator of obesity. Various BMI cutoffs are used for the diagnosis of underweight, overweight, and obesity in different parts of the world. Future studies with other robust markers of obesity, like waist-hip ratio, waist circumference, and dual-energy X-ray absorptiometry, are needed to evaluate the obesity paradox in COPD.
ORCID
Varinder Saini https://orcid.org/0000-0002-5791-8870
Shivani Jaswal https://orcid.org/0000-0002-7202-7902
Jasbinder Kaur https://orcid.org/0000-0001-9694-0213
Shristi Krishna https://orcid.org/0009-0008-4013-5248
Manpreet Kaur https://orcid.org/0009-0003-6931-3179
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