Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disorder characterised by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response of the airways and lungs to noxious particles and gases [1]. It is a leading cause of morbidity and mortality worldwide, with 212.3 million prevalent cases and 3.3 million deaths recorded globally in 2019 [2], and ranks as the second leading cause of death and disability-adjusted life years lost in India [3].

For many years, disease severity in COPD was graded solely by the forced expiratory volume in one second (FEV1). This single-variable approach has well-recognised shortcomings: FEV1 correlates only modestly with symptom burden, exercise tolerance and health-related quality of life, and it captures nothing of the extrapulmonary consequences of the disease. Recognition that COPD produces systemic effects — weight loss, skeletal muscle wasting, osteoporosis, depression and increased cardiovascular risk — prompted a shift towards multidimensional assessment [4,5].

Celli and colleagues addressed this need with the BODE index, a ten-point composite scale incorporating four independent predictors: body mass index (B), the degree of airflow obstruction assessed by FEV1 (O), dyspnoea measured on the modified Medical Research Council scale (D), and exercise capacity assessed by the six-minute walk distance (E) [6]. The BODE index predicts all-cause and respiratory mortality more accurately than FEV1 alone [6] and has subsequently been validated as a predictor of exacerbation risk [7]. Each constituent carries independent prognostic weight. The mMRC scale is a five-level instrument based on the patient's perception of breathlessness during daily activity [8]; it is a simple and valid measure of disability in COPD [9] and relates more closely to health and psychological status than FEV1 [10]. The six-minute walk test is a straightforward, well-tolerated measure of functional exercise capacity that correlates closely with treadmill and cycle ergometry [11], serves as a standard outcome measure in pulmonary rehabilitation [12,13], and independently predicts survival in severe disease [14]. Low body mass index, in turn, is an established independent predictor of mortality in COPD.

Running parallel to this conceptual shift has been the search for a circulating biomarker of the systemic inflammatory process. C-reactive protein, an acute-phase reactant produced by hepatocytes in response to interleukin-6, reflects the total systemic inflammatory burden and is elevated in COPD both in the stable state and during exacerbation [15]. Elevated CRP has been linked to metabolic and functional impairment in advanced disease [16], to clinically important predictive outcomes in stable disease [17], and to hospitalisation and death in population cohorts [18].

The logical next question is whether CRP relates to the multidimensional BODE index and, if so, whether that relationship is driven by any particular component. The available evidence is inconsistent: several groups report significant correlations between CRP and the BODE score [17,19,20], while findings on individual components — particularly body mass index and six-minute walk distance — conflict markedly between studies [16,21,22]. Data from Indian populations, in whom mean body mass index is substantially lower and biomass exposure more prevalent than in the Western and Turkish cohorts that dominate this literature, are limited. The present study was therefore designed to correlate serum CRP with the BODE index and each of its components in patients with COPD at a tertiary care centre in southern India.

This descriptive cross-sectional hospital-based study was carried out in the Department of General Medicine, Rajarajeswari Medical College and Hospital, Bengaluru, over 18 months from January 2021 to June 2022. Participants were recruited from patients with COPD attending the outpatient and inpatient services of the department. Ethics: Institutional Ethics Committee clearance was obtained before commencement. Written informed consent was taken from every participant prior to data collection. Sample size and sampling: With an average of three eligible cases per month over 18 months, the expected population was N = 54. Using the Yamane formula for a known population, n = N/(1 + Ne²) with a 5% margin of error at 95% confidence, n = 54/(1 + 54 × 0.05²) = 47.78, rounded to a final sample size of 50. Purposive sampling was used until this number was achieved. Eligibility: Patients above 40 years of age with chronic cough and expectoration, mMRC dyspnoea grade ≥3, exposure to tobacco (current or former) or to occupational dusts and chemicals, and post-bronchodilator FEV1 <80% predicted with FEV1/FVC <0.7 after 400 µg inhaled salbutamol were included. Patients with asthma, tuberculosis, bronchiectasis, acute coronary syndrome, myocardial infarction within six months, congestive cardiac failure, collagen vascular or autoimmune disease, pulmonary embolism, malignancy, renal insufficiency or hepatic cirrhosis were excluded, as were those with active infection, recent trauma or surgery, or prior use of statins or hormone replacement therapy, since each independently influences CRP concentration. Anthropometry (B): Height was measured to the nearest centimetre with a stadiometer, the subject standing barefoot with heels together, back and head against the rod and eyes directed forward. Weight was recorded to the nearest 0.1 kg on an electronic scale in light clothing. Body mass index was calculated as weight (kg)/height (m)². Airflow obstruction (O): Spirometry was performed with an automated flow-sensing spirometer (Helios v3.1.80) with the subject seated, following the 2005 ATS/ERS standardisation recommendations [23]. Three to eight acceptable forced expiratory manoeuvres were obtained and the highest FEV1 and FVC used; measurements were repeated 20 minutes after salbutamol nebulisation. Predicted values were based on age, sex, height and ethnicity. Dyspnoea (D): Severity of breathlessness was graded on the modified Medical Research Council dyspnoea scale by direct interview. Exercise capacity (E): The six-minute walk distance was measured as the distance a patient could walk briskly on a flat, hard surface in six minutes, following American Thoracic Society guidelines [24]. The test was conducted along a 50-metre hospital corridor; any rest periods taken were included within the six-minute test period. BODE index computation: Points were assigned as follows — FEV1 (% predicted): ≥65 = 0, 50–64 = 1, 36–49 = 2, ≤35 = 3; six-minute walk distance (m): ≥350 = 0, 250–349 = 1, 150–249 = 2, ≤149 = 3; mMRC grade: 0–1 = 0, 2 = 1, 3 = 2, 4 = 3; body mass index (kg/m²): >21 = 0, ≤21 = 1. The four component scores were summed to yield a total ranging from 0 to 10, with higher scores denoting greater severity. Biochemical assay: Venous blood was collected with the patient at rest after four hours of fasting and before any other investigation. Serum CRP was estimated by latex agglutination. Chest radiography, electrocardiography, two-dimensional echocardiography, complete blood count and renal function tests were performed as clinically indicated. Statistical analysis: Data were entered in Microsoft Excel and analysed with SPSS version 26.0. Categorical variables are presented as frequencies and percentages and continuous variables as mean ± standard deviation. Analysis of variance was used to compare means between groups, and Pearson's correlation coefficient to assess associations between continuous variables. Significance was set at 5% (α = 0.05).

Table 1. Baseline demographic and clinical characteristics (n = 50)

The cohort comprised elderly patients with a strong male predominance (90%) and established, advanced disease — 78% were in GOLD grades 3–4 and none had mild obstruction. Mean symptom duration approached five years with an average of nearly three exacerbations annually. Mean serum CRP of 4.50 ± 2.40 mg/L represents the modest, persistent elevation typical of chronic low-grade systemic inflammation rather than acute infection.

Table 2. Component B — Distribution by body mass index (n = 50)

Mean body mass index was 19.2 ± 4.0 kg/m², at the lower end of the normal range. Forty per cent of patients (20) were frankly underweight and a further 48% (24) were in the normal band, with only 6 patients (12%) overweight or obese. This low anthropometric profile is characteristic of advanced COPD, in which increased work of breathing, systemic inflammation and reduced dietary intake combine to produce cachexia; it also reflects the generally lower baseline body mass index of Indian populations.

Table 3. Component D — Distribution by mMRC dyspnoea grade (n = 50)

All participants were severely breathless, with 37 patients (74%) at grade 3 and 13 (26%) at grade 4, giving a mean grade of 3.26 ± 0.44. This uniformly high and narrowly distributed dyspnoea burden is a direct consequence of the mMRC ≥3 inclusion criterion, and the resulting restriction of range is important when interpreting the correlation analysis below.

Table 4. Component E and composite score — Six-minute walk distance and BODE index (n = 50)

Mean six-minute walk distance was 266.42 ± 57.48 m, well below the 350 m threshold that attracts zero points on the BODE scale and indicating markedly impaired functional exercise capacity. Combined with a mean post-bronchodilator FEV1 of 0.43 ± 0.11 L, low body mass index and high mMRC grade, this produced a mean BODE score of 6.32 ± 1.23 — a value in the high-risk quartile associated with substantially increased four-year mortality in the original validation cohort.

Table 5. Distribution by BODE index score (n = 50)

The distribution was concentrated in the upper half of the scale. Thirty patients (60%) scored 5–6 and 18 (36%) scored 7–10, so that 96% of the cohort fell in the two highest BODE quartiles; only 2 patients (4%) scored 3–4 and none scored below 3. This confirms that the study population represented advanced multidimensional disease severity, not merely advanced spirometric impairment.

Table 6. Correlation of serum CRP with the BODE index and its components (n = 50)

*Significant at p<0.05. †Reported for completeness; the obstruction domain is the one component that retained an independent association with CRP.

Serum CRP showed a statistically significant positive correlation of modest strength with the composite BODE index (r = 0.303, p = 0.032), indicating that patients with greater aggregate disease severity carried a higher systemic inflammatory burden. Among the individual domains, only the obstruction component (post-bronchodilator FEV1) retained a significant, inverse association with CRP (r = –0.444, p = 0.001). Body mass index (r = –0.003, p = 0.981), mMRC dyspnoea grade (r = –0.037, p = 0.797) and six-minute walk distance (r = –0.069, p = 0.632) all showed correlations that were negligible in magnitude and far from statistical significance. The pattern therefore indicates that the association between CRP and the BODE index is not attributable to any single non-spirometric domain, but emerges from the composite when the four dimensions are summed.

The present cohort, with a mean age of 65.56 ± 9.69 years and 90% male preponderance, was demographically comparable to the series of Rossato Silva et al. (64.8 ± 8.5 years) and Milačić (67.76 ± 9.39 years; 73.2% male), and to Aksu et al., in whom 86.5% were male [19,25,26]. Mean body mass index of 19.2 ± 4.0 kg/m² was substantially lower than the 27.58 ± 4.89 kg/m² reported by Aksu et al. and the 26.61 ± 6.28 kg/m² of Milačić [25,26], with 40% of our patients underweight. Mean mMRC grade of 3.26 ± 0.44 was correspondingly much higher than the 1.1 ± 0.9 of Aksu et al. Mean six-minute walk distance of 266.42 ± 57.48 m was far shorter than the 421.38 ± 106.71 m of the Turkish cohort, and mean BODE score of 6.32 ± 1.23 greatly exceeded their 1.99 ± 1.96 [26]. Meshram et al. found 76% of their Indian patients scoring above 3, whereas all our patients did so [27]. These consistent differences confirm that the present cohort represented considerably more advanced disease, an expected consequence of the mMRC ≥3 entry requirement and tertiary referral bias. The principal finding — a significant positive correlation between CRP and the composite BODE index (r = 0.303, p = 0.032) — accords with Ghobadi et al., de Torres et al., Aksu et al. and Sarioglu et al., all of whom demonstrated significant CRP–BODE associations [17,20,21,26]. The consistency of this observation across populations of very different anthropometric and functional profile strengthens the inference that the systemic inflammatory burden scales with multidimensional disease severity. More instructive is the discordance at component level. Correlation between CRP and body mass index was absent in our data (r = –0.003, p = 0.981), whereas Broekhuizen et al., Rossato Silva et al. and Agarwal et al. all reported significant associations [16,19,22]. A plausible explanation is restriction of range: with 88% of our patients at or below a body mass index of 24.9 and a narrow standard deviation, there was insufficient anthropometric variability for a correlation to emerge. Similarly, CRP showed no relationship with six-minute walk distance (r = –0.069, p = 0.632), contrasting with the significant correlations of Broekhuizen et al., Garrod et al., Aksu et al., Agarwal et al. and de Torres et al. [5,16,17,22,26]. Again, the compression of walk distance around a low mean, and the inclusion of patients in acute exacerbation, are likely explanations. The absence of correlation with mMRC grade (r = –0.037, p = 0.797) is almost certainly artefactual, since the entry criterion confined the entire cohort to grades 3 and 4, leaving a variance too small to detect any association. The single component retaining significance was FEV1 (r = –0.444, p = 0.001), consistent with Broekhuizen et al., de Torres et al., Corsonello et al., Dahl et al., Lazovic, Aksu et al. and Agarwal et al. [16,17,18,22,26,28,29], though Ghobadi et al. found no such link [20]. Limitations: The single-centre design, sample of 50, purposive sampling and semi-quantitative latex agglutination assay restrict generalisability. The narrow range of mMRC grade and body mass index materially limits the power to detect component-level associations, and the cross-sectional design precludes causal or prognostic inference.

In this cross-sectional study of 50 patients with predominantly severe COPD, serum C-reactive protein correlated significantly and positively with the composite BODE index (r = 0.303, p = 0.032), but showed no significant correlation with body mass index, mMRC dyspnoea grade or six-minute walk distance considered individually; among the four domains, only post-bronchodilator FEV1 retained an independent inverse association. The cohort was characterised by low body mass index (mean 19.2 ± 4.0 kg/m²), severe breathlessness (mean mMRC 3.26 ± 0.44), markedly reduced exercise capacity (mean six-minute walk distance 266.42 ± 57.48 m) and a high mean BODE score of 6.32 ± 1.23.

These findings indicate that systemic inflammation in COPD is reflected in the aggregate, multidimensional burden of disease rather than in any single anthropometric, symptomatic or functional domain, and they support the use of composite severity indices in preference to isolated variables when relating inflammatory biomarkers to disease severity. Serum CRP, being inexpensive and universally available, may therefore complement the BODE index in stratifying patients in resource-limited settings. Larger multicentre studies enrolling the full spectrum of disease severity, using high-sensitivity CRP assays and longitudinal follow-up, are required to determine whether CRP adds prognostic information beyond that already provided by the BODE index.

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