Comparing triggers and comorbidities of acute exacerbations in COPD: Smokers versus non-smokers

Currently, chronic obstructive pulmonary disease (COPD) is ranked as the third-highest contributor to global mortality, resulting in approximately 3.23 million deaths. The majority of COPD-related deaths among individuals under 70 years old occur in low and middle-income countries (LMICs), accounting for nearly 90% of cases (1). Globally, COPD is a leading cause of morbidity and mortality that induces an economic and social burden, which is projected to increase in the coming decades because of continued exposure to COPD risk factors and the ageing of the population (2, 3).

In patients with COPD, the disease course is punctuated by exacerbations (an acute worsening of symptoms). In COPD, exacerbations are the major cost drivers, either directly or indirectly. COPD patients who have experienced one episode of exacerbation are at increased risk of recurrence. Frequent exacerbations are defined as two or more episodes per year (4). Exacerbations have been associated with an accelerated decline in pulmonary function, a negative impact on the quality of life and a decrease in survival rates (5).

Smoking is known as the most important cause of COPD, amounting to about 85% of COPD cases, of which 50% are smokers and 15% are non-smokers (6). This includes approximately 50% current smokers and 35% former smokers, with 25%–30% of COPD cases occurring in non-smokers due to factors such as biomass fuel exposure and air pollution (6, 7). Approximately 70% of COPD cases are attributable to smoking, while 25%–30% occur in non-smokers due to factors such as biomass fuel exposure, air pollution, occupational hazards and respiratory infections (6, 7). To clarify, smoking (current and former) accounts for approximately 70%–75% of COPD cases globally, with 40%–50% attributed to current smokers and 25%–30% to former smokers; the remaining 25%–30% occur in never-smokers, primarily due to biomass fuel exposure, air pollution, occupational hazards and respiratory infections, particularly in regions like India, where environmental exposures are prevalent (6, 7). Although much of the evidence has concentrated only on smokers, it has been reported that at least one-fourth of patients with COPD are non-smokers (7). Risk factors of COPD in non-smokers may include genetic factors, long-standing asthma, outdoor air pollution (e.g. from traffic and other sources), environmental smoke exposure, biomass smoke, occupational exposure, diet, recurrent respiratory infection in early childhood, tuberculosis (TB) and so on (7).

In the Asian region, indoor/outdoor air pollution and poor socioeconomic status may play important roles in the pathogenesis of non-smoking-related COPD (8, 9).

Few studies have compared acute exacerbation triggers and comorbidities between smokers and non-smokers. This study aimed to compare the variables associated with acute exacerbations of COPD (AECOPD) and to evaluate the role of comorbidities in exacerbation severity among smokers and non-smokers. Therefore, this study was designed to identify these factors and assess their impact, addressing the gap in understanding non-smoking-related COPD triggers.

The present hospital-based prospective comparative study was conducted in the Department of Respiratory Medicine at a tertiary care hospital. Patients were selected from those admitted to the Department between January 2018 and June 2019 with a clinical diagnosis of acute exacerbation of COPD (AECOPD), based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 guidelines (10).

Inclusion criteria comprised:

• adults aged ≥40 years,

• a documented history of chronic respiratory symptoms (dyspnea, cough, sputum production),

• confirmed AECOPD defined by increased dyspnea, sputum volume and/or sputum purulence, with or without systemic symptoms (e.g. fever, fatigue)

Exclusion criteria included patients with:

• asthma-COPD overlap syndrome (ACOS),

• asthma or other chronic lung diseases (e.g. interstitial lung disease, bronchiectasis),

• cardiac failure as primary diagnosis,

• those admitted for other medical/surgical conditions but diagnosed as COPD during their hospital stay

Patients were classified as smokers who had smoked at least 100 cigarettes in their lifetime and non-smokers who had never smoked or had smoked fewer than 100 cigarettes in their lifetime (11, 12).

All included patients were either previously diagnosed with COPD or diagnosed during their hospitalization for acute exacerbation. For patients diagnosed for the first time during an exacerbation, post-exacerbation spirometry was conducted at the time of discharge. Pulmonary function tests (PFTs), including pre- and post-bronchodilator forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio, were performed to confirm the diagnosis and assess severity, adhering to American Thoracic Society (ATS)/European Respiratory Society (ERS) standards.

The study included 70 patients diagnosed with COPD exacerbation, with a male predominance (43 males, 61.4%; 27 females, 38.6%). The highest prevalence was observed in the 61–70 years age group (25 patients, 35.7%), followed by 21 patients (30%) aged 51–60 years. The proportion of patients aged ≤50 years was 14.3%, while 14 patients (20%) were >70 years.

COPD remains a significant global health concern, ranking as the third leading cause of mortality worldwide (1). While smoking has long been recognized as the principal risk factor for COPD, non-smoker COPD is an emerging entity that warrants greater attention. The proportion of non-smoker COPD patients varies significantly across studies, ranging from 9.4% to 68.6% (13). In this study, nearly half (48.6%) of COPD patients were non-smokers, which aligns with findings from Brashier et al. (14), who reported a prevalence of 68.6% among COPD patients. In India, the leading causes of COPD in non-smokers include biomass fuel exposure, as millions rely on wood, cow dung and crop residues for cooking in poorly ventilated homes (8, 9). Air pollution, both outdoor (vehicular emissions, industrial pollutants) and indoor (chulha smoke, incense burning), significantly contributes. Occupational exposure to dust, chemicals and fumes in industries like construction and agriculture also plays a key role. Additionally, respiratory infections (childhood pneumonia, TB) and poor early-life lung development further increase susceptibility to COPD in non-smokers.

The mean age of COPD patients in this study was 62.73 ± 10.7 years, similar to the findings of Crisafulli et al. (15) and Sinha et al (16). The observed male predominance (61.4%) was consistent with previous studies by Baneen and Naseem (17) and Bajpai et al. (18). COPD was traditionally more common in men due to higher smoking rates and occupational exposures. Whereas, in India, the gender gap is narrowing as women face increased risk from biomass fuel exposure, indoor air pollution and secondhand smoke. Studies suggest women may be more susceptible to COPD at lower exposure levels compared with men (17). Women already face a heightened risk of developing COPD due to prolonged exposure to biomass smoke from cooking. This risk is further exacerbated when they are also exposed to passive smoke from their husband’s smoking. However, gender distribution in COPD varies geographically due to differential exposure to risk factors such as biomass fuel, occupational hazards and environmental pollutants. Notably, a study by Sijapati et al. (19) reported a female predominance (66%), highlighting regional variations in COPD epidemiology. Demographic comparisons showed no significant differences in age or gender between smokers and non-smokers, suggesting that differences in AECOPD are driven by triggers and comorbidities rather than demographic factors.

This study found no significant difference in PFT parameters between smokers and non-smokers, which aligns with findings by Zeng et al. (7), who reported that non-smokers with COPD had less impairment in airflow limitation and gas exchange compared with smokers. In contrast, Zhang et al. (20) reported significantly lower FEV1 and FVC values in non-smokers with COPD compared with smokers, suggesting greater lung function impairment in non-smokers. Additionally, Bajpai et al. (18) found significantly higher FEV1 and FVC values in non-smokers, indicating more preserved lung function in this subgroup. Although COPD is characterized by largely irreversible airflow obstruction, smokers often demonstrate lower bronchodilator responsiveness compared to non-smokers. This is attributed to the extent of fixed airway remodelling and alveolar destruction resulting from chronic tobacco exposure. Non-smokers may have persistent impairment, often linked to biomass smoke or pollution, with slower disease progression and occasionally better reversibility in spirometry. Variations in study populations, disease severity and underlying environmental factors may contribute to these discrepancies. To address the study’s aim, smokers exhibited significantly higher mMRC dyspnoea (P = 0.002) and CCQ scores (P = 0.025), indicating greater symptom severity, likely due to tobacco-induced airway inflammation, while non-smokers showed a trend toward more severe exacerbations (Odds ratio: 1.39, P = 0.60) and higher comorbidity burdens, particularly hypertension, diabetes and TB, which may exacerbate AECOPD severity (21).

Although lung function parameters were similar, symptom burden differed significantly between the two groups. Smokers exhibited significantly higher mMRC dyspnoea and Clinical COPD Questionnaire (CCQ) scores, indicating greater symptom severity. These findings align with the study by Zhang et al. (20), which demonstrated a significant correlation between smoking exposure and higher dyspnoea scores. One plausible explanation is that chronic smoking contributes to increased airway inflammation, small airway remodelling and greater dynamic hyperinflation, leading to a higher perception of breathlessness. Additionally, smokers may delay seeking medical attention, attributing chronic cough and dyspnoea to their smoking habits.

Interestingly, the CAT scores did not differ significantly between smokers and non-smokers, suggesting that overall disease impact on quality of life may be similar. This is in line with findings by Pleasants et al. (22), who noted that CAT scores provide a broad assessment of COPD-related impairment and may not capture subtle variations in symptom perception.

The higher comorbidity burden in non-smokers, particularly hypertension, diabetes and previous TB, aligns with Mohapatra and Janmeja (21), who noted increased cardiovascular and infectious comorbidities in non-smoker COPD. These conditions, especially TB (more prevalent in non-smokers), may exacerbate AECOPD severity, as seen in the trend toward more severe exacerbations in non-smokers (Table 5). Regional factors, such as high TB prevalence in India, likely contribute to this pattern, causing lung damage that predisposes to COPD. The lack of statistical significance in comorbidity differences (Table 2) may reflect the small sample size, necessitating larger studies. Smokers’ higher mMRC and CCQ scores suggest greater airway inflammation, consistent with Zhang et al. (20). These findings emphasise the need for comprehensive comorbidity screening in COPD management, particularly for non-smokers, to optimize treatment and reduce exacerbation risk.

GOLD staging analysis revealed a higher prevalence of severe COPD exacerbation in non-smokers, though this difference was not statistically significant. These findings emphasize the need for further research on non-smoking-related COPD, particularly in populations with significant exposure to biomass smoke, indoor air pollution and occupational hazards. Recent evidence suggests that individuals with a history of childhood respiratory infections, long-standing asthma or recurrent exacerbations are at higher risk of developing severe COPD, regardless of smoking history (23).

The evolving recognition of non-smoker COPD necessitates a shift in diagnostic and management approaches. Non-smoking-related COPD is increasingly associated with unique phenotypic characteristics, including greater small airway involvement, heightened airway inflammation, and increased susceptibility to respiratory infections (24). Furthermore, recent studies have underscored the role of environmental pollutants, genetic predisposition and metabolic disorders in the pathogenesis of non-smoker COPD (25).

Future research should focus on identifying distinct biomarkers and therapeutic targets for this subgroup. The integration of precision medicine approaches, including transcriptomic and proteomic profiling, may aid in differentiating smoker and non-smoker COPD phenotypes (26). Additionally, large-scale multi-centre studies are warranted to validate these findings and develop targeted interventions for non-smoker COPD patients.

This study has certain limitations. It was a single-centre study with a relatively small sample size, which may affect the generalizability of the findings. Additionally, the assessment of risk factors relied on patient-reported history, which may introduce recall bias. Future studies with larger, more diverse cohorts and objective exposure assessments are needed to strengthen these conclusions.

This study highlights the significant burden of acute exacerbations in COPD (AECOPD) among both smokers and non-smokers, emphasizing the influence of co-morbidities and environmental factors in disease progression. Despite similar pulmonary function parameters, smokers exhibited a higher symptomatic burden, as reflected in significantly higher mMRC dyspnoea and CCQ scores. In contrast, non-smokers had a greater prevalence of severe COPD exacerbations and comorbidities, reinforcing the multifactorial nature of COPD beyond smoking. Smokers’ greater symptom severity and non-smokers’ higher comorbidity burden, particularly hypertension, diabetes and TB, underscore the need for tailored management targeting these factors.

The findings underscore the importance of recognizing non-smoking-related risk factors, such as biomass fuel exposure, recurrent respiratory infections and poor socioeconomic conditions, which can contribute significantly to COPD pathogenesis. The higher comorbidity burden in non-smokers also suggests that comprehensive patient evaluation is crucial for effective COPD management. Given that COPD exacerbations are major drivers of morbidity, mortality and healthcare costs, tailored preventive strategies, early interventions and personalized treatment approaches are essential to reduce the disease burden.

Future research should focus on identifying distinct COPD phenotypes, incorporating biomarkers and employing precision medicine approaches to differentiate and optimize treatment strategies for smoker and non-smoker COPD patients. Addressing alternative risk factors and ensuring early diagnosis in non-smokers will improve overall COPD outcomes and quality of life for affected individuals.