Discussion
Given the growing importance of early detection of clinical deterioration, our study identified the risk factors for acute exacerbation and disease progression in young patients with COPD. Compared with other cohorts for young COPD patients, our patients were predominantly male, had a lower BMI, fewer current smokers, less emphysema and a higher blood eosinophil count.4 5 During the 5 years of observation, 41.5% of the patients experienced moderate-to-severe exacerbation, and 80.7% initiated regular inhalation therapy. The annual FEV1 decline rate was a median of −18 mL/year, and rapid FEV1 decline (<−60 mL/year) was found in 33% of young patients with COPD, which was numerically higher than those (−4 mL/year of annual FEV1 decline rate and 25% of rapid FEV1 decline) of the COPD patients with age ≥40 years.17 Young COPD patients with a history of asthma or pulmonary tuberculosis, current respiratory symptoms such as sputum, high blood eosinophil counts, or structural or functional pulmonary impairment need to be distinguished as a high-risk group for worsening the clinical course of COPD. Our findings emphasise the importance of recognising and addressing high-risk features in young COPD patients, especially a syndemic occurrence of respiratory comorbidities, as it can be beneficial in preventing acute exacerbation and disease progression.18
The severity and activity of the disease in young patients with COPD are similar to those in older patients with COPD.13 19 Although there are no clinical trials specifically targeting young patients with COPD, a recent study was conducted on pre-COPD patients—symptomatic smokers without spirometric airflow limitation.20 However, the study could not find the benefit of indacaterol/glycopyrronium in improving symptoms .Therefore, it is still necessary to identify whether young patients with COPD or pre-COPD patients can potentially benefit from early intervention. Further studies including young patients will be needed to investigate whether early clinical management in specific subgroup populations can prevent disease progression of COPD.
The FEV1 decline rate has been considered a conventional indicator of disease progression.21 However, as FEV1 decline is usually not invariably progressive, multidimensional approaches are needed.22 Exacerbation can be regarded as an important marker of clinically important deterioration in patients with COPD. Acute exacerbations become more frequent with progression of COPD.23 Conversely, frequent exacerbations affect COPD severity.24
Initiation of COPD treatment can be an indirect indicator of disease progression. Early initiation of regular inhaled therapy may have benefits in slowing disease progression, although this association is often influenced by confounding by indication.25 26 Among smokers with normal lung function, 12.6% were prescribed regular inhaled treatment, and factors associated with this empiric treatment were respiratory symptoms, presence of emphysema on imaging studies, history of asthma and prior exacerbations.26 COPD patients with mild symptoms and no history of acute exacerbation had an option of using short-acting bronchodilators instead of long-acting bronchodilators.2 In patients who only use short-acting bronchodilators, maintain mild symptoms and do not experience exacerbations, the initiation of regular inhalation treatment might be delayed. In the clinical context, a shortened duration from diagnosis to initiation of treatment for COPD suggests a more rapid progression to clinical COPD.5
Considering our patients’ high blood eosinophil count and history of asthma, misdiagnosing actual asthma as COPD is a concern. In a meta-analysis, a high baseline blood eosinophil count and a history of asthma were more found in young patients with COPD than in general COPD patients.27 In the GOLD 2023 report, a history of childhood asthma was proposed as an important etiotype of COPD and classified as COPD-A, suggesting distinct subtypes of COPD.2 Because 33 (9.6%) patients showed bronchodilator positivity or between-visit variability in FEV1, it is plausible that some of our patients had asthmatic features. However, 333 (97.4%) maintained fully reversible airflow limitation (post-BDR FEV1/FVC <0.7) in follow-up spirometric examination without symptom variability and lung function variability. Therefore, it is more likely that some COPD patients had asthmatic features rather than a majority of the included patients were pure asthmatics.
Current evidence suggests that Th2 or eosinophilic inflammation is related to the severity or activity of COPD. Blood eosinophil count, a Th2 inflammatory biomarker in COPD, was higher in COPD patients with an advanced disease stage or at an increased risk of exacerbation.28 In our study, a high blood eosinophil count was an independent risk factor for moderate-to-severe exacerbation or earlier initiation of regular inhaled therapy in young patients with COPD. This finding suggests that Th2 inflammation may play a pathological role in the progression of COPD in young patients. In contrast, cigarette smoking, which usually exacerbates neutrophilic airway inflammation, was not a significant risk factor for acute exacerbation or disease progression in our study. This finding is concurrent with that of a recent study that reported no association between cigarette smoking and acute exacerbation in young patients with COPD.29
The FVC and DLCO can be adjunctive biomarkers for COPD progression in young patients. FVC decline is associated with a higher risk of acute exacerbation in patients with COPD.30 In particular, FVC was more declined in early stage of COPD.31 In a prospective cohort study, patients with preserved ratio impaired spirometry usually showed a lower FVC and higher mortality than those with COPD GOLD 1.32 Our study showed that FVC was impaired in more than half of the young patients with COPD. Moreover, young patients with COPD with a lower FVC (%) had more moderate-to-severe exacerbations or accelerated FEV1 decline. In addition, it is well known that impaired DLCO is related to the advanced stages of COPD.33 Impaired DLCO has been reported as an independent risk factor for future exacerbation.34 In our study, DLCO had been impaired in 41.4% of young patients with COPD. We found that DLCO was related to earlier initiation of COPD treatment or an accelerated lung function decline rate. DLCO seems an important physiological biomarker of parenchymal, alveolar, and capillary damage in patients with COPD.
A history of tuberculosis is associated with the development of COPD.35 In the GOLD 2023 report, tuberculosis-associated COPD was proposed as an important etiotype of COPD, which is classified as COPD-I, suggesting distinct subtypes of COPD.2 Post-tuberculosis lung damage is related to accelerated lung function decline and the development of airflow limitation.36 37 In our study, a history of tuberculosis was related to an accelerated FEV1 decline rate. Recent studies have reported the benefits of bronchodilators in patients with bronchiectasis and airflow limitation and have proposed a role for inhaled corticosteroids based on blood eosinophil counts.38 39 Further studies are needed to determine the optimal treatment for patients with tuberculosis-associated COPD.
Our study has several limitations. First, this study was performed retrospectively with a small number of young patients with COPD in two teaching hospitals. Because of the nature of study design and data constraints, analysing important indicators such as the BODE Index was not possible. In our medical centres, 6 min walk test was not routinely performed for COPD patients. The information regarding symptoms was obtained based on records from outpatient clinics, which makes the specific details limited, potentially leading to an underestimation of prevalence. Further prospective studies can provide better evidence on the natural course of COPD in young patients. Second, as the data were obtained from teaching hospitals, there is a risk of selection bias in that symptomatic patients were more likely to be included. Therefore, the findings of our study might not be representative to all young COPD population. Third, the majority of identified risk factors related to COPD progression were not treatable traits. Based on previous studies, sputum production, impaired lung function and high blood eosinophil count may be potential treatable traits favouring inhaled corticosteroid use in young patients with COPD.40–42 As for patients at high risk, particularly those with non-treatable factors, they necessitate intensive surveillance and close follow-up for early identification of exacerbations and disease progression. Future clinical trials are imperative to determine the efficacy of therapeutic interventions in preventing exacerbations and disease progression in young COPD patients. Fourth, it may be arbitrary that the early initiation of regular inhalation therapy was within 3 years of COPD diagnosis. The definition of early regular inhalation therapy needs to be optimised through long-term observation of the natural course in asymptomatic COPD patients.
In conclusion, young COPD patients with a history of asthma or pulmonary tuberculosis, current respiratory symptoms, high blood eosinophil count, or structural or functional pulmonary impairment are indicative of potential high-risk factors for the clinical deterioration of COPD such as acute exacerbation, requirement of early regular inhalation treatment and accelerated lung function decline.