Chronic obstructive pulmonary disease (COPD) is a prevalent and progressive respiratory disease that is characterized by persistent airflow limitation and inflammation of the lungs [1]. Worldwide, it is one of the leading causes of death, contributing significant burdens to healthcare systems [2]. One of the most concerning events of COPD is acute exacerbation COPD (AECOPD), which is defined by sudden deterioration of respiratory symptoms that require additional therapy [3]. Exacerbations are associated with increased mortality, accelerated lung function decline, and a greater likelihood of future exacerbations [4]. Moreover, exacerbations place a significant burden on healthcare systems, due to frequent hospitalization and the increased use of medical resources [2,5,6].

Multiple factors influence the susceptibility to AECOPD. The most robust predictor of future events is a history of previous exacerbation, while other clinical and environmental contributors, such as poor lung function, comorbidities, and ambient air pollution, also play a substantial role [7-10]. Recent findings suggest that sarcopenia may increase the exacerbation risk in COPD, as muscle wasting and diminished physical performance undermine both functional capacity and immune defense [11-13]. Furthermore, respiratory infections, whether viral or bacterial, frequently trigger acute exacerbations, indicating the importance of effective infection control measures [3,11,14].

Efforts to prevent AECOPD have been extensive, with significant progress being made in pharmacologic treatments over the past few decades. The use of long-acting bronchodilators that include long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) has significantly lowered exacerbation risk, and improved lung function and symptom control [15-17]. In patients with high exacerbation risk, especially those with elevated blood eosinophil counts, treatments such as combination inhaled corticosteroid (ICS) and LABA regimens, or triple therapy (ICS+LABA+ LAMA), are recommended to reduce future exacerbations and reduce mortality [18-21]. Long-term macrolides have also demonstrated efficacy in preventing exacerbations among frequent exacerbators [22], while phosphodiesterase-4 (PDE4) inhibitors and biologic agents have shown promise in certain patient subsets [23,24]. Although pharmacologic treatments for COPD have made significant advances, non-pharmacologic interventions have historically received less attention. The importance of smoking cessation, being both the primary cause of COPD and a major contributor to AECOPD, has long been emphasized in COPD management [25]. In the early 2000s, lung volume reduction surgery (LVRS) was shown to reduce mortality and the risk of exacerbations, though its application has been limited to a selected group of patients [26,27]. More recently, bronchoscopic interventions have emerged that provide favorable outcomes, such as improved health-related quality of life, lung function, and reduced risk of exacerbations [28-31]. Pulmonary rehabilitation (PR) has consistently demonstrated its effectiveness, with recent research focusing on the optimal timing to initiate such programs [32-34]. Vitamin D supplementation in COPD management has shown promising outcomes in reducing exacerbation risk, although some conflicting results suggest that further research is needed [35-38]. Furthermore, the coronavirus disease 2019 (COVID-19) pandemic has shown insight into the efficacy of shielding measures to reduce exacerbations [14,39-43]. Other non-pharmacologic interventions that include vaccination, diet and nutrition, and non-invasive ventilation (NIV) may be important in reducing AECOPD. This narrative review aims to provide recent evidence that is focused on the non-pharmacologic interventions that prevent AECOPD (Figure 1).

PR is defined as a comprehensive intervention that includes exercise training, education, and behavioral changes, and is designed to improve the physical and psychological condition of individuals with chronic respiratory diseases [1,44]. The effectiveness of PR in COPD has been well-established over the years, consistently demonstrating improvements in exercise capacity, symptom control, and quality of life [33,45-47]. Recently, the 2023 American Thoracic Society guidelines have recommended PR for patients with a wide range of chronic lung diseases, particularly those with persistent symptoms, or following an exacerbation [34]. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2024 reports emphasize the importance of PR, stating that it is essential for patients in GOLD groups B and E [1].

In a recent study using data from the Korean Health Insurance Review and Assessment Service (HIRA), the research group demonstrated that PR significantly reduces the risk of acute exacerbations, while lowering mortality in COPD patients [48]. Moreover, with the recent inclusion of PR in insurance coverage, the prescription rates have increased, leading to a reduction in healthcare costs among patients who receive PR. These findings further emphasize the importance of public health policies in ensuring access to PR for eligible patients.

While the benefits of PR are well-recognized, several research questions remain unanswered; these include the effectiveness of PR in early-stage COPD, interventions to improve healthcare provider referrals to PR, the optimal timing for initiating PR after an exacerbation, and ways to increase PR uptake following an acute exacerbation [34].

Recent studies have specifically focused on the impact of PR initiated after exacerbation. A Cochrane review in 2016 reported that PR started after AECOPD reduced the risk of hospital readmission; however, at that time, the analysis of recent studies showed no statistically significant results [33]. Jenkins et al. [49] updated that review, conducting a meta-analysis of studies published between October 2015 and August 2023, focusing on PR initiated within 3 weeks of hospital discharge, while excluding studies that solely implemented inpatient PR. This updated analysis showed that PR initiated within 3 weeks of discharge significantly reduced hospital readmissions, and improved exercise capacity and quality of life.

Further, recent studies have evaluated the effectiveness of PR during hospitalization. Moecke et al. [50] conducted a meta-analysis of randomized controlled trials (RCTs) published up to August 2022, comparing in-hospital PR with usual care. The study assessed both the safety and efficacy of PR, and found that compared to usual care, inpatient PR did not increase the length of hospital stay. Moreover, patients who received PR showed improvements in exercise capacity and quality of life. Similar meta-analysis by Meneses-Echavez et al. [32], which included RCTs published between 2020 and 2022, also compared inpatient PR with usual care. This study confirmed that compared to the usual care group, the PR group showed a lower risk of re-exacerbation. Additionally, both short-term (4 to 12 weeks) and long-term (12 to 96 weeks) analyses showed that PR reduced the risk of AECOPD-related hospitalizations, and provided sustained improvements in dyspnea.

Despite the well-established benefits of PR, the low uptake of PR in the clinical field remains a critical barrier. A large-scale analysis of medicare beneficiaries in the United States showed that only 1.9 % of patients hospitalized for a COPD exacerbation received PR within 6 months of discharge, even after coverage was established [51]. Several factors were identified that negatively impacted PR use, including advanced age (≥75 years), lower socioeconomic status, and living more than 10 miles distance from a PR facility. An analysis of National Health Insurance reimbursement data in South Korea revealed similarly low utilization, with only 1.43 % of COPD patients receiving PR [48]. Although this represents a gradual increase from (0.03 to 1.4) % over 4 years following insurance coverage, the overall rates remain of concern. These barriers show the urgent need for strategies to improve access to, and adherence to, PR in the clinical setting. Home-based PR or tele-rehabilitation programs have emerged as a promising approach, potentially overcoming geographic and mobility restrictions, while maintaining center-based PR in carefully selected patient populations [52-54].

In the early 2000s, research on LVRS revealed clear benefits for patients with severe emphysema, not just in terms of survival, but also in improving lung function, exercise capacity, and the overall quality of life [26,55,56]. One of the landmark studies, the National Emphysema Treatment Trial (NETT), found that patients who received LVRS showed improvement in forced expiratory volume in 1 second (FEV₁), an increase in exercise tolerance, and enhanced quality of life [26]. Importantly, the trial also showed that patients with upper-lobe predominant emphysema and low exercise capacity experienced the most pronounced survival benefits.

Washko et al. [27] conducted an early study in 2008 on the impact of LVRS on AECOPD. This study focused on patients with FEV₁ <45% predicted and bilateral emphysema evident on computed tomography (CT) scans. Comparison of patients receiving medical treatment to those undergoing LVRS showed that exacerbation-free survival was significantly better in the surgery group, with a 30% reduction in the frequency of exacerbations. Notably, surgical responders, defined as those with an improvement in FEV₁ >200 mL within 6 months, demonstrated superior exacerbation-free survival, compared to non-responders.

Despite the positive outcomes, LVRS posed substantial risks, particularly for patients with severe COPD, where surgical operability was often a challenge. The need for careful patient selection limited the broader application of the procedure. However, several bronchoscopic lung volume reduction techniques that have been developed in recent years offer a less invasive alternative to surgery [30,31,57,58]. These interventions have been presented as important treatment options for advanced COPD in the GOLD 2024 reports [1]. Among these, the endobronchial valve (EBV) has emerged as the most widely adopted and well-validated procedure. The Zephyr® EBV (Pulmonx Inc., Redwood City, CA, USA) is the most widely used EBV, which received U.S. Food and Drug Administration (FDA) approval in 2018 for the treatment of severe emphysema [59]. In the European Endobronchial Valve for Emphysema Palliation Trial (VENT) study cohort, unilateral Zephyr valve placement led to significant improvements in FEV₁, exercise capacity, and quality of life, compared with medical management alone, with benefits persisting up to 12 months [58]. Patients who achieved complete fissure and lobar occlusion on CT demonstrated the greatest lobar volume reduction and clinical gains. Although the overall safety profile was acceptable, clinicians should be aware of potential complications, particularly pneumothorax, which can occur in up to 4.5% of cases within the first 3 months after the procedure. Further studies have shown that EBV has corresponding benefits in improving exercise capacity, enhancing the quality of life, and improving lung function, leading to a GOLD recommendation of Evidence A [1,30,31,57].

Brock et al. [28], in a single-center retrospective analysis, recently explored the role of EBV in preventing AECOPD. The study included patients with severe emphysema who underwent EBV implantation, and compared the frequency of exacerbations 1 year before, and after, the procedure. The results showed an improvement in FEV₁, and a reduction in residual volume after the procedure. Moreover, the number of exacerbations decreased from 2.5 to 1.8 per year (p=0.009). A subgroup analysis of patients who achieved complete lobar atelectasis revealed an even more significant reduction in exacerbations, from 2.8 to 1.4 per year (p<0.001).

Tobacco smoking remains the most significant risk factor and cause of COPD [60], leading to the destruction of alveolar structures, causing emphysema, and inducing airway remodeling, which contributes to small airway disease [61,62]. The well-known Fletcher-Peto curve clearly shows the relationship between smoking and lung function decline, indicating that smoking accelerates the rate of lung function deterioration; however, once smoking is stopped, the rate of decline returns to the normal baseline progression [63]. Tobacco smoke contains numerous hazardous materials, causing airway inflammation, and subsequently increases the risk of AECOPD [25,64].

In 2009, Au et al. [25], using data from the large U.S. cohort Ambulatory Care Quality Improvement Project (ACQUIP), analyzed the effect of smoking cessation on COPD exacerbations in a multicenter randomized trial of a quality improvement intervention. The study included 23,971 patients, and found that those who quit smoking experienced a 22% reduction in the risk of acute exacerbations, compared to those who continued smoking. Moreover, the longer the period of smoking cessation, the greater the reduction in the risk of exacerbations. This trend was observed both in patients with a prior diagnosis of COPD, and in those who had not yet been diagnosed.

In recent years, the use of electronic cigarettes (ECs) has increased dramatically [65]. As a result, there has been growing interest in the potential benefits and risks associated with ECs. While some studies have shown that ECs can activate inflammatory pathways similar to conventional cigarettes, others indicate that ECs may trigger different inflammatory markers, suggesting a combination of overlapping and distinct pathways [66]. Bowler et al. [67] analyzed data from two large U.S. COPD cohorts, Genetic Epidemiology of COPD (COPDGene) and SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS), to examine the risks and benefits associated with EC use, and found that over a 10-year period, the use of ECs increased significantly. However, EC users were found to have continued tobacco consumption, with higher overall nicotine use. This was associated with a greater percentage of lung function decline, indicating that in real-world settings, EC use did not aid COPD patients successfully quit smoking, or improve health outcomes. Thus, EC use was unlikely to reduce the risk of AECOPD or other clinical indicators in COPD patients.

On the other hand, Polosa et al. [68-70] conducted a series of studies examining the outcomes of patients who switched from conventional cigarettes to ECs. The most recent study, a 5-year prospective follow-up, reported that most EC users successfully quit smoking [70]. In this group, the number of exacerbations dropped from 2.3 to 1.1 per year (p<0.001), while over the same period, the cigarette-smoking group showed no significant change. Additionally, EC users showed statistically significant improvements in both FEV₁ and exacerbation risk, compared to cigarette smokers (p=0.004 and p=0.046, respectively). The annual rate of COPD exacerbations was also lower in the EC group, and these benefits persisted over the 5 years. Furthermore, while in the cigarette-smoking control group, FEV₁ continued to decline, EC users demonstrated a steady increase in lung function over the same period.

Although ECs contain various hazardous materials and should not be widely recommended, selective and cautious switching to ECs may be a viable option for patients who find it difficult to quit smoking. However, this approach requires careful consideration, and due to several safety concerns, should be tailored to individual patient needs. First, severe forms of lung damage known as e-cigarette or vaping-associated lung injury (EVALI) have been reported, with rehospitalization or death occurring in susceptible patients, particularly those with chronic respiratory or cardiac comorbidities [71]. EC use has also been associated with the detection of potentially harmful substances such as acetaldehyde, acrolein, and formaldehyde, which may pose additional health risks [66,72]. Furthermore, nicotine content in ECs can often exceed that of conventional cigarettes, and potentially lead to stronger nicotine dependence [73]. In consequence, most public health authorities do not currently endorse ECs as a proven smoking cessation tool. In 2019, the American Medical Association called for a ban on the sale and distribution of all EC and vaping products that were not approved by the FDA for tobacco cessation purposes [74]. To date, the FDA has not authorized EC products as cessation aids [75].

Given the predominantly negative implications of EC use, including acute lung injuries like EVALI, unconfirmed long-term safety, and the risk of high nicotine dependence, clinicians should remain cautious when discussing the switching to e-cigarettes with COPD patients. Instead, emphasis should be placed on established smoking cessation strategies, including behavior therapy, pharmacological aids, and structured follow- up, to maximize success in quitting, and minimize potential harm.

Vitamin D is a fat-soluble vitamin that plays a critical role in maintaining bone health and calcium-phosphate homeostasis [76]. It is synthesized in the skin in response to sunlight exposure, and can also be obtained through diet and supplements. Beyond its role in bone health, vitamin D has been recognized for its influence on the immune system, particularly in modulating both innate and adaptive immune responses [77]. Low levels of vitamin D are shown to be associated with increased susceptibility to infections, inflammation, and various chronic diseases, including respiratory conditions like COPD [78-80]. Vitamin D levels are regulated by vitamin D-binding protein (VDBP); when VDBP levels are elevated, vitamin D bioavailability decreases, weakening the immune response, and increasing susceptibility to infections, which may contribute to a higher risk of exacerbations [36,77].

In 2012, Lehouck et al. [37] conducted one of the early studies to examine the role of vitamin D supplementation in COPD patients. This single-center, double-blind, RCT included 182 patients with moderate-to-severe COPD and a history of recent exacerbations. The study investigated the effects of high-dose vitamin D supplementation (100,000 IU every 4 weeks for 1 year), compared to placebo. The results showed no significant differences between the vitamin D and placebo groups in terms of exacerbation or death from any cause. However, a subgroup analysis of patients with severe vitamin D deficiency (serum 25(OH)D levels below 10 ng/mL) revealed a significant reduction in the risk of exacerbations (relative risk, 0.57; 95% confidence interval [CI], 0.33 to 0.98; p=0.042) in the vitamin D group.

Subsequently, Jolliffe et al. [35] conducted a meta-analysis to investigate the relationship between vitamin D and AECOPD. The findings were consistent with the previous study, showing no significant benefit of vitamin D supplementation in the general COPD population; however, among patients with severe vitamin D deficiency (serum 25(OH)D levels below 25 nmol/L), vitamin D supplementation significantly reduced the incidence of exacerbations (adjusted incidence rate ratio, 0.55; 95% CI, 0.36 to 0.84; p=0.006).

Conversely, a recent multicenter RCT by Rafiq et al. [38] showed contradictory results. This trial included COPD patients with at least one exacerbation in the previous year and vitamin D deficiency of 15 to 50 nmol/L. The patients were randomly assigned to receive either 16,800 IU of vitamin D3 or placebo, weekly for 1 year. The primary outcome, annual exacerbation rate, showed no significant reduction in either the overall population, or in patients with severe deficiency (25 nmol/L or below). Additionally, no improvements were observed in exercise capacity, lung function, or inflammatory markers. These results suggest that the role of vitamin D in reducing AECOPD remains controversial, and further research is required to clarify its effectiveness.

The prevalence of vitamin D deficiency is considerably high in Korea, with the Korea National Health and Nutrition Examination Survey IV 2008 indicating that approximately 47.3% of males and 64.5% of females had serum 25(OH)D levels below 50 nmol/L [81]. This deficiency was particularly pronounced among younger adults—a finding attributed to an indoor-oriented lifestyle—resulting in a lower mean 25-(OH)D level in the Korean population, compared with Western countries. In the context of COPD, a Korean study involving 236 patients found that individuals with concurrently low vitamin D (<20 ng/mL) and elevated plasma fibrinogen (≥350 mg/dL) exhibited worse lung function, higher severity indices, and increased frequency of severe exacerbations [82]. Although a direct correlation between 25(OH)D levels and inflammatory markers was not established, the study showed the potential interaction between vitamin D deficiency and COPD severity, suggesting that vitamin D deficiency, combined with elevated inflammatory markers, could identify a subgroup of patients at particularly high risk of exacerbations.

The COVID-19 pandemic provided an unexpected opportunity to observe the impact of shielding measures on preventing AECOPD [83,84]. During the pandemic, clinical practice revealed a noticeable reduction in AECOPD, a trend supported by several large-scale studies [14,40-43,83]. For example, a nationwide study in France compared hospital admissions for AECOPD between the pre-COVID period 2016−2019 and the pandemic years 2020−2021 [41]. The study found a significant decrease in hospital admissions for AECOPD during the pandemic. However, it also noted an increase in in-hospital mortality rates for AECOPD, indicating that while the overall number of admissions decreased, the severity of cases, particularly those complicated by COVID-19, had worsened.

This pattern was not unique to France. Numerous studies conducted globally during the pandemic reported similar findings, with a significant reduction in AECOPD cases. The most likely explanation for this decrease is the widespread use of shielding measures [84-86]. Patients adhered more strictly to protective behavior, such as regular handwashing, social distancing, and the use of face masks, all of which may have contributed to reduced exposure to respiratory infections that typically trigger exacerbations.

A study by Trujillo et al. [43], using data from the Veteran Cohort, further highlighted the importance of these protective measures. During the COVID-19 pandemic, there was a marked 45 % reduction in the number of individuals with COPD who experienced an exacerbation. In patients whose exacerbations decreased to fewer than two, high adherence to protective measures, such as handwashing, avoiding poorly ventilated areas, staying shielded at home, consistently wearing masks, and practicing social distancing, was observed. These findings indicate the effectiveness of shielding measures in reducing the risk of exacerbations, and highlight their potential role in managing COPD, even outside the context of a global pandemic.

On the other hand, the shielding measures may have potential downsides. Decreased physical activity, social isolation, and psychological stress have been reported, presenting the importance of balancing infection control with the patient’s overall well-being [84]. Such negative impacts on mental and physical health can potentially contribute to disease progression and reduced quality of life, particularly if shielding is prolonged, or overly restrictive. Moreover, certain exacerbations, especially those driven by specific endotypes (e.g., eosinophilic endotypes in COPD), may not be effectively managed solely through shielding [87]. During the pandemic, a marked reduction in exacerbations was observed predominantly in non-eosinophilic subsets, whereas patients with eosinophilic COPD appeared to experience a comparable rate of exacerbations, despite infection control measures. This finding shows the heterogeneity in COPD pathophysiology, and the need for a more comprehensive approach that includes individualized treatment, targeted anti-inflammatory therapy, and potentially different infection-prevention strategies according to specific disease endotypes.

Vaccination is known to be one of the most important non-pharmacological COPD managements, given that AECOPD is frequently triggered by viral and bacterial infections [88,89]. Influenza vaccination has been shown to reduce hospitalization and mortality rates related to respiratory infections, especially in high-risk groups such as the elderly, those with cardiac comorbidity, residence in long-term care, or home oxygen user [90]. Likewise, pneumococcal vaccination has demonstrated efficacy in preventing community-acquired pneumonia and AECOPD in patients with COPD [91]. Moreover, since the emergence of COVID-19, health organizations have recommended vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in COPD populations to alleviate severe disease outcomes [1,92]. A meta-analysis suggested that COVID-19 vaccination decreased the AECOPD leading to hospital admission by 50 %, due to reduction in respiratory virus infection in the COVID-19 pandemic period. Consequently, the GOLD 2024 reports recommend routine immunization with influenza, pneumococcal, and COVID-19 vaccines as part of a comprehensive COPD care plan [1].

Recent evidence has shown the significant impact of nutrition and muscle mass on the risk of AECOPD. Sarcopenia, characterized by low skeletal muscle mass and strength, is increasingly recognized as a major comorbidity that accelerates disease progression and increases the risk of AECOPD [8,10]. Longitudinal data show that individuals experiencing a steeper decline in muscle mass also face a more rapid decline in lung function, and an increased likelihood of exacerbations [10]. Similarly, malnourished COPD patients, or those with sarcopenia during an AECOPD, are at higher risk of poor clinical outcomes, including readmissions and mortality [7,9,93]. These findings present the importance of systematic screening for muscle depletion, and addressing nutritional deficits early in the disease course.

Studies have shown that appropriate nutritional supplementation may help preserve muscle mass, stabilize pulmonary mechanics, and potentially reduce AECOPD in malnourished or cachectic COPD patients [93,94]. When combined with PR, these dietary approaches can further enhance exercise capacity, improve quality of life, and potentially mitigate the burden of AECOPD. Early detection of muscle loss and tailored nutritional intervention are therefore essential steps to minimize the burden of AECOPD and enhance long-term clinical outcomes.

Previous studies have shown that long-term NIV may help reduce recurrent AECOPD in selected patients with persistent hypercapnia. In a prospective trial, continuing home NIV after hospitalization lowered the incidence of recurrent hypercapnic respiratory failure compared to low-pressure continuous positive airway pressure, indicating a benefit in preventing severe exacerbations [95]. Moreover, a large multicenter RCT confirmed that long-term NIV, specifically targeting a substantial reduction in arterial carbon dioxide pressure (PaCO₂), markedly improved 1-year survival rates among patients with advanced, stable hypercapnic COPD [96]. Further, economic analyses have demonstrated that domiciliary NIV can lead to substantial cost savings by decreasing hospital admissions, intensive care unit stays, and overall healthcare expenditures [97]. Reflecting these findings, the European Respiratory Society has recommended long-term NIV in hypercapnic COPD to reduce hospital admissions and improve outcomes [98].

Various pharmacologic and non-pharmacologic measures have been studied and proven effective in preventing AECOPD. While pharmacologic treatments have seen remarkable advances, non-pharmacologic interventions have shown more modest results. This review has summarized recent evidence regarding non-pharmacologic strategies to prevent exacerbations. PR plays a critical role in reducing the risk of exacerbations and mortality, and has demonstrated socioeconomic benefits through the reduction of healthcare costs. Recent studies have confirmed the safety and efficacy of early post-exacerbation PR and inpatient PR, suggesting that PR should be implemented more aggressively in patients following an acute exacerbation. LVRS has been well-established as effective in reducing mortality and exacerbations in COPD, while bronchoscopic lung volume reduction methods, such as EBV placement, have also shown potential in lowering exacerbation risk. Smoking cessation remains essential to prevent exacerbations. Although large observational studies suggest that EC use does not aid smoking cessation or improve clinical outcomes, a prospective study has shown that switching from cigarettes to ECs can reduce exacerbations. However, due to the potential harmful effects of ECs, their use should be considered selectively for patients who are unable to quit smoking through other means. Vitamin D supplementation has demonstrated benefits in reducing exacerbations in patients with severe deficiency, as noted in several studies, and recommended by GOLD guidelines. However, recent contradictory findings indicate that further research is necessary to clarify its role. The COVID-19 pandemic has reinforced the importance of shielding measures, such as mask-wearing and social distancing, in preventing exacerbations. Educating patients on these protective behavioral changes may continue to yield significant benefits in COPD management. Finally, vaccination, diet and nutrition, and implementation of NIV may also play important roles in the reduction of AECOPD.