Identification and treatment of GOLD stages I and II chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is the most prevalent chronic respiratory disease globally, posing a major challenge to global public health. In 2021, the age-standardized spirometry-defined prevalence of COPD was estimated to be 2,512.86 (95% uncertainty interval 2,293.93 to 2,748.52) per 100,000 globally (1). In China, the epidemiological data have underscored the substantial healthcare burden. A nationwide survey revealed a prevalence of 8.6% among individuals aged 40 years or greater (2). By 2018, an updated epidemiological study indicated that this figure had surged to 13.6% (Table S1) (3). This alarming trajectory highlights that the prevention and control of COPD is a growing challenge requiring urgent attention.

However, healthcare providers are confronted with a disparity between the high prevalence of disease and low rates of early diagnosis. More than 90% of patients with COPD have mild to moderate airflow obstruction [Global Initiative for Obstructive Lung Disease (GOLD) stage I and II] (3). Due to its insidious nature, COPD is frequently under recognized until patients develop significant lung function impairment. Hence, it is the time for the global medical community to move beyond the conventional symptom-based diagnosis to more proactive screening to prevent disease progression.

In accordance with the joint statement from GOLD/Global Lung Initiatives that forced expiratory volume in one second (FEV₁) is no longer regarded as a marker of the severity of COPD (4), the reliance on symptoms (e.g., dyspnea, sputum production) may result in the underdiagnosis of mildly or intermittently symptomatic patients whose lung function is rapidly deteriorating (5,6). The multidimensional diagnostic schema for COPD which integrates respiratory symptoms, quality of life, spirometry, and structural lung abnormalities has been recently proposed (7,8) (Table 1). There might also be nuanced differences in the underlying pathophysiology between asymptomatic individuals with mild airflow obstruction (early COPD without clinical manifestations) and patients with GOLD stage I and II COPD diagnosed based on symptoms or exacerbations (multidimensional abnormalities except airflow obstruction), making further phenotyping necessary for prognostication.

Table 1. Multidimensional diagnostic criteria for COPD.

Major criterion
Post-bronchodilator FEV1/FVC <0.70
Minor criteria
Emphysema
Bronchial wall thickening
Dyspnea
Poor quality of life
Chronic bronchitis

The multidimensional diagnostic schema includes the major diagnostic category (the major criterion plus at least 1 of 5 minor criteria) and the minor diagnostic category (least 3 of 5 minor criteria) (8). Please note that this proposed multidimensional diagnostic schema serves as an academic framework awaiting further validation, rather than a formal clinical diagnostic standard intended to supersede official GOLD criteria. COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in one second; FVC, forced vital capacity; GOLD, Global Initiative for Obstructive Lung Disease.

Notably, a patient with asymptomatic airflow obstruction does not conform to the diagnosis of COPD according to GOLD; however, many “asymptomatic” individuals may limit their activities to avoid breathlessness. Hence, it is the time for medical community to move beyond conventional symptom-based definitions and acknowledge that pathological progression of COPD may begin long before clinical symptoms manifest (7,9). More attention should be paid to developing candidate treatments for patients diagnosed with multidimensional criteria (e.g. emphysema on computed tomography, chronic bronchitis) since the diagnostic schema of COPD is rapidly moving forward.

Early screening and treatment

Due to subclinical manifestations in many COPD patients, the risks and benefits of proactive treatment have been frequently debated. Considering the moderate certainty that screening for COPD in asymptomatic adults (who do not recognize or report respiratory symptoms) enrolled in prospective, randomized trials but not from the community settings conferred no net benefit, the 2022 US Preventive Services Task Force recommended against screening for COPD in asymptomatic adults (10). These recommendations were based on the review of pharmacological and nonpharmacological studies that early COPD diagnosis and treatment did not result in a significant reduction in exacerbations or improvement in other clinically relevant endpoints. The US Preventive Services Task Force recommendations explicitly state that this does not apply to patients at high risk for COPD with exposures to environmental inhaled toxins or smoking (10). Notably, a more proactive approach is needed to improve healthcare for GOLD stage I and II COPD because our target population consists of the exposed high-risk smokers or occupational cohorts.

To date, spirometry is essential for confirming the diagnosis of COPD, and spirometry should be promoted as the gold standard for community-based screening (11,12). Among individuals aged 40 years or younger, particularly those with a history of smoking, environmental, occupational pollutant exposure, or prior lung infection such as tuberculosis, pulmonary function testing should be a mandatory component of routine health check-ups, rather than a test only reserved for those presenting with dyspnea (when FEV₁ typically falls below 50% predicted). Mildly or intermittently symptomatic individuals are less likely to actively participate in community or hospital-based lung function screening and hence would be more readily under diagnosed in conventional settings.

Notably, conventional spirometry is human resource-dependent. Integrated with the evolving artificial intelligence (AI)-based technologies, such as animations to encourage forced inspiration and expiration and correct for any artifacts (e.g., premature termination of expiration, coughing), the development of small portable spirometers might help reduce the time to acquire quality-controlled records to justify effective screening and formal diagnosis (13,14). A field survey conducted in China showed that pre-bronchodilator spirometry with a single acceptable flow-volume curve could effectively screen for GOLD stage I and II COPD from communities (by reducing ~90% of the duration for completing spirometry procedures) (15). This is essential to detect mildly or intermittently symptomatic airflow limitations and capture the optimal window for intervention, where lung function decline is most rapid yet potentially reversible. To accelerate spirometry testing within communities, we are planning to implement programs within China to deploy AI-integrated portable spirometers for rapid screening with one acceptable flow-volume curve, followed by the complete spirometry among those with susceptible airflow limitation.

Given that small airway pathology invariably precedes overt airflow limitation, the role of oscillometry and imaging-based assessments (such as parametric response mapping) should be given serious consideration as part of routine screening (16,17). In line with multidimensional diagnostic schema (7), these tools would enable a shift of the prevention threshold forward by detecting pathological changes before they become irreversible.

It has become clear that early intervention in previously undiagnosed COPD patients may provide tangible benefits in terms of reduced exacerbation frequency and improved quality-of-life (18). The next important issue would be which specific modalities would work best. Conventional treatment mainly consists of smoking cessation (for smokers), pharmacologic interventions and non-pharmacologic interventions. Here, we primarily focus on pharmacologic interventions. Over-treatment remains a major concern (12), particularly among patients with mild airflow obstruction (GOLD I) among whom the evidence pertaining to the decreased rate of lung function decline with active pharmacological interventions has not been convincingly shown (19) although patients derive symptomatic benefit. Active smoking cessation may help halt the accelerated lung function decline. Following community-based effective screening (particularly among asymptomatic individuals), the next prime task would be to generate high-level evidence (e.g., via randomized controlled trials) to determine which interventions are effective and the comparative effectiveness among the most needed patient population (e.g. those needing treatment or even more intensified treatment). Accumulating evidence supports early intervention of GOLD stage I and II COPD (Table S2) (20-23). A randomized controlled trial of a two-year intervention with tiotropium (a single long-acting antimuscarinic bronchodilator) addressed the benefit of bronchodilator treatment in a population of patients identified with mild airflow obstruction by community screening. 75% of patients in this cohort has a CAT score <10 and the study demonstrated that pharmacological intervention significantly improved lung function, reduced the frequency of acute exacerbations, and enhanced overall quality of life in GOLD stage I and II COPD recruited mainly from communities, although no clear evidence of a slower annualized rate of lung function decline could be demonstrated (20).

For the debate of over-treatment to be settled, more work should be done to demonstrate the efficacy of pharmacological interventions among certain subgroups of GOLD stage I and II COPD, particularly the asymptomatic individuals with a rapid annualized lung function decline or frequent exacerbations, or those with minor lung function impairment but a significant symptom burden. Despite the inherent challenges in implementation (e.g., the reluctance of asymptomatic patients to adhere to treatment), the extensive community engagement and persistent efforts have safeguarded the completion of the Tie-COPD trial. To date, this trial remains one of the only studies to address interventions in screening populations and lung cancer screening initiatives provide an opportunity for larger scale studies investigating interventions in GOLD stage I and II COPD.

Strategic recommendations for comprehensive management

There are notable differences in the recommendations for the pharmacological management of COPD. The American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society guidelines stress treatment strategies based on the spirometry-defined staging (24), while the GOLD guidelines provide recommendations based on its own grouping schemes. Table S3 demonstrates the core aspects of recommendations.

To effectively implement the whole-chain management of COPD, we propose the following strategic actions (Figure 1).

Figure 1.

Key pathways to refine the screening and treatment of GOLD stages I and II COPD. There are three pathways to refine the screening and treatment of COPD. It is important to shift the focus from GOLD stage III–IV COPD to GOLD stage I–II COPD, particularly among individuals with a rapid lung function decline, prominent respiratory symptoms or frequent exacerbations. Empowering lung function screening with artificial intelligence softwares may help identify individuals with COPD which is not readily included in conventional screening programs. Finally, the generation of high-level evidence from randomized controlled trials will help build up the tiered treatment schemes for GOLD stage I–II COPD. The Figure 1 was partially generated via artificial intelligence with the input from the authors followed by a critical revision of the texts. COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Pulmonary Disease; RCT, randomized controlled trial.

Proactive prevention and risk stratification

The gateway to comprehensive COPD prevention should be moving upstream; that is, reinforcing active case finding, diagnosis and treatment, as well as exposure reduction or prevention. Community-based non-pharmacological interventions should target high-risk populations, such as those with chronic bronchitis, before airflow limitation becomes clinically significant. Smoking cessation remains the single most effective measure to slow the rate of lung function decline, and earlier cessation of smoking has been associated with greater prognostic benefits (25). To avoid over-treatment, the establishment of a robust “risk stratification” system is preferable to a “one-size-fits-all” approach, and patients may be categorized into low-risk groups (requiring close monitoring or monotherapy) and high-risk groups (e.g., those with poor baseline lung function or frequent exacerbations to receive intensified therapies such as dual or triple combination treatments) (26,27). Randomized controlled trials are urgently needed to fully address benefits of intensified therapies in certain subgroups of GOLD stage I and II COPD. For instance, inclusion of individuals who satisfy multidimensional diagnostic criteria for COPD (e.g., having radiologic manifestations, symptoms or exacerbations, small airway disorders) in future clinical trials is necessary (7,8). Because of the notable heterogeneity of clinical presentation, any single metric might not fully capture the event driving disease progression, and this has encouraged the development of composite endpoints such as the clinically important deterioration (CID), defined as meeting three criteria: a ≥100 mL annualized decline in forced expiratory volume in one second; COPD Assessment Test (CAT) score increasing by ≥2 points; a patient having experienced at least two moderate or one severe exacerbations during the past year (28,29). A lower threshold for annual lung function decline (e.g., 60 mL) could be applied in real-world observational studies because the 100-ml threshold was mainly derived from clinical trials (30,31), where this could be influenced using bronchodilators. Furthermore, clinically important improvement could be adopted in future clinical trials. Although the CID has now been mostly used in clinical trials, caution should be exercised regarding its practical use; the regulatory approval and validation in real-world community settings are warranted. To translate these strategies into practice, respiratory health cohorts can be established to enable a precise identification of individuals requiring pharmacotherapy.

A tiered therapeutic goal system

It is recommended that a multi-dimensional framework for treatment objectives is adopted. As a short-term goal, symptom relief is fundamental to patient engagement and adherence. For achieving a mid-term goal, reducing exacerbations may hinder disease progression. Every exacerbation may precipitate a further irreversible decline in lung function, so the prevention of recurrent exacerbations is important for preserving quality of life, as well as increased risk of serious or even fatal cardiovascular events (32). We recommend setting the long-term goal as slowing the decline of lung function, which is the ultimate “holy grail” of COPD management. By targeting the slope of lung function decline, interventions that repair airway remodeling and mitigate the aggravated inflammation could be explored. Integration of small-airway metrics (e.g., resonant frequency measured with impulse oscillometry) or computed tomography metrics (e.g., parametric response imaging for emphysema or small-airway disease) may help unveil the therapeutic effects in clinically “silent zones”. For instance, in the unpublished PIONEER 1.0 randomized controlled trial, these two important dimensions of small-airway metrics have been incorporated in the efficacy endpoints to determine the effects of long-acting dual bronchodilators in GOLD stage I and II COPD (Chinese Clinical Trial Registry No.: ChiCTR2200064765). Importantly, however, not all COPD patients show accelerated lung function decline and about half of them may suffer from COPD because they never achieved a normal peak lung function in early adulthood without excessive loss of lung function thereafter (33). Their best management strategy is still to be defined (34).

Evaluating the bona fide efficacy of intervention of GOLD stage I and II COPD requires moving beyond simple symptom scores. Because clinical deterioration in terms of frequent exacerbations and/or worsening quality of life may take place independent of rapid lung function decline, composite endpoints that prioritize the disease activity and stability and the prevention of CID could be considered in future clinical trials. For GOLD stage I and II COPD, the rate of lung function decline is more essential for long-term therapeutic success (among those who have achieved a normal peak lung function in early childhood), which necessitates rigorous and consistent patient follow-up as well as the well-powered study design (only a proportion of patients would have rapid lung function decline). To improve continuous patient healthcare, it is advised that at-risk individuals be followed on an annual basis and that patients with COPD be followed on a quarterly interval. Future studies addressing the role of disease progression in GOLD stage I and II COPD will mean longer and more expensive trials than typically conducted in GOLD stage III and IV COPD focused on short-term exacerbations.

Fostering multidisciplinary integration

The prevention and treatment of GOLD stage I and II COPD cannot rely solely on respiratory physicians working in isolation. Breaking through existing bottlenecks requires an extensive multidisciplinary fusion, which includes: (I) public health, AI and big data: epidemiologists should assist in precisely identifying high-risk cohorts for early screening, and the emerging AI system could be harnessed to track the trajectories of individuals to better identify important events leading to rapid deterioration and encouraging more proactive patient-physician communications and follow-up visits (35); (II) rehabilitation and nursing: rehabilitation specialists need to intervene early, harnessing pulmonary rehabilitation to prevent functional loss; (III) health economics: economists also play a crucial role in demonstrating that while early intervention requires upfront investment, it yields substantial long-term savings by averting the exorbitant costs associated with severe disease management; (IV) raising awareness of COPD, including its progressive nature and high mortality among the general public to encourage them to participate in early diagnosis programs, stop smoking and adhere to therapy regimes.

Improving the global awareness of early screening and treatment

While the disease burden escalates, the response to the management of GOLD stage I–II COPD remains reactive rather than proactive. The prevailing reliance on symptomatic presentation as a trigger for the diagnosis represents a fundamental flaw in current approach, resulting in the systematic exclusion of patients at stage I to II—the most critical phase of pathological development.

Technological advancement alone is insufficient without addressing the lack of public awareness. Existing data highlight a global lack of urgency regarding COPD, particularly when symptoms are mild or atypical. Therefore, robust educational initiatives are essential to improve public cognition and foster a proactive mindset toward screening and long-term treatment adherence. There are several structural barriers that need to be addressed, including the gaps in primary care workforce training, establishment of reimbursement policies for community spirometry screening, and patient health literacy deficits which significantly limits the screening uptake. The incorporation of primary care of COPD into the national fundamental public healthcare system represents an important solid step in improving the well-being of COPD patients in community settings.

In summary, the evidence presented here calls for a rigorous re-evaluation of existing clinical paradigms. The transition from symptom-based management to pathology-based prevention is not merely an incremental improvement but also a structural necessity. By integrating early spirometry screening into routine health assessments and adopting a risk-stratified therapeutic approach, the medical community can effectively close the gap between prevalence and diagnosis. Ultimately, these strategies may help mitigate the global burden of COPD. This requires a concerted effort to dismantle the barriers of diagnostic inertia and to prioritize the preservation of lung function over the palliation of established symptoms. Considering the recent progress in research and practice, a systematic application of evidence-based early intervention will translate into better management of COPD globally.

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