Interpretation of the 2024 GOLD Global Strategy for the Diagnosis, Treatment, Management and Prevention of Chronic Obstructive Pulmonary Disease (COPD).

Authors: Chen Dian, Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Chen Yahong

Preface

First published in 2001, the GOLD Global Strategy for the Diagnosis, Treatment, Management and Prevention of Chronic Obstructive Pulmonary Disease (COPD) aims to provide an unbiased review of the available evidence for the assessment, diagnosis and treatment of chronic obstructive pulmonary disease (COPD) in order to mitigate and reduce the impact of symptoms while reducing the risk of adverse health events in the future. The GOLD report is the fifth major revision of the GOLD guidelines, incorporating a reassessment and revision of COPD diagnosis, evaluation, and treatment recommendations. The GOLD report is an update of the GOLD report, which has been revised/expanded in 10 aspects on the basis of retaining the overall content, and was first published in November of this year. This article provides an introduction and interpretation of the GOLD report.

Definition and overview of COPD

COPD is a heterogeneous disease characterized by chronic respiratory symptoms (dyspnea, cough, sputum production, acute exacerbations) caused by airway (bronchitis, bronchiolitis) and/or alveolar abnormalities (emphysema), resulting in airflow limitation that continues to progressively worsen. Risk factors for COPD are classified as genetic (G) - environmental factors (E) - life-cycle events (T) (GETomics), which cause lung tissue destruction and alter the normal lung development or aging process. The main environmental exposures to COPD are tobacco smoke, inhalation of toxic particles and gases from indoor and outdoor air pollution, but other environmental and host factors, including lung dysplasia and accelerated aging, can also contribute to the occurrence. The most relevant (but rare) genetic factor for COPD is alpha-1 antitrypsin deficiency (AATD) due to mutations in the SERPINA1 gene, and mutations in other genes are associated with decreased lung function and the risk of developing COPD, but the corresponding effect size is small. According to the definition of COPD and risk factors, the diagnosis of COPD is confirmed by a spirometry with an FEV1/FVC < of 0.7 after inhalation of bronchodilators, indicating the presence of incomplete reversible airflow limitation. Some patients may have respiratory symptoms and/or destruction of lung structures (emphysema) and/or physiologic abnormalities (eg, FEV1 decline, gas trapping, hyperinflation, diffusion dysfunction, and/or rapid decline in FEV1), but no airflow limitation (FEV1/FVC ≥0.7 after inhalation of bronchodilators). These patients are classified as "pre-COPD". Abnormal spirometry (PRISm), which retains the ratio, is used to screen patients with normal ratios but abnormal lung ventilation. These two groups of people are at high risk of developing airflow limitation, but not all patients will develop airflow limitation. Typical symptoms of COPD are dyspnea, limited mobility, and/or cough with or without sputum production, which can be accompanied by an acute exacerbation of respiratory symptoms, known as an acute exacerbation of COPD, and requires a prophylactic and therapeutic strategy. Patients with COPD often have other comorbidities that affect disease status and prognosis, and require targeted therapy. Comorbidities mimic and contribute to exacerbations. COPD is a common preventable and treatable disease, but there are serious underdiagnoses and misdiagnoses, resulting in untreated or inappropriate treatment. Early and correct diagnosis of COPD is of great public health significance. Early life exposure, including tobacco smoke, affects the occurrence and development of COPD in young people, and paying attention to pre-COPD and PRISm is helpful for disease prevention, early diagnosis, and rapid and appropriate intervention and treatment.

The 2024 version of GOLD expands on the concept of PRISm and adds lung hyperinflation.

1. Extension of the PRISm concept

Population-based studies have found that the prevalence of PRISm ranges from 7.1%~11%, while in populations of current and former smokers (e.g., COPD Gene cohorts), the prevalence of PRISm is between 10.4%~11.3%. PRISm is not always a stable phenotype. Over time, pulmonary function tests in patients with PRISm can change to normal or airflow obstruction (about 20% to 30%). In addition, not all people with pre-COPD or PRISm will eventually develop fixed airflow obstruction (followed by COPD) over time, but they should all be considered "patients". Therefore, this segment of patients should be cared for and treated. The challenge is that there is no evidence on what is the best treatment for these patients.

2. Hyperinflation of the lungs

When spontaneous exhalation ends, if the amount of air in the lungs is higher than normal, the lungs are overinflated. Lung hyperinflation is associated with the clinical presentation of patients with COPD and results in dyspnea, impaired exercise tolerance, increased risk of hospitalization, respiratory failure, and increased risk of death in patients with COPD. In patients with COPD, hyperinflation occurs due to decreased elasticity of the lungs and obstruction of expiratory airflow. Expiratory airflow obstruction is caused by a combination of destruction of the lung parenchyma (emphysema) and airway abnormalities (eg, mucus obstruction, airway edema, increased bronchial tone, airway wall remodeling). In patients with moderate to severe obstruction, the level of dynamic hyperinflation was more strongly associated with impaired diffusion capacity, severity of small airway obstruction, and a higher ventilatory response to exercise compared with FEV1.

Diagnosis and initial evaluation of COPD

COPD should be considered in patients with dyspnea, chronic cough or sputum production, a history of recurrent lower respiratory tract infections, and/or a history of exposure to risk factors for the disease. Pulmonary function tests are necessary to confirm the diagnosis of COPD. FEV1/FVC < 0.70 confirms the presence of persistent airflow limitation. The goal of COPD evaluation is to determine the degree of airflow limitation, the impact of the disease on the patient's health status, and the long-term adverse risk (e.g., acute exacerbation, hospitalization, or death of COPD) to guide treatment. Patients with COPD who remain symptomatic despite initial treatment should be further evaluated for lung volume, diffusion function, exercise testing, and/or chest imaging. Patients with COPD often have a variety of chronic diseases (comorbidities) such as cardiovascular disease, skeletal muscle dysfunction, metabolic syndrome, osteoporosis, depression, anxiety, and lung cancer. Regardless of the degree of COPD airflow limitation, these comorbidities affect hospitalization and death. Therefore, all patients with COPD should be actively searched for comorbidities and given appropriate treatment.

The 2024 version of GOLD highlights pulmonary function tests prior to inhaled bronchodilators, screening of the target population for COPD, updated instructions on blood eosinophil counts, and radiographic partial lung interstitial abnormalities.

1. Pulmonary function test before inhalation of bronchodilators

The GOLD guidelines have previously recommended the use of pulmonary function measures after inhaled bronchodilators for the diagnosis of COPD, which are considered more appropriate and reproducible for diagnosing airflow limitation. However, bronchodilator-specific responses have little diagnostic value in differentiating asthma from COPD, while lung function measures prior to inhaled bronchodilators are more reproducible, and airway obstruction is uncommon after inhaled bronchodilators. Therefore, the latest version of the GOLD guidelines states that pulmonary function tests prior to inhaled bronchodilators can be used to initially assess for airflow limitation in patients with clinical manifestations. If pulmonary function tests do not show airway obstruction prior to inhaled bronchodilator, post-inhaled bronchodilator pulmonary function tests are not required unless the patient has a high clinical suspicion of COPD. In this case, the FEV1/FVC may be less than 0.7, and further investigation of the patient's etiology and follow-up is warranted, including repeat pulmonary function tests. If pulmonary function results prior to bronchodilator use have shown airflow limitation, the diagnosis of COPD should be made using measurements following inhaled bronchodilator. Individuals with a pre-inhaled FEV1/FVC < 0.7 and an inhaled bronchodilator FEV1/FVC ≥ 0.7 are at high risk of future progression to COPD and should be followed closely.

2. Screening of the target population of COPD

The 2024 version of GOLD recommends screening for people at high risk of COPD, including those who require annual low-dose chest CT (LDCT) to detect lung cancer or those with lung abnormalities (e.g., emphysema, thickened airway walls, bronchiectasis) and clinical complaints of respiratory symptoms. Lung cancer and COPD share common risk factors, and COPD is also an independent risk factor for lung cancer and is a key comorbidity affecting the survival of lung cancer patients. Therefore, a thorough assessment of symptoms and pulmonary function testing of individuals screened for lung cancer by LDCT is a particular opportunity to simultaneously screen patients for the presence of underlying COPD symptoms and airflow limitation. In addition to smoking, other factors increase the risk of COPD (e.g., development, genetics, environmental exposures, childhood infections), and these patients may undergo chest imaging to assess for respiratory symptoms. These people have no or very little smoke and are usually younger. Unlike those who are screened for lung cancer annually by LDCT, CT scans themselves can help identify individuals at increased risk of COPD in the non-lung cancer screening population and suggest that pulmonary function tests may be considered.

3. Update the instructions for blood eosinophil count

Blood eosinophil count can be used to predict the prophylaxis of inhaled corticosteroids (ICS) for future exacerbations, so the GOLD guidelines recommend blood eosinophil count as part of ICS medication management. Blood eosinophil counts are higher in patients with COPD and correlate with the number of eosinophils in the lungs and the expression of type II inflammatory markers. Blood eosinophil count can be used as a biomarker in conjunction with clinical evaluation when making decisions about the use of ICS because it helps clinicians assess the likelihood of a beneficial preventive response to the addition of ICS to regular bronchodilator therapy.

4. Lung interstitial abnormalities

Parenchymal fibrosis or inflammation of the lungs is common on chest CT images in both smokers and non-smokers, and when found incidentally in patients without interstitial lung disease (ILD), it is referred to as interstitial lung abnormalities (ILA). Patients with suspected ILD have a significant increase in respiratory symptoms and mortality. Fibrous ILA (i.e., traction bronchiectasis, structural twisting, and honeycomb changes) is more likely to develop disease progression and is associated with poor outcomes, particularly when associated with emphysema. Given the clinical relevance of ILA, multiple studies support clinical assessment, risk stratification, and follow-up monitoring in individuals with the above symptoms.

Prevention and management of COPD

Smoking cessation is key to COPD therapy. Medication and nicotine replacement therapy do improve long-term quit rates. Legislative smoking bans and counselling provided by medical professionals have increased smoking cessation rates. At present, the effectiveness and safety of e-cigarettes as an adjunct to smoking cessation are uncertain. The main goal of COPD therapy is to reduce symptoms and the risk of future exacerbations, and management strategies for stable COPD should be based primarily on clinical symptoms and assessment of a history of exacerbations. Drug therapy can reduce COPD symptoms, reduce the frequency and severity of exacerbations, improve patient health and exercise tolerance, delay the rate of decline in lung function and reduce mortality. Each drug regimen should be individualized based on the severity of symptoms, risk of exacerbations, adverse effects, comorbidities, availability and cost of medications, and patient response, preferences, and ability to use various drug delivery devices. The COVID vaccine can effectively prevent COVID infection, and COPD patients should be vaccinated according to national recommendations. Influenza and pneumococcal vaccines reduce the incidence of lower respiratory tract infections. Adolescent patients with COPD who have not received Tdap vaccine (dTaP/dTPa) should be given catch-up vaccination to prevent the development of pertussis, tetanus, and diphtheria, while patients aged 50 years and older with COPD should receive herpes zoster vaccine. The core components of pulmonary rehabilitation, including the combination of exercise training and health education, can improve exercise capacity, symptoms, and quality of life in patients with COPD of varying severity. Long-term oxygen therapy improves survival in patients with severe resting chronic hypoxemia (PaO2≤55 mm Hg or <60 mm Hg with concomitant cor pulmonale or secondary polycythemia). Long-term oxygen therapy should not be routinely given to patients with stable COPD and moderate decreased oxygenation at rest or exercise. However, individual patient factors must be taken into account when assessing a patient's need for supplemental oxygen. In patients with a history of hospitalization for severe chronic hypercapnia and acute respiratory failure, long-term noninvasive ventilation reduces mortality and prevents rehospitalization. For some patients with advanced emphysema who do not respond to medical treatment, surgical or bronchoscopic interventions may be beneficial. Palliative care is an effective way to manage symptoms of advanced COPD.

The 2024 edition of GOLD combines Chapters 3 and 4 of the previous GOLD guidelines into a collective term for COPD prevention and management, revises the smoking cessation section, and updates indoor and outdoor air pollution, occupational exposure, respiratory syncytial virus vaccine recommendations, inhalation therapy management, and pharmacotherapy for smoking cessation.

1. Revise the smoking cessation section

Quitting smoking is more challenging for smokers with COPD than smokers without COPD, who are more dependent on nicotine, have lower self-efficacy, and are less confident in quitting. In addition, depression is more common in smokers with COPD, which can lead to failed attempts to quit. Despite these disadvantages, if effective time and resources are devoted to smoking cessation, the long-term smoking cessation rate can reach 14%~27%. Smoking cessation therapy for patients with COPD should be tailored to individual needs and degree of tobacco dependence, and a combination of counseling and medication is the most effective smoking cessation treatment for COPD. The complexity of the smoking cessation process largely depends on the degree of nicotine addiction. Therefore, all patients should be accurately assessed for nicotine dependence. In addition to adopting an individual approach to quitting smoking, legislative smoking bans can be effective in increasing smoking cessation rates and reducing the harm of secondhand smoke exposure.

2. Indoor and outdoor air pollution

Reducing exposure to domestic and outdoor air pollution requires a combination of public policies, local and national resources, cultural change, and protective measures taken by individual patients. Reducing exposure to biofuel fumes is a key goal to reduce the global prevalence of COPD. Efficient ventilation, non-polluting stoves, and similar interventions should be recommended.

3. Occupational exposure

There are no studies to demonstrate whether interventions to reduce occupational exposure also reduce the burden of COPD, but patients are advised to avoid ongoing exposure to potential irritants such as dust, fumes, and gases as much as possible.

4. Respiratory syncytial virus (RSV) vaccine

People at highest risk of severe RSV disease include adults with chronic heart or lung disease, weakened immune systems, and those living in nursing homes or long-term care facilities. The new respiratory syncytial virus bivalent fusion F protein vaccine and the pre-fusion F protein vaccine are recommended for people aged 60 years and older.

5. Inhalation therapy management

GOLD 2024 merges the "Inhalation Therapy-related Issues" in Chapter 3 of the original GOLD 2023 and "Inhalation Therapy Management" in Chapter 4 into "Inhalation Therapy Management" in the existing Chapter 3, and further divides it into two parts: "Ability to Use Drug Delivery System Correctly" and "Selection of Inhalation Devices". On average, more than two-thirds of patients make an error at least once when using an inhalation device. Although the type and frequency of inhalation errors vary from device to device depending on their characteristics, any device must be explained, demonstrated, and regularly inspected for inhalation techniques. It is better to use a "teach-back" approach (where the patient is asked to demonstrate how to use the device), i.e. interventions led by pharmacists, doctors, physiotherapists, and nurses, as well as lay health guidance, improve inhalation technique and adherence in patients with COPD. If the patient is receiving inhalation therapy and is able to use their current device correctly, the same device is preferable for the new treatment regimen. If the patient is unable to use the current device correctly, or if there is no other suitable drug for the same device, a systematic procedure should be used to select a new drug delivery device and ensure that the patient is able to use the device. Healthcare professionals must provide appropriate education, including hands-on demonstrations, videos, or demonstrations based on the correct technique, as well as on-site verification of the patient's mastery of inhalation techniques. It is essential to check regularly, preferably at every visit, that the patient continues to use the equipment correctly. Encouraging patients to bring their personal use devices to the clinic is also an effective option.

6. Pharmacotherapy for smoking cessation

Medications for smoking cessation include control medications (nicotine patches, bupropion, and varenicline) aimed at achieving long-term quitting and drugs for rapid relief of acute withdrawal symptoms (short-acting nicotine). Nicotine replacement therapy (nicotine gum, inhalers, nasal sprays, transdermal patches, sublingual tablets, or lozenges) is effective in increasing long-term smoking cessation rates and is more effective than placebo. E-cigarettes are an effective nicotine replacement therapy for smoking cessation. However, the effectiveness of e-cigarettes in quitting smoking remains controversial.

Management of acute exacerbations of COPD

An acute exacerbation of COPD is defined as an event characterized by dyspnea and/or worsening cough and sputum production within 14 days. Acute exacerbations of COPD are often associated with increased local and systemic inflammation due to airway infections, air pollution, or other lung damage. Because these symptoms are not specific to COPD, relevant differential diagnoses should be considered, particularly pneumonia, congestive heart failure, and pulmonary embolism. The goal of treating an acute exacerbation of COPD is to minimize the negative effects of the current exacerbation and to prevent subsequent events.

☞ Short-acting beta-2-agonists alone, with or without short-acting anticholinergics, are recommended as initial treatment for exacerbations. Long-acting bronchodilator maintenance therapy should be initiated as soon as possible.

☞ In patients with frequent exacerbations and elevated blood eosinophil levels, the addition of ICS to a dual bronchodilator regimen should be considered.

☞ In patients with severe exacerbations, systemic glucocorticoids improve lung function (FEV1) and oxygen and shorten recovery time (including length of hospital stay). The duration of treatment should generally not exceed 5 days.

☞ Antibiotics can be used to shorten recovery time, reduce risk of early recurrence, reduce treatment failure, and shorten length of hospital stay when clinically indicated. The duration of treatment should be 5 days.

☞ Methylxanthines are not recommended as they increase the risk of side effects.

☞ Noninvasive mechanical ventilation is the preferred mode of ventilation for patients with acute respiratory failure in COPD without absolute contraindications, as it improves gas exchange, reduces work of breathing and intubation, shortens hospital stays, and improves survival.

☞ The recovery time of an acute exacerbation will vary, usually taking 4~6 weeks, and some patients will not be able to return to the functional state before the acute exacerbation. After an exacerbation occurs, appropriate measures to prevent it should be initiated.

GOLD 2024与GOLD 2023基本一致。

Chronic obstructive pulmonary comorbidities

COPD is often associated with other diseases and has a significant impact on prognosis. Overall, the presence of comorbidities should not alter the treatment regimen for COPD, and comorbidities should be treated according to routine criteria, independent of the presence of COPD. Cardiovascular disease is a common and important comorbidity of COPD. Lung cancer is common in patients with COPD and is the leading cause of death. People with COPD due to smoking should be screened for lung cancer once a year. Because there are no data to determine that the benefits outweigh the harms, annual LDCT screening for lung cancer is not recommended in people with COPD caused by non-smoking. Osteoporosis and depression/anxiety are common and important comorbidities of COPD, often missed and associated with poor health status and prognosis. Gastroesophageal reflux (GERD) is associated with an increased risk of acute exacerbations of COPD and poor health. When COPD is part of a multi-disease treatment plan, care should be taken to ensure simplicity of treatment and to minimize polypharmacy.

GOLD 2024 added several studies to the three comorbidities of cardiovascular disease, obstructive apnea with insomnia and frailty, compared to GOLD 2023.

1. Cardiovascular disease

A large study in patients with COPD without a history of cardiovascular disease found a 25% increased risk of major adverse cardiac events, including acute myocardial infarction, stroke, or cardiovascular death. After adjusting for cardiovascular risk factors, comorbidities, and other variables, the incidence of major adverse cardiovascular events (including acute myocardial infarction, stroke, or cardiovascular death) was 25% higher in patients with COPD than in patients without COPD (odds ratio [odds] 1.25, 95% CI 1.23-1.27).

2. Obstructive apnea and insomnia

Insomnia in patients with COPD is associated with higher rates of outpatient visits and hospitalizations. After adjusting for confounders, insomnia was associated with higher rates of outpatient visits, hospitalizations, and use of corticosteroids and/or antibiotics, longer hospital stays, and increased hospital costs over a 12-month period. These findings highlight the importance of treating insomnia to reduce the burden of COPD on patients and the healthcare system.

3. Debilitation

The results of a meta-analysis showed that frailty and pre-frailty were associated with all-cause mortality, exacerbations, and hospitalizations in patients with COPD. Assessment of frailty in patients with COPD can facilitate secondary prevention and early intervention.

COVID-19 and COPD

Patients with COPD who develop new or worsening respiratory symptoms, such as fever and/or any other symptoms that may be associated with COVID-19, should be tested for possible SARS-CoV-2 infection, even if these symptoms are mild. Patients should continue to treat COPD with oral and inhaled medications as directed. During periods of high COVID-19 prevalence in the community, pulmonary function tests should be limited to patients who are urgent or necessary to diagnose COPD, and/or to assess lung function status in interventional or surgical patients. Social distancing and protection, or appropriate isolation, should not lead to social isolation and inactivity. Patients can communicate remotely to keep in touch with friends and family, continue to be active, and should ensure they have adequate medications. Patients should be encouraged to use authoritative and trusted sources to obtain medical information about COVID-19 and its management. Remote (telephone/virtual/online) follow-up guidance for COPD patients and a printed checklist is provided.

Drug therapy for patients with COPD with suspected or confirmed COVID-19: nebulization can be used if nebulization is indicated, and COVID-19 can be treated with antivirals, glucocorticoids, and immunomodulatory therapy.

1. Provide COPD-related drug therapy for patients with COPD and COVID-19

When providing pharmacotherapy to patients with COPD with suspected or confirmed COVID-19, maintaining the original COPD treatment requires ensuring adequate drug availability and using antibiotics and oral corticosteroids consistent with recommendations for the treatment of acute exacerbations. GOLD 2024 supplements that, if necessary, nebulization therapy can be used in conjunction with personal protective equipment.

2. Provide drug treatment for COVID-19 for patients with COPD and COVID-19

Antivirals, glucocorticoids, and immunomodulators may be used when providing treatment for COVID-19 to patients with COPD who are suspected or confirmed to have COVID-19. Randomized clinical trials for COVID-19 treatments focus on antiviral and anti-inflammatory treatments. Some drugs have had positive results in treating hospitalized patients with severe COVID-19, including systemic glucocorticoids. Current studies lack subgroup data and analysis of patients with COPD, and recommend that patients with COPD with COVID-19 receive the same standard of care as other patients with COVID-19, including antiviral drugs, glucocorticoids, IL-6 blockers, and baricitinib.