**4. Research progress on prevention and management of COPD**

#### **4.1 Smoking cessation**

Smoking cessation is the first step in the treatment of COPD and the key to reducing the progressive decline of lung function. Lung function and smoking-related comorbidities (lung cancer and cardiovascular disease) increase mortality rate over time in COPD patients. Cooking with stoves instead of open fires can reduce the progressive decline in lung function by reducing indoor air pollution in a manner similar to smoking cessation. It is different for COPD patients with high tobacco dependence to smoking cessation. Thus, up to 40% of patients, even those with severe COPD, are persistent smokers. Drug therapy and nicotine replacement therapy can improve long-term abstinence rates. Smoking legislation and counseling by medical professionals can also improve abstinence rates. Currently, the effectiveness and safety of e-cigarettes as a smoking cessation aid are uncertain.

### **4.2 Physical activity**

Increasing physical activity of daily living is as important as smoking cessation in reducing morbidity and mortality rate in COPD patients. In the early stage of the disease, lack of physical activity is closely related to hospitalization and mortality. In COPD patients, walking for 15 minutes per day reduced the risk of death by 14%, and an increase of 600 steps per day was associated with a lower risk of hospitalization. GOLD 2022 introduces the meta-analysis that included a total of 23 studies with 1663 participants. Compared with other groups, the mean deviation of 6 minutes walking distance (6MWD), FEV1 as a percentage of predicted values, SGRQ scores, and Chronic Respiratory Disease Questionnaire (CRQ ) scores in Tai Chi group were significantly improved [23]. Tai Chi may have the potential to reduce dyspnea, improve exercise ability and quality of life in patients with COPD. Patients with COPD may benefit from practicing Tai Chi, but more effective programs need to be further studied.

#### **4.3 Pulmonary rehabilitation**

"Rehabilitation 2030" is a new strategic approach to prioritizing and strengthening rehabilitation services in the health system. As part of the WHO initiative, a series of rehabilitation interventions is being developed that includes pulmonary rehabilitation for COPD. Inpatient or outpatient pulmonary rehabilitation for patients with COPD is effective in improving multiple clinically relevant outcomes. There is evidence that the core components of pulmonary rehabilitation, including exercise training combined with disease-specific education and self-management interventions, can benefit almost every COPD patient.

Pulmonary rehabilitation is an effective multidisciplinary treatment strategy that improves dyspnea, exercise tolerance, and health-related quality of life. Classical exercise programs with individualized endurance and strength training remain the cornerstone of pulmonary rehabilitation, and education to promote behavior change and self-management are also necessary for successful intervention. Tele-rehabilitation has been proposed as an alternative to traditional methods. The results of multiple trials conducted in groups and individuals with multiple tele-rehabilitation delivery platforms (videoconferencing, telephoneonly, websites with telephone support, mobile applications with feedback, centralized "hubs" for people to gather) show that tele-rehabilitation is safe and has similar benefits to center-based respiratory rehabilitation in a range of outcomes [24]. However, the evidence is still evolving and best practices have not yet been established.

*Exploration of Multi-Aspect Development of Chronic Obstructive Pulmonary Disease… DOI: http://dx.doi.org/10.5772/intechopen.106643*

## **4.4 Pharmacotherapy**

Medical therapy for COPD is used to reduce symptoms, decrease the frequency and severity of exacerbations, and improve exercise tolerance and health. Maintenance drug therapy in the stable phase aims to improve symptoms, improve health-related quality of life, improve exercise intolerance, and reduce the risk of deterioration. In terms of airflow restriction, reduction of air entrapment, and improvement of exercise intolerance, inhaled long-acting beta2 agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) have similar effects. LAMA tiotropium appears to be superior to LABA in preventing exacerbations and is as effective as the combination of inhaled corticosteroids and LABA. Therefore, LAMA monotherapy should be superior to LABA monotherapy in patients with a history of exacerbation. Acute exacerbations occurred significantly less during LABA-LAMA (indacaterolglycopyrrolate) therapy than during LAMA (glycopyrrolate) monotherapy. Besides, the addition of LAMA and inhaled corticosteroids to LABA resulted in less aggravation than LABA and inhaled corticosteroids alone. Clinicians are concerned about whether further escalation from LABA-LAMA to triple therapy consisting of LABA, LAMA, and inhaled corticosteroids will provide additional benefits. Two largescale studies found that triple therapy (LABA/LAMA/ICS) can reduce the death rate of COPD [25, 26]. For the benefit of fixed triple therapy for AECOPD, ETHOS research published evidence-based medicine evidence in the New England Journal of Medicine in June 2020. In this study, 8578 patients with chronic COPD were enrolled, aged 40 ~ 80 years, with smoking history of ≥10 packs/year, cat score ≥ 10 points, maintenance treatment with ≥2 inhalants before screening, maintenance treatment time ≥ 6 weeks, FEV1 estimated value ≥25% and < 65%, and moderate or severe AECOPD history 12 months before screening; To compare the efficacy and safety of budesonide/glulomonium bromide/formforminhaled aerosol (MDI) and dual therapy (bud/form and gly/form) with two ICs doses, all cause death was the secondary endpoint; compared with laba/lama, the use of triple therapy containing high-dose ICs (not low-dose ICs) is associated with lower mortality. The results of this study have important clinical significance, and further research or analysis may help to determine whether specific patient subgroups show greater survival benefits. The potential benefit of reducing acute exacerbation by adding inhaled corticosteroids to LABA needs to be judged and weighed the potential risk of pneumonia. When fluticasone, an inhaled corticosteroid, is added to LABA, COPD patients with low eosinophil counts may have an increased risk of pneumonia. This suggests that there is a subgroup with a high eosinophil count, and the benefits of inhaled corticosteroids outweigh the risks. Clinicians must judge whether glucocorticoid treatment needs to be combined or stopped according to the clinical symptoms, acute exacerbation risk, asthma, bronchiectasis, pulmonary tuberculosis, blood eosinophils, and other indicators of patients, and select the route, dose, and course of glucocorticoid administration according to the heterogeneity of AECOPD. Eosinophils can predict the risk of acute exacerbation, and ICS has guiding value in preventing future AECOPD. The survey data showed that the blood eosinophil count was <100 cells/ μl of COPD patients who were less likely to benefit from the treatment with the treatment plan containing ICS. In addition, the presence of Proteus, Haemophilus, and increased bacterial infections and pneumonia was associated with lower blood and sputum eosinophil counts. Therefore, a lower blood eosinophil count can identify characteristic individuals of the microbiome with an increased risk of clinical

deterioration caused by pathogenic bacteria. Higher blood eosinophils and lung eosinophils in COPD patients were associated with higher levels of type 2 airway inflammation markers. These differences in airway inflammation may explain the different responses of eosinophils to ICS therapy. The estimated value of eosinophil whose number is <100cells/μl and ≥ 300 cells/μl can be used to predict the different probability of treatment benefit. It should be noted that the use of eosinophils, which can predict the efficacy of ICS, should always be combined with clinical assessment of the risk of acute exacerbation. In the population with low ICS use rate, a greater decrease in FEV1 was observed in mild to moderate COPD patients with high blood eosinophil count, which indicates that blood eosinophils can be used as a biomarker of decreased lung function and are not affected by ICS use. In young persons without COPD, higher eosinophil counts were associated with an increased risk of subsequent COPD [27]. In conclusion, blood eosinophils can help clinicians evaluate the possibility of beneficial preventive response to the addition of ICS to conventional bronchodilator therapy. Therefore, blood eosinophils count can be used as biomarkers combined with clinical evaluation when making decisions about the use of ICS. In view of the increasing importance of clinical features and individualized treatment decisions, further treatment options for this subgroup should be carefully examined. Bronchodilator therapy (LABA, LAMA, or a combination of both) has been proved to be generally safe in randomized controlled trials. However, owing to these trials usually excluding patients who have severe heart disease, clinicians should be aware of the cardiac events reported in meta-analysis and observational studies. Patients reported that symptoms of chronic bronchitis may benefit from the addition of oral phosphodiesterase 4 inhibitor roflukast, especially those who have been hospitalized for COPD deterioration or have received more than two deterioration treatments in the outpatient department. Macrolide therapy is recommended for long-term and low-dose use in patients who have smoked. However, it is necessary to consider the side effects associated with propenolactone, the uncertainty of treatment for more than 1 year, and the resistance of bacteria to macrolides. The World Health Organization (WHO) has formulated the necessary intervention measures for COPD in low- and middle-income countries, and it pointed out that if the symptoms persist, low-dose theophylline can be added according to drug availability. Gold2022 suggests that FEV1 accounts for 35% ~ 60% of the estimated value, and COPD patients with smoking history are the best subjects for α 1 antitrypsin deficiency (AATD) augmentation therapy (evidence level B). The existing clinical trials and registration data are almost completely concentrated on patients with ZZ (ZZAATD/PiZZ) genotype. Recent studies have shown that the risk of mild COPD in Z gene heterozygotes is increased. Different from ZZ genotype, Z gene heterozygotes will not develop COPD in the condition of non-smoking. Therefore, it is considered that quitting smoking can prevent the development of this kind of patients [28].

There are limitations in the evidence base of drug therapy for COPD. Almost all drug treatment studies included patients who had smoked for at least 10 years and excluded patients with asthma. It is not clear how effective COPD drugs are in patients who have never smoked or who have asthma. Due to the complexity of airway inflammation and related clinical phenotypes in COPD, a single inflammatory pathway or mechanism may not be enough to continuously inhibit inflammation in all patients with COPD. Each drug treatment plan should be individualized according to the severity of COPD symptoms, the risk of acute exacerbation, adverse reactions, complications, the availability and cost of drugs, as well as the patient's response, preference, and ability to use various drug delivery devices.

*Exploration of Multi-Aspect Development of Chronic Obstructive Pulmonary Disease… DOI: http://dx.doi.org/10.5772/intechopen.106643*

#### **4.5 Interventional treatments**

For some patients with advanced emphysema whose medical treatment is ineffective, surgery or bronchoscopic intervention may benefit. Individualized treatment decisions should be based on the characteristics of emphysema, such as heterogeneous and homogeneous, complete lobar fissure or collateral ventilation. For most patients, the therapeutic effect needs to be combined with potential complications such as pneumothorax and pneumonia. Other interventions, including hot steam or sclerotherapy, can show some efficacy, but may lead to more complications. For patients with advanced COPD, lung transplantation is still an option to improve the quality of life and exercise endurance, but it has no effect on the overall survival rate. Palliative treatment is an effective method to control the late COPD symptoms.

#### **4.6 Oxygen and ventilatory support**

For patients with stable COPD and moderate decline of oxygenation index when they rest or exercise, long-term oxygen therapy should not be conducted routinely, but individual factors of patients must be considered when evaluating patients' demand for supplemental oxygen. For patients with severe resting hypoxemia ([pao2] ≤ 55 mmHg) or moderate hypoxemia (PaO2 ≤ 60 mmHg) and signs of heart failure, pulmonary hypertension, or polycythemia, long-term oxygen therapy can improve their survival rate. The application of transnasal high flow oxygen therapy (HFNC) in the rehabilitation of COPD is a hot spot in recent years. A meta-analysis from 10 RCTs compared HFNC with conventional oxygen therapy (COT) or NIV in improving respiratory rate, FEV1, tidal volume, oxygen partial pressure, total SGRQ score, 6MWD, and exercise tolerance time [29]. The comprehensive data of six studies showed that the respiratory rate of COPD patients in HFNC group was lower. The comprehensive data of three studies showed that FEV1 of HFNC group was lower. There was no difference in tidal volume between patients with COPD in HFNC group and control group; There was no significant improvement in oxygen partial pressure between HFNC group and control group. In the subgroup analysis of HFNC and COT, the total score of SGRQ in HFNC group increased. Two multicenter RCTs showed an increase in 6MWD after HFNC, but no increase in exercise tolerance time. The differences in evidence quality included in this meta-analysis are prominent, which indicate that more high-quality RCTs are needed to verify these evidences. For patients with stable hypercapnia and high inspiratory pressure, noninvasive positive pressure ventilation aims to reduce the partial pressure of carbon dioxide (PaCO2) in arterial blood by at least 20% or lower than 6.5 kPa, which can improve the survival rate. Therefore, patients who meet the condition and have a special home care environment can consider this method.

#### **4.7 Treatment of comorbidities**

Comorbidities affect a large part of patients with COPD. A cluster analysis was conducted on 213 COPD patients, and five unique clusters of comorbidities were established: (1) fewer comorbidities; (2) cardiovascular clusters, including hypertension and atherosclerosis, (3) cachexia clusters, including low body mass index (BMI), muscle atrophy, osteoporosis, and impairment of renal function; (4) metabolic clusters, including high BMI, dyslipidemia, hypertension, and atherosclerosis sclerosis; (5) psychological cluster, including anxiety and depression. Cardiovascular disease

is a common and important complication of COPD. Although the lung function is similar, there are important differences in dyspnea and quality of life in different clusters. Systemic inflammation in cardiovascular and metabolic clusters is at a high level. Lung cancer is common in COPD patients and is the leading cause of death. The United States Preventive Services Task Force (USPSTF) updated its recommendations for lung cancer screening in 2021,which recommend that conduct LDCT annual lung cancer screening for adults aged 50 ~ 80 who have 20 packs per year of smoking history and currently smoke or quit smoking within the past 15 years [30]. Osteoporosis and depression/anxiety are common complications of COPD, which are often missed, and are related to poor health status and prognosis. Gastroesophageal reflux is associated with increased risk of AECOPD and poor health. Overall, COPD combined with other that has a great impact on the prognosis. The existence of comorbidities should not change the treatment plan of COPD, and the comorbidities should be treated according to the conventional standard, which has nothing to do with the existence of COPD. When COPD is part of a multi-disease care plan, attention should be paid to ensuring the simplicity of treatment and minimizing multidrug treatment. Some drugs for COPD have been evaluated as well as the effects of treatment outside the lung. The inhaled combination of fluticasone furoate and viranterol (an inhaled corticosteroid and a LABA) did not affect mortality or cardiovascular outcomes in patients with moderate COPD and increased risk of cardiovascular disease, but it improved cardiac insufficiency associated with hyperinflation. In a meta-analysis, there were fewer major cardiovascular events after roflukast treatment, but no randomized controlled study has been conducted to test the potential benefits of roflukast treatment on cardiovascular outcomes in COPD.

## **4.8 Treatment of exacerbations of COPD**

Exacerbation of COPD is an acute exacerbation of respiratory symptoms (dyspnea, cough, expectoration, and suppuration) that requires a change in treatment strategy. AECOPD can be caused by a variety of factorshe, and the most common cause is viral or bacterial respiratory tract infection. Patients are often hospitalized with dyspnea as the main symptom. The exacerbation of respiratory symptoms in COPD patients needs to be identified as AECOPD or other causes. One important differential diagnosis is pulmonary embolism (PE). In a study that included 740 AECOPD patients, 44 patients were diagnosed with PE within 48 hours after being admitted to hospital [31]. Among the 670 patients who were considered to have no venous thromboembolism and did not receive anticoagulant therapy at the time of admission, five patients developed PE during the follow-up period, of which three patients developed PE related death. The overall case fatality rate in 3 months was 6.8%. In the patients with COPD admitted due to acute deterioration of respiratory symptoms, 5.9% detected PE using predefined diagnostic algorithms. Further studies are needed to understand the possible role of systematic screening for PE in this patient population. At the same time, cardiovascular events and pneumonia also need to be excluded during acute attack. The deterioration negatively affects lung function decline, health-related quality of life, and prognosis. The treatment goal of ECOPD is to minimize the adverse effects caused by this acute exacerbation and prevent the occurrence of acute exacerbation in the future. Recommended single-use short effect β receptor agonists with or without short acting anticholinergic drugs are the initial treatment for AECOPD. Short-term systemic glucocorticoid therapy (e.g., 40 mg prednisone for 5 days) with or without short course antibiotics is the preferred treatment for acute episode events. Severe exacerbations

### *Exploration of Multi-Aspect Development of Chronic Obstructive Pulmonary Disease… DOI: http://dx.doi.org/10.5772/intechopen.106643*

require hospitalization and individualized treatment, including noninvasive ventilation support (preferred), oxygen therapy, treatment of associated diseases (such as heart failure, pneumonia), and finally, weaning or invasive ventilation. Cohort studies have shown that more than half of AECOPD patients have cardiovascular disease. Even without clinical symptoms of cardiac involvement, biochemical evidence of cardiac dysfunction (such as high concentration of troponin I or B-type natriuretic peptide) is common during treatment. About 20% of AECOPD may be due to the deterioration of underlying cardiovascular disease, and such patients have poor prognosis after admission. In Europe, 11% of patients died within 90 days after admission. The hospital stay of 50% of the patients was extended to 3 months; 35% of the patients were readmitted within 90 days. Gold2022 gives discharge criteria and follow-up recommendations: record the ability to perform physical activities during the follow-up of 1–4 weeks and consider whether the patient is suitable for participating in lung rehabilitation, at the same time, increasing protective measures such as wearing masks, reducing social contact, and washing hands frequently can reduce the frequency of AECOPD.
