(I) Treatment objectives
To reduce symptoms and stop the progression of the disease; to improve mobility and quality of life; and to reduce the death rate of the disease.
(B) Education and management
Education and management can improve patients’ and related personnel’s understanding of COPD and their ability to deal with the disease, better cooperate with treatment and strengthen preventive measures, reduce recurrent exacerbations, maintain the stability of the disease and improve the quality of life. The main contents include.
1. educating and urging patients to quit smoking, the only measure to effectively delay progressive decline in lung function is to quit smoking.
2.To enable patients to understand the pathophysiology and clinical basics of COPD.
3. mastering general and some specific treatment methods
4. to learn techniques for self-control of the disease, such as abdominal breathing and lip retraction breathing exercises
5. to understand the timing of visits to hospitals
6. Regular follow-up management by community doctors.
(iii) Control occupational or environmental pollution
Avoid or prevent inhalation of dust, fumes and harmful gases.
(iv) Drug treatment
The existing commonly used drugs mainly include the following categories: bronchodilators, glucocorticoids, antibiotics, mucolytics, immunomodulators, vaccines, etc. The new target drugs currently under development mainly involve: type 4 phosphodiesterase inhibitors, leukotriene receptor (LTB4) blockers, cytokine inhibitors, chemokine inhibitors, protease inhibitors, etc. However, studies have proven that none of the existing therapies are effective in stopping the continued progression of airway obstruction.
Bronchodilators
The main therapeutic effect of bronchodilators is to relieve the symptoms by relieving the spasm of bronchial smooth muscles and diastolic bronchial tubes, thus reducing the degree of airflow obstruction. However, these drugs do not improve the elastic retraction of lung tissue and therefore do not improve lung function in all patients. Bronchodilators can relieve patients’ symptoms if applied on a short-term basis as needed, while long-term regular use can prevent attacks, reduce patients’ symptoms, and restore their exercise tolerance. Inhalation agents are currently preferred for treatment because of their better safety profile. Although long-acting bronchodilators are more expensive, their efficacy is much better than short-acting preparations. Many studies have proven that the combination of drugs with different mechanisms of action or different duration of action is much stronger than the effect of a single drug and less likely to have adverse effects. For example, when β2-agonists are combined with anticholinergic drugs or theophylline, the pulmonary function and health-related quality of life of COPD patients can be further improved. Since airflow limitation persists in COPD patients, the duration of drug action during the stabilization phase is far more important than the rapid onset of action, so long-acting cholinergic receptor antagonists are currently preferred for treatment. Bronchodilators include: β2-agonists, anticholinergic drugs, theophylline drugs, etc.
β2-agonists
Currently, the β2-agonists commonly used in clinical practice are divided into two categories: short-acting and long-acting. Short-acting β2-agonists are mostly quantitative nebulized inhalers, such as salbutamol. Long-acting agents such as salmeterol inhalation or oral bambuterol and formoterol are mostly used to relieve nocturnal or early morning symptoms. A series of studies have found that long-acting bronchodilators can reduce acute exacerbations and improve health-related quality of life in COPD patients. the TORCH study found that salmeterol significantly reduced the rate of FEV1 decline in COPD patients compared to placebo. Combining the results of the TORCH and UPLIFT trials, salmeterol/fluticasone and tiotropium each had a similar effect on improving the rate of FEV1 decline in COPD patients compared with placebo, and even the combination of these drugs did not further increase the benefit of patients on this measure. In addition, the effects of salmeterol, tiotropium, and salmeterol/fluticasone were largely similar in terms of morbidity and mortality in COPD patients. However, some studies have shown that these drugs increase bronchial inflammatory susceptibility while dilating the bronchi and relieving symptoms, thereby decreasing bronchoprotection and thereby increasing respiratory-related morbidity and mortality. Several new long-acting β2 agonists are in clinical development, such as indantaterol and carmeterol. Indantaterol can effectively dilate the small airways of patients, maintain the dilating effect of bronchus for more than 24 hours, and has a rapid onset of action, with no significant toxic side effects or drug resistance in current studies, and has a broad clinical application prospect.
Anticholinergic drugs
In normal human airways, there is also a certain cholinergic tension, which makes the airway in a slightly constricted state and has a weak response to anticholinergic drugs. Because of the significant airway narrowing in COPD patients, the same magnitude of cholinergic tone will have a greater effect on airway resistance. Thus blocking the vagus nerve, which innervates bronchial smooth muscle, dilates the spastic bronchial smooth muscle. The mechanism of action of anticholinergic drugs is directed at this link. Currently, tiotropium bromide is the first inhaled dosage form that can be administered once daily for a maintenance period of more than 24 h. UPLIFT found that patients in the tiotropium bromide group had significantly better key lung function parameters than controls at all time points during the study cycle, with mean FEV1 and FVC significantly higher than before treatment. Tiotropium improved health-related quality of life, reduced the number of acute exacerbations, significantly delayed the time to first acute exacerbation by a mean of 4.1 months (P<0.01), and significantly reduced the number of acute exacerbations per year (P<0.01), and reduced all-cause mortality by 13%. In addition, tiotropium bromide significantly relieved patients' symptoms of wheezing and shortness of breath, but did not reduce cough and chest tightness. The efficacy of adiponectin (a new generation of inhaled long-acting anticholinergic drugs) has been reported to be comparable to that of tiotropium, with a more rapid onset of action, rapid relaxation of airway smooth muscle, and rapid drug metabolism, reducing the incidence of cardiovascular adverse events.
Theophylline drugs
With the in-depth study of theophylline, the therapeutic effect of theophylline on COPD is no longer limited to the expansion of bronchial smooth muscle, it is recognized that it can not only dilate the bronchus, it also has anti-inflammatory and immunomodulatory effects. More importantly, it can also increase the sensitivity of COPD patients to hormones. And these effects only appear when applied in small doses, which also reduces the chance of adverse reactions.
1. Non-selective PDE inhibitor: It can increase the level of intracellular cyclic adenosine monophosphate and cyclic adenosine monophosphate/cyclic guanosine monophosphate. This reduces the inflammatory process by inhibiting the expression of inflammatory factors, the activation of inflammatory cells, and reducing the release of reactive oxygen species. In addition, theophylline improves cilia clearance. This mechanism is also associated with elevated intracellular levels of cyclic adenosine monophosphate, increased cilia oscillation frequency and water transport across the epithelium. After oral administration of small doses of theophylline, sputum levels of IL-8 and myeloperoxidase were decreased in COPD patients, and the level of LTB4 in sputum was reduced, while the percentage of neutrophils and the level of TNF-a in sputum could be reduced.
2. Adenosine receptor antagonist: At therapeutic doses, theophylline has a significant antagonistic effect on A1 and A2 adenosine receptors, and an insignificant effect on A3 receptors. Thus, it can improve the contraction force and endurance of respiratory muscles, especially the diaphragm, thus improving the effect of alveolar ventilation.
3. Complex histone deacetylase activity: The application of small doses of theophylline can enhance the anti-inflammatory effect of hormones. In addition, theophylline and glucocorticoids have synergistic anti-inflammatory effects, which can significantly enhance the anti-inflammatory effect of glucocorticoids. For COPD patients who have difficulty in controlling symptoms, the combination of low-dose theophylline is more effective than simply increasing the dosage of hormones
Glucocorticoids
It is now accepted that hormones should be used in acute exacerbations of COPD. Systemic use of hormones in stable patients is contraindicated due to their obvious side effects, even in small doses. The role of long-term regular use of inhaled glucocorticoids in the treatment of patients with stable COPD is still controversial. The TORCH study showed that inhaled hormones combined with inhaled long-acting bronchodilators did not further inhibit the decline in FEV1 in patients with stable COPD. However, the use of inhaled hormones in patients with moderate-to-severe COPD in the stable phase reduced the number of acute exacerbations. Although inhaled hormones combined with inhaled long-acting bronchodilators do not significantly reduce the risk of acute exacerbations in COPD (except for moderate exacerbations) compared with long-acting bronchodilators or anticholinergics alone, they may be effective in this index in COPD patients with FEV1 ≤ 40% of predicted values. In addition, it has been shown that triple inhalation therapy (long-acting β2 agonists, long-acting anticholinergics, and glucocorticoids) is superior to long-acting bronchodilators alone in increasing patients’ deep inspiratory volume and reducing severe acute exacerbations in patients with moderate-to-severe COPD.
Antibiotics
Routine use of antibiotics is not required for stable patients. However, newer studies have found that low-dose macrolide antibiotics open up a new therapeutic avenue in addition to anti-infective therapy, namely thanks mainly to significant anti-inflammatory and immunomodulatory effects. The anti-inflammatory effect of azithromycin significantly reduces the number of acute exacerbations and improves the quality of life of patients. Another randomized double-blind study also found that administration of erythromycin (250 mg, BiD) significantly reduced the number of acute exacerbations in COPD patients compared to placebo . In another experimental study on clarithromycin, it prevented smoking-induced emphysema in mice.
Other anti-inflammatory drugs
Phosphodiesterase (PDE) inhibitors
This class of drugs has strong anti-inflammatory and immunomodulatory effects and relaxes airway smooth muscle. The newly marketed second-generation PDE-4 inhibitor, roflumilast, has excellent efficacy and safety. It is used as an alternative drug in the 2011 version of the COPD Global Strategy. The results of a study showed that roflumilast significantly reduced the number of acute exacerbations and improved lung function in patients could slow disease progression.
Leukotriene receptor blockers
Leukotrienes include both cysteine leukotriene (CysLT) and leukotriene B4 (LTB4). Several studies have shown that LTB4 levels are significantly higher in exhaled air condensate, in sputum, and in serum of COPD patients than in controls.
CysLT receptor antagonists: The CysLT receptor antagonists currently in clinical use are montelukast and zallustat, which are mainly used for the treatment of bronchial asthma. Recently, several clinical studies in COPD patients have been conducted to observe their therapeutic effects. A randomized controlled clinical study showed that montelukast significantly improved FVC, FEV1 and arterial partial pressure of oxygen (PaO2), and significantly improved dyspnea scores and quality of life scores in patients, while none of these indicators changed significantly in the control group.
Receptor antagonists: LTB4 is a major chemokine for neutrophils, lymphocytes and macrophages, and one of the important inflammatory factors in COPD. Theoretically, LTB4 receptor antagonists should have better anti-inflammatory effects in response to the inflammation in COPD patients. Several new LTB4 receptor antagonists are in development and have not yet entered full clinical use.
Chemokine inhibitors
is an inflammatory process involving neutrophils, CD8+ T lymphocytes. A variety of chemokines are involved in neutrophil chemotaxis, the major ones being the CXC family, of which interleukin-8 (also known as chemokine CXCL8) is the most prominent member. interleukin-8 levels in sputum of COPD patients are positively correlated with disease severity. A human interleukin-8 monoclonal antibody is in clinical trials. Because the regulation of chemokines in the inflammatory response is extremely complex, there is a limit to the therapeutic effect that can be achieved by single antagonism of a particular chemokine. Several other chemokine inhibitors are currently in the clinical research phase.
Protease inhibitors
Currently, the first protease inhibitor in clinical use is 1-antitrypsin (1-AT). Although alternative treatments to 1-AT have begun to be used in Europe and the United States and are generally well tolerated by patients, there are randomized controlled trials showing that the efficacy of alternative treatments is not definitive. There was only a slight improvement in the extent of emphysema in the trial group and studies have shown that neither significantly improved FEV1 decline .
Statins
Statins are not only widely used lipid-lowering drugs, but they also have some anti-inflammatory activity and are used to play an active role in the prevention and treatment of COPD. Some studies suggest that the use of statins effectively reduces all-cause mortality, frequency of acute exacerbations, and delays the decline of pulmonary function in COPD patients; and improves patients’ exercise tolerance; and the reduction of morbidity and mortality in COPD patients is dose-dependently related to statins. The mechanism is mainly achieved through the following links: inhibition of metalloproteinases; inhibition of inflammatory mediators and cytokines; there are other possible mechanisms to be confirmed by further research, such as: anti-oxidative stress, inhibition of adhesion molecule expression, reduction of C-reactive protein levels, etc.
Other therapeutic drugs
Expectorants (mucolytics)
Patients have a hypersecretory state of airway mucosa with a large amount of secretion, which can easily lead to infection. Expectorants can reduce sputum viscosity, make sputum easy to expel and improve ventilation, but the clinical efficacy is not very precise and is not recommended for routine use. N-acetylcysteine may have antioxidant effects and can reduce the number of acute exacerbations in COPD patients who are not treated with inhaled hormones.
Immunomodulators
They are mainly used in COPD patients with frequent acute exacerbations to enhance the immunity of the body, and may have a role in reducing the severity and frequency of acute exacerbations in COPD patients. Because there are no results of long-term, multicenter clinical studies, they are not recommended for routine use.
Vaccine
Clinical studies have demonstrated that influenza vaccination (but not pneumococcal vaccine) can reduce the risk of death from all causes in COPD patients. Promoting the use of pneumococcal vaccine in COPD patients allows patients to be prevented and treated through passive immunization, thereby reducing the risk of acute exacerbation of COPD or making the infection easier to control. These two vaccines can also be combined to significantly reduce hospital admissions and mortality rates in COPD patients compared with influenza vaccine alone or pneumococcal vaccine alone .
(v) Oxygen therapy
Long-term home oxygen therapy during the stabilization period can improve survival in patients with chronic respiratory failure. Long-term home oxygen therapy should be applied in patients with grade IV, i.e., very severe COPD, with the following specific indications: (1) PaO2 ≤ 55 mmHg or arterial oxygen saturation (SaO2) ≤ 88%, with or without hypercapnia. (2) PaO2″ 55 or SaO2 <89% with pulmonary hypertension, heart failure edema or erythrocytosis (erythrocyte ratio >55%). Long-term home oxygen therapy is usually oxygen inhalation via nasal cannula with a flow rate of 1.0-2.0 L/min, and the duration of oxygen inhalation >15 h/d.
(vi) Rehabilitation therapy
Rehabilitation therapy can improve the mobility and quality of life of patients with progressive airflow limitation, severe dyspnea and little activity, and is an important treatment measure for COPD patients. It includes respiratory physiological treatment, muscle training, nutritional support, psychiatric treatment and education, and other measures.
(vii) Surgical treatment
1.Pulmonary decompression surgery: In patients with indications, it can reduce the degree of dyspnea and improve the lung function after surgery. Preoperative chest CT examination, arterial blood gas analysis and comprehensive evaluation of respiratory function are very important for deciding whether to operate. Removing part of the lung tissue reduces lung overinflation, improves respiratory muscle work, and improves exercise capacity and health status, but does not prolong the patient’s life.
2, lung transplantation: For patients with advanced COPD who are selected appropriately, lung transplantation can improve quality of life and lung function, but it is technically demanding and costly, so it is difficult to promote its application.