Chronic obstructive pulmonary disease: clinical guidelines

List of Abbreviations

BODE - B - body mass index, O - obstruction, D - dyspnea, E - exercise tolerance

CAT - COPD (chronic obstructive pulmonary disease) Assessment Test

COPD - chronic obstructive pulmonary disease

FiO2 - fraction of inspired oxygen

GOLD - Global Initiative for Chronic Obstructive Lung Disease

mMRC - Modified Medical Research Council Dyspnea Scale

MMAD - mass median aerodynamic diameter

PaO2 - partial pressure of oxygen in arterial blood

PaCO2 - partial pressure of carbon dioxide in arterial blood

SGRQ - St. George's Respiratory Questionnaire

V_A/Q - ventilation-perfusion ratio

SaO2 - oxygen saturation of hemoglobin, %

SpO2 - oxygen saturation of hemoglobin determined by pulse oximetry, %

BA – bronchial asthma

BD - bronchodilator test

NOS - not otherwise specified

GCs - glucocorticoids (H02AB)

pMDI - pressurized metered-dose inhaler

LAMA - long-acting muscarinic antagonists (ATC N04A Anticholinergic agents)

LABA - long-acting β₂-agonists (ATC R03AC Selective beta-2-adrenoreceptor agonists)

LABD - long-acting bronchodilators

LTNV - long-term non-invasive ventilation

LTOT – long-term oxygen therapy

DPI - dry powder inhaler (dry powder inhaler devices, code 256560)

IMV - invasive mechanical ventilation

ICS - inhaled corticosteroids (Corticosteroids ATC - R03BA)

SAMA - short-acting muscarinic antagonists (anticholinergic agents; ATC - R03BB)

SABA - short-acting β₂-agonists (selective beta-2-adrenoreceptor agonists; ATC R03AC)

CT — computed tomography

HRCT - high-resolution computed tomography

LHI - pulmonary hyperinflation

NIV - non-invasive ventilation

AE – adverse events

ARF - acute respiratory failure

TLC - total lung capacity

FEV₁ - forced expiratory volume in 1 second

PEF – peak expiratory flow

RCT — randomized controlled trial

FVC - forced vital capacity

CRF - chronic respiratory failure

COPD - chronic obstructive pulmonary disease

Terms and Definitions

Chronic bronchitis is generally defined clinically as the presence of cough with sputum production for at least 3 months in each of 2 successive years.

Emphysema is a syndromic concept characterized by abnormal permanent enlargement of air spaces distal to the terminal bronchioles, accompanied by the destruction of alveolar walls and without obvious fibrosis.

Pulmonary hyperinflation is a pathological increase in the volume of air remaining in the lungs after a normal passive expiration.

Pulmonary hypertension is a clinical syndrome characterized by an elevation in mean pulmonary arterial pressure greater than 25 mm Hg.

Bronchodilators (synonyms: bronchodilating agents, broncholytics) – medications from various pharmacological classes grouped together by their shared ability to relieve bronchospasm by acting on bronchial smooth muscle tone and various regulatory pathways. ATC: Drugs for obstructive airway diseases (R03).

Harmful occupational factor - an occupational factor whose exposure to an employee may lead to occupational disease (Article 209 of the Labor Code of the Russian Federation No. 197-FZ of December 30, 2001).

Hygienic occupational standards - levels of working environment factors which, when exposed daily (except weekends) for 8 hours per day, but not more than 40 hours per week, throughout the entire working career, should not cause diseases or health disorders detectable by modern research methods during work or in the remote periods of life of the present and subsequent generations. Compliance with hygienic standards does not rule out health impairment in individuals with hypersensitivity (Guidelines R 2.2.2006-05).

Industrial aerosol - airborne particles of solid or liquid substances generated during various manufacturing processes.

Industrial dust - airborne particles of solid substances generated during various manufacturing processes.

Maximum allowable concentration - the concentration of a harmful substance which, with daily exposure (except weekends) for 8 hours per day and not more than 40 hours per week over the entire work career, should not cause diseases or health abnormalities detectable by modern research methods during work or in remote periods of life of current and future generations. Exposure to a harmful substance at the MAC level does not exclude health disorders in hypersensitive individuals.

Occupational disease - a disease developed as a result of exposure to risk factors arising from a person's occupational activity (adopted by the 13th International Conference of Labour Statisticians, 1982, Geneva).

Chronic occupational disease - a disease resulting from prolonged exposure of an employee to harmful occupational factor(s).

Work area - a space up to 2 m high above the floor or platform level where permanent or temporary (non-permanent) workstations of employees are located. A permanent workstation is where an employee spends the majority of their working time (more than 50% or more than 2 hours continuously). If work is carried out at various points of the work area, the entire work area is considered the permanent workstation.

Workstation - the place where an employee must be or to which they need to report in connection with their work and which is directly or indirectly under the control of the employer (Article 209 of the Labor Code of the Russian Federation No. 197-FZ of December 30, 2001).

Occupational hygiene characteristics of working conditions - a description of the sanitary state of the production environment with a conclusion on the degree of its compliance with hygienic requirements and standards established by sanitary legislation.

Working conditions - the combination of factors of the working environment and the labor process that affect the working capacity and health of the employee (Article 209 of the Labor Code of the Russian Federation dated December 30, 2001, No. 197-FZ).

Occupational chronic obstructive pulmonary disease - a disease characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar pathology caused by an abnormal inflammatory response of the lung tissue to harmful particles or gases in the working environment.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, sputum production) and exacerbations due to airway damage (bronchitis, bronchiolitis) and/or alveoli (emphysema), which cause persistent, often progressive airflow limitation [1]. Exacerbations and comorbid conditions are an integral part of the disease and contribute significantly to the clinical picture [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Risk factors

Both endogenous factors and environmental exposures play a role in the development of COPD. Smoking remains the leading cause of COPD. According to some estimates, in industrial countries smoking contributes to about 80% of male and 60% of female mortality, while in developing countries it contributes 45% of male and 20% of female mortality [3]. In developing countries, the use of biomass for cooking and space heating has a significant damaging effect on the respiratory system.

Occupational hazards, passive smoking, and outdoor air pollution can also play an etiological role. In Europe and North America, the contribution of workplace air pollution to the development of COPD is estimated at 15-20% [2]. This contribution is likely to be significantly higher in countries where occupational hazards are less strictly controlled. Workplace air pollution with biological and mineral dust, gases, and smoke (based on patients' self-reports) was associated with a higher prevalence of COPD [4].

Endogenous risk factors include genetic, epigenetic, and other patient characteristics such as bronchial hyperresponsiveness and a history of bronchial asthma (BA) [5], as well as a history of severe respiratory infections in childhood. At the same time, bronchial hyperresponsiveness is a risk factor for COPD even in the absence of BA [6, 7]; there is also evidence that chronic bronchitis symptoms may increase the risk of COPD [8, 9].

Congenital alpha-1 antitrypsin deficiency is an autosomal recessive hereditary disease predisposing to COPD, detected in less than 1% of cases [10, 11]. Other genetic risk factors for COPD are complex, and their contribution to disease development is currently not fully understood. The development of COPD is associated with polymorphism of multiple genes, but only a few of these associations have been demonstrated in independent population samples [12]. The involvement of various etiological factors in the development of COPD is presented in Table 1 [1].

Table 1. Etiological factors in the development of COPD.

Pathogenesis

Airway inflammation

COPD is characterized by an increase in the number of neutrophils, macrophages, and T lymphocytes (especially CD8+) in various parts of the airways and lungs. An increased number of inflammatory cells in COPD patients is found in both proximal and distal airways. During an exacerbation, some patients may show an increase in the number of eosinophils.

Oxidative stress, i.e., the release of increased amounts of free radicals in the airways, has a powerful damaging effect on all structural components of the lungs and leads to irreversible changes in the pulmonary parenchyma, airways, and pulmonary vessels.

An important role in the pathogenesis of COPD is played by the proteinase-antiproteinase imbalance, which results from both increased production or activity of proteinases and decreased activity or production of antiproteinases. This imbalance is often a consequence of inflammation induced by exposure to noxious agents.

Airflow limitation and pulmonary hyperinflation

Expiratory airflow limitation is the main pathophysiological disorder in COPD. It is based on both reversible and irreversible components. Irreversible components include:

• Fibrosis and narrowing of the airway lumen;

• Loss of lung elastic recoil due to alveolar destruction;

• Loss of alveolar support for the lumen of small airways.

Reversible causes include:

• Accumulation of inflammatory cells, mucus, and plasma exudate in the bronchi;

• Contraction of bronchial smooth muscle;

• Pulmonary hyperinflation - PHI (i.e., increased lung volume/airiness).

PHI is caused by incomplete emptying of alveoli during expiration due to the loss of lung elastic recoil (static PHI) or insufficient expiratory time under conditions of severe expiratory airflow limitation (dynamic PHI).

According to recent studies, lumen narrowing and a decrease in the number of terminal bronchioles precede the development of emphysematous alveolar destruction in both centriacinar and panacinar emphysema.

PHI is reflected by an increase in lung volumes (functional residual capacity, residual volume, total lung capacity (TLC)) and a decrease in inspiratory capacity. Dynamic PHI increases during physical exertion because the respiratory rate increases during exertion, which shortens expiratory time and causes an even greater fraction of lung volume to be trapped at the alveolar level.

Adverse manifestations of PHI are:

• flattening of the diaphragm, leading to impaired function of the diaphragm and other respiratory muscles;

• limitation of the ability to increase tidal volume during physical exertion;

• increase in hypercapnia during physical exertion;

• creation of intrinsic positive end-expiratory pressure;

• increase in the elastic load on the respiratory system.

Functional parameters reflecting PHI, in particular changes in inspiratory capacity, have a very high correlation with dyspnea and exercise tolerance in patients.

Gas exchange disorders

Severe COPD is characterized by the development of hypoxemia and hypercapnia. The main pathogenetic mechanism of hypoxemia is impaired ventilation-perfusion ratio—V_A/Q balance (V_A - alveolar ventilation, Q-cardiac output). Areas of the lungs with a low V_A/Q ratio are the major contributors to hypoxemia. The presence of areas with an elevated V_А/Q ratio leads to increased physiological dead space, as a result of which an increase in total pulmonary ventilation is required to maintain a normal partial pressure of carbon dioxide in arterial blood (PaCO₂). An increase in blood flow shunting does not usually occur in COPD, except in particularly severe cases of exacerbation requiring respiratory support.

Pulmonary hypertension

Pulmonary hypertension may develop already in late stages of COPD due to hypoxia-induced spasm of small pulmonary arteries, which ultimately leads to structural changes: intimal hyperplasia and later hypertrophy/hyperplasia of the smooth muscle layer. An inflammatory reaction similar to that in the airways, as well as endothelial dysfunction, is observed in the vessels. Progressive pulmonary hypertension can lead to right ventricular hypertrophy and ultimately to right ventricular failure (cor pulmonale).

Systemic effects

A characteristic feature of COPD is the presence of systemic effects, the main ones being systemic inflammation, cachexia, skeletal muscle dysfunction, osteoporosis, cardiovascular events, anemia, depression, etc. The mechanisms underlying these systemic manifestations are quite diverse and not yet fully understood. It is known that hypoxemia, smoking, sedentary lifestyle, systemic inflammation, and others play an important role among them.

1.3 Epidemiology of the Disease or Condition

COPD is a disease that places a heavy burden on society and is acquiring increasing social significance.

Currently, COPD is one of the most common human diseases, driven by ongoing environmental pollution, increasing tobacco smoking, and recurrent respiratory infections. According to WHO data, in 2019, 212.3 million people worldwide suffered from COPD. COPD caused 3.3 million deaths, and the DALYs indicator was 74.4 million. The prevalence of COPD was 2638.2 per 100,000 population, and mortality was 42.5 per 100,000 population [13]. In Russia, according to the Ministry of Health, 2.4 million people suffer from COPD. In reality, according to epidemiological studies by the Russian Respiratory Society, the figure is about 11 million, including undiagnosed cases.

COPD is the 3rd leading cause of death worldwide, with approximately 2.8 million people dying from COPD annually, accounting for 4.8% of all deaths [14]. In Europe, COPD mortality varies significantly: from 0.2 per 100,000 population in Greece, Sweden, Iceland, and Norway. The primary cause of death for COPD patients is the progression of the underlying disease. In Russia, according to Rosstat, the proportion of COPD in the morbidity structure is 14.1%, and in the mortality structure, it is 26%. About 50-80% of COPD patients die from respiratory causes: either during COPD exacerbations, from lung tumors (from 0.5 to 27%), or from other respiratory problems.

COPD and impaired pulmonary function are independently associated with an increased risk of cardiovascular events [224, 225]. A decrease in lung function (FEV₁) is as strong a risk factor for cardiovascular mortality as major cardiovascular risk factors. According to The Lung Health Study (5887 smokers aged 35–60 years with moderate bronchial obstruction), a 10% decrease in FEV₁ was associated with a 14% increase in overall mortality, a 28% increase in cardiovascular mortality, and a 20% increase in the risk of developing coronary artery disease [226].

1.4 Features of Coding the Disease or Condition

Chronic obstructive pulmonary disease (J.44):

J44.0 - Chronic obstructive pulmonary disease with acute lower respiratory infection (including pneumonia)

J44.1 - Chronic obstructive pulmonary disease with acute exacerbation, unspecified (without pneumonia)

J44.8 - Other specified chronic obstructive pulmonary disease

Chronic bronchitis: asthmatic (obstructive) NOS, emphysematous NOS, obstructive NOS

J44.9 - Chronic obstructive pulmonary disease, unspecified

Chronic obstructive pulmonary disease NOS:

Z57.2 - Occupational exposure to dust

Z57.3 - Occupational exposure to other air pollutants

Z57.4 - Occupational exposure to toxic agents in agriculture

Z57.5 - Occupational exposure to toxic agents in other industries

1.5 Classification of the disease or condition

Previously, COPD classification was based on lung function parameters derived from post-bronchodilator forced expiratory volume in 1 second (FEV₁) values, identifying 4 stages of the disease (Table 2).

Table 2. Spirometric classification of bronchial obstruction in COPD according to GOLD 2023 (FEV1/FVC <0.7 — all values are post-bronchodilator)

In the 2023 revision of the GOLD (Global Initiative for Chronic Obstructive Lung Disease) document, a new assessment of COPD categories was proposed [1]. It takes into account not only the severity of bronchial obstruction (degree of airflow limitation) based on spirometry results (unforced respiratory volumes and flows), but also clinical data on the patient: the number and severity of COPD exacerbations per year and the severity of clinical symptoms according to the mMRC (modified Medical Research Council Dyspnea Scale) and the CAT (COPD Assessment Test). COPD categories according to the GOLD 2023 recommendations are as follows (see Fig. 1). The criteria for assigning patients to categories A and B have not changed. Groups C and D were combined into group E to emphasize the irrelevance of symptom severity in the stable state for initiating therapy in patients at high risk of exacerbations. The authors of GOLD 2023 acknowledge that this proposal needs to be confirmed by clinical studies.

Fig. 1. Diagnostic criteria and COPD categories [1].

To assess the risk of COPD exacerbations, it is necessary to consider anamnestic data on the frequency of disease exacerbations, including those requiring hospitalization over the past 12 months.

If a patient experienced even one exacerbation leading to hospitalization (i.e., a severe exacerbation) in the previous year, they should be classified as high risk.

Taking the above into account, the COPD diagnosis may look as follows:

"Chronic obstructive pulmonary disease..." followed by the assessment of:

• severity of airflow limitation (I–IV);

• severity of clinical symptoms: high (CAT ≥10, mMRC ≥2), low (CAT <10, mMRC <2);

• frequency of exacerbations: infrequent (0–1), frequent (≥2); including those requiring hospitalization;

• COPD phenotype (if applicable);

• complications (respiratory failure, pulmonary hypertension, etc.);

• comorbidities.

COPD phenotypes (Table 3):

1. Predominantly bronchitis phenotype.

2. Predominantly emphysematous phenotype.

Table 3. Clinical and laboratory features of the two main COPD phenotypes.

COPD-asthma overlap

Combination of asthma and COPD features:

• age over 35 years, with a long-term history of either disease,

• COPD more frequently develops in patients with preexisting asthma than vice versa,

• the overlap of COPD in asthma is associated with prolonged exposure to COPD risk factors (smoking, occupational or domestic hazards),

• long-term follow-up of patients reveals progressive respiratory failure,

• decreased efficacy of inhaled corticosteroids,

• reduced exercise tolerance.

Frequent exacerbator COPD phenotype refers to patients with frequent exacerbations (2 or more exacerbations in the previous year, or 1 or more exacerbations leading to hospitalization). The importance of this phenotype is determined by the fact that patients recover from an exacerbation with diminished lung function parameters, and the frequency of exacerbations directly affects patient life expectancy, requiring a personalized approach to treatment.

1.6 Clinical presentation of the disease or condition

COPD exacerbation

COPD exacerbation is an event characterized by increased dyspnea and/or cough with sputum, worsening within ≤14 days:

• may be accompanied by tachypnea and/or tachycardia,

• is often associated with increased local and systemic inflammation caused by respiratory tract infections, pollutants, or other injuries to the airway system [1].

The development of exacerbations is a characteristic feature of the course of COPD. COPD exacerbation is one of the most frequent reasons for patients to seek emergency medical care. Frequent exacerbation development in COPD patients leads to prolonged deterioration (up to several weeks) in respiratory function and gas exchange parameters, more rapid disease progression, a significant decrease in patient quality of life, and is associated with substantial economic healthcare costs. Moreover, COPD exacerbations lead to decompensation of concomitant chronic conditions. Severe COPD exacerbations are the leading cause of patient death. Within the first 5 days from the onset of an exacerbation, the risk of acute myocardial infarction increases by more than 2-fold.

GOLD 2023 proposes an updated definition and severity classification of COPD exacerbations, termed the Rome Proposal of the joint Task Force [15] (Fig. 2).

* if determinable

Fig. 2. Classification of COPD exacerbation severity [15].

This classification differs in that severity criteria are based on specific clinical markers rather than healthcare resource utilization levels. It is noted that COPD exacerbations most commonly occur in the autumn and winter months.

The most frequent causes of COPD exacerbations are bacterial and viral respiratory infections and atmospheric pollutants, although the cause remains unidentified in approximately 20-30% of cases. Among bacteria in COPD exacerbations, non-typable Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis play the major role. Patients with severe COPD exacerbations may more frequently harbor gram-negative Enterobacteriaceae and Pseudomonas aeruginosa. Rhinoviruses can also play a significant role in the etiology of COPD exacerbations as one of the most frequent pathogens of acute respiratory viral infections. Conditions that may mimic exacerbations and/or worsen their course include pneumonia, pulmonary embolism, congestive heart failure, arrhythmias, pneumothorax, and pleural effusion. These conditions should be differentiated from exacerbations and treated appropriately if present.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of COPD should be established based on the patient's complaints and medical history, the results of functional diagnostic tests, chest computed tomography (A06.09.005), and the exclusion of other diseases [1].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

When establishing a diagnosis of COPD, the following diagnostic criteria should be considered for early diagnosis:

1. Respiratory impairment (dyspnea):

• progressive (worsens over time),

• typically worsens with physical exertion,

• persistent.

2. Chronic cough:

• may be episodic and may be non-productive, accompanied by recurring wheezing.

3. Chronic sputum production:

• any chronic sputum production may indicate COPD.

4. Recurrent lower respiratory tract infections.

5. Risk factors:

• genetic factors, congenital respiratory malformations, and others,

• tobacco smoking (including popular local smoking methods),

• kitchen smoke and domestic fuel smoke,

• occupational dust pollutants and chemicals.

6. Family history of COPD and/or childhood risk factors:

• low birth weight, childhood respiratory infections.

7. Functional respiratory parameters:

• FEV1/FVC <0.7 or less than the lower limit of normal after bronchodilator use, or

• annual FEV1 decline >60 ml/year, or

• DLCO decrease <80% of predicted.

8. Chest CT:

• small airway obstruction or wall thickening,

• emphysema (>5%).

2.1 Complaints and Anamnesis

The main symptoms of COPD are dyspnea on exertion, reduced exercise tolerance, and chronic cough [16].

The following criteria must be applied to all patients:

• In all patients with suspected COPD, it is recommended to use the modified mMRC scale (Appendix G1) to assess the severity of dyspnea and determine the category (A, B, E) [17].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

• In all patients with suspected COPD, it is recommended to use the CAT questionnaire for a comprehensive assessment of COPD symptoms, as an alternative method for evaluating dyspnea and determining the category (A, B, E) (Appendix G2) [18].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: The CAT scale better reflects the impact of COPD on daily life and patient well-being, and correlates closely with health status.

• In all patients with suspected COPD, it is recommended to assess smoking status during history taking and calculate the smoking index to quantify this risk factor [1].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• In all patients with suspected COPD, it is recommended to evaluate occupational history and career path to identify occupational risk factors and occupational COPD [233-243].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: The occupational history should include data on employment involving exposure to industrial aerosols of various compositions—dusts, gases, vapors, and fumes throughout the entire occupational career. Data on exposure to other adverse occupational factors that may exacerbate the negative impact of industrial aerosols on the bronchopulmonary system, such as physical overexertion and an adverse microclimate, must also be collected.

• In all patients with suspected COPD, it is recommended to assess the frequency of previous COPD exacerbations during history taking to evaluate the risk of future exacerbations and determine the category (A, B, E) [19].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: The best predictors of frequent exacerbations (2 or more per year) are the frequency and severity of previous exacerbations and the severity of COPD.

• In all patients with suspected COPD, it is recommended to conduct an evaluation to identify comorbidities that increase the risk of COPD exacerbations and mortality [20].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comments: Since COPD typically develops in middle-aged individuals with a long smoking history, these patients often have various smoking- and age-related conditions. COPD is frequently accompanied by cardiovascular diseases, skeletal muscle dysfunction, osteoporosis, lung cancer, and depression.

The COPD Assessment Questionnaire (Appendix G3) may provide certain assistance in establishing the diagnosis.

Comment: COPD is a pulmonary disease associated with a significantly increased risk of geriatric syndromes and frailty syndrome, which complicates adequate management of COPD, impairs quality of life, and increases the risk of hospitalization, loss of autonomy, and death [1–4]. Achieving COPD control is essential for the prevention and treatment of frailty. Screening for frailty syndrome in elderly and senile patients with COPD and their long-term follow-up should be carried out in accordance with the clinical guidelines for "Frailty" and other clinical guidelines in the field of "geriatrics" depending on the identified geriatric syndromes.

2.2 Physical Examination

• All patients with suspected COPD are recommended to undergo a physical examination to identify signs of bronchial obstruction, emphysema, respiratory failure, assess respiratory muscle function, and rule out comorbidities [1].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Physical signs of bronchial obstruction and air trapping are usually detected in patients with already severe COPD. Although physical examination is an important part of diagnosis in general, it has low sensitivity and specificity for diagnosing mild to moderate COPD.

2.3 Laboratory Diagnostics

2.4 Instrumental Diagnostics

Functional Diagnostics

• All patients with suspected COPD are recommended to undergo unforced respiratory volume and flow testing (spirometry) to detect and assess the severity of airway obstruction (for testing methodology, see Appendix G4) [1, 21].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Unforced respiratory volume and flow testing (spirometry) is the main method for diagnosing and documenting changes in pulmonary function in COPD. The classification of COPD by the severity of obstructive disorders is based on the parameters of this test.

• In all patients with suspected COPD, unforced respiratory volume and flow testing (spirometry) is recommended to confirm the diagnosis of COPD; the criterion is a post-bronchodilator FEV1/FVC <0.7 confirming expiratory airflow limitation [1] (Fig. 3).

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Using this fixed physiological criterion for all age groups may lead to overdiagnosis compared to using the lower limit of normal criterion in elderly patients [22, 23].

Fig. 3. Changes in unforced respiratory volume and flow parameters (spirometry) during obstruction.

• In all patients with suspected COPD who show initial signs of bronchial obstruction (FEV₁/FVC <0.7), it is recommended to perform a bronchodilator test to determine the post-bronchodilator value and the degree of reversibility of obstruction under the influence of bronchodilators (Appendix A3) [24].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)

With the progression of bronchial obstruction, there is a further decrease in expiratory flow, an increase in air trapping and lung hyperinflation, which leads to a decrease in FVC values.

• To rule out mixed obstructive-restrictive disorders in all patients with suspected COPD and decreased FVC, it is recommended to determine TLC by body plethysmography [25, 26].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• In all patients with suspected COPD, it is recommended to use TLC and diffusing capacity of the lungs to assess the severity of emphysema [25, 26].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment. Determination of DLco is a useful tool for assessing the gas exchange capacity of the respiratory system and complements spirometry data. In smokers without airflow limitation, DLco <80% indicates an increased risk of developing COPD over time.

DLco determination should be performed in every COPD patient with symptoms (dyspnea) that do not correspond to the existing degree of airflow limitation.

Every COPD patient with symptoms (dyspnea) inconsistent with the existing degree of airflow limitation must be evaluated to rule out chronic heart failure (CHF). COPD is recognized as a risk factor for the clinical variant of CHF with preserved left ventricular ejection fraction (LVEF). It is necessary to conduct a thorough cardiac history analysis, examine clinical signs and symptoms of CHF (pulmonary congestion, jugular venous distention, edema), and evaluate laboratory and instrumental tests (electrocardiography (ECG), echocardiography (EchoCG), chest X-ray (NMEC code – A06.09.007), natriuretic peptides – BNP and NT-proBNP) to confirm/exclude the diagnosis of CHF [227, 228].

• In all patients with COPD, it is recommended to use pulse oximetry to assess arterial oxygen saturation (SaO₂) [27].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: Hypoxemia is a major problem in patients with COPD, determining exercise intolerance and disease prognosis. If a patient with COPD presents with erythrocytosis, hypoxemia should be suspected.

• To determine exercise tolerance in patients with COPD, it is recommended to perform exercise testing, such as the 6-minute walk test or, in certain cases, cycle ergometry [28, 29].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Radiological methods

Comments: Chest X-ray lacks sufficient sensitivity to detect moderate to medium severity emphysema.

Comments: HRCT of the chest may be performed for the differential diagnosis of COPD.

• Chest HRCT (including with the use of artificial intelligence) is recommended for COPD patients with severe pulmonary emphysema to determine the appropriateness of lung volume reduction surgery [263].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Chest HRCT is the most sensitive and specific method for detecting, assessing the severity, and morphological characterization of pulmonary emphysema. High-resolution computed tomography of the chest allows the detection of early signs of emphysematous remodeling of lung tissue.

2.5 Other Procedures

• In case of increased daytime sleepiness, it is recommended to perform nocturnal pulse oximetry for primary screening diagnosis of sleep-related breathing disorders, followed by diagnosis confirmation using polysomnography or cardiorespiratory monitoring techniques [32, 33].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

The main prognostic factors in a patient with COPD are the degree of bronchial obstruction (FEV₁), dyspnea severity, 6-minute walk test distance, and body mass index [34].

Differential Diagnosis of COPD

At certain stages of COPD development, especially at the initial encounter with a patient, it becomes necessary to differentiate COPD from a number of diseases with similar symptoms: asthma, chronic (non-obstructive) bronchitis, lower respiratory tract infection (including tuberculosis), lung cancer, interstitial lung diseases, and cardiovascular diseases. The main distinguishing features of these nosologies are presented in Table 4.

Table 4. Features for differentiating COPD from other diseases.

• When performing differential diagnosis of asthma and COPD in a population of patients with spirometric signs of expiratory airflow limitation, it is recommended to consider the clinical presentation, smoking history, comorbidities, and family history [35].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Differentiating between asthma and COPD is a common diagnostic challenge. Although the same medications are often used to treat these conditions, they differ in etiology, pathogenesis, and prognosis.

COPD and asthma are frequently found in the same patient. In smoking patients with asthma, cellular components of inflammation may be similar to those in patients with COPD.

• Performing differential diagnosis of asthma and COPD in a population of patients with spirometric signs of expiratory airflow limitation based solely on the results of the bronchodilator reversibility test during spirometry is not recommended [24, 35, 36].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: The bronchodilator test during spirometry does not reliably differentiate asthma from COPD, as patients with asthma do not always exhibit significant reversibility of bronchial obstruction, whereas approximately 25-50% of patients with COPD demonstrate significant reversibility.

• If pulmonary function normalizes as a result of treatment with inhaled corticosteroids (ICS) (R03BA), e.g., budesonide** (R03BA02), it is recommended to reject the diagnosis of COPD in favor of asthma [1, 37].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: If ICS treatment has not led to a significant change in pulmonary function, COPD is a more likely diagnosis than asthma.

ICS treatment does not always differentiate between asthma and COPD, as a number of patients with COPD show favorable responses to ICS administration. On the other hand, in some patients with asthma, ICS monotherapy does not cause improvement.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Goals of COPD therapy

The goals of COPD treatment can be divided into 4 main groups:

• Relief of symptoms and improvement in quality of life;

• Reduction of future risks, i.e., prevention of exacerbations;

• Slowing the progression of the disease;

• Reduction of mortality.

COPD therapy includes pharmacological and non-pharmacological approaches. Pharmacological treatments include bronchodilators (drugs for obstructive airway diseases), combinations of ICS and long-acting bronchodilators (LABAs), phosphodiesterase-4 inhibitors, theophylline, as well as influenza and pneumococcal vaccination.

Non-pharmacological methods include smoking cessation, pulmonary rehabilitation, oxygen therapy, respiratory support, and surgical treatment.

Therapy for COPD exacerbations is considered separately.

3.3 Conservative Management

When treating patients with stable COPD, it is necessary to [1]:

• prescribe a short-acting bronchodilator (drugs for obstructive airway diseases) for as-needed use,

• provide smoking cessation advice,

• train the patient in the correct use of inhalers,

• prescribe therapy in accordance with clinical guidelines,

• if SpO2 <88% recommend long-term oxygen therapy (LTOT),

• recommend influenza and pneumococcal vaccination.

Smoking cessation

• Smoking cessation is recommended for all patients with COPD [38, 39].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Smoking cessation is the most effective intervention with a major impact on COPD progression [38]. Routine physician advice leads to smoking cessation in 7.4% of patients (2.5% higher than controls), while a 3-10 minute counseling session raises the cessation rate to about 12%. With greater time investment and more complex interventions including skill-building, problem-solving training, and psychosocial support, the cessation rate can reach 20-30% [39].

• In the absence of contraindications, to support smoking cessation efforts, it is recommended to prescribe pharmacotherapy for tobacco dependence [40-45].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: Pharmacotherapy effectively supports smoking cessation efforts. First-line drugs for tobacco dependence include varenicline and nicotine. The combination of physician advice, support groups, skill training, and nicotine replacement therapy results in 1-year smoking cessation in 35% of cases, with 22% remaining non-smokers at 5 years [46].

Principles of pharmacotherapy for stable COPD

Pharmacological classes of drugs used in COPD therapy are presented in Table 5.

Table 5. Pharmacological classes of drugs used in COPD therapy.

Note: SABA – short-acting β₂-agonists (ATC R03AC Selective beta-2-adrenoreceptor agonists), SAMA – short-acting muscarinic antagonists (ATC R03BB Anticholinergics), LABA – long-acting β₂-agonists (ATC R03AC Selective beta-2-adrenoreceptor agonists), LAMA – long-acting muscarinic antagonists (ATC R03BB Anticholinergics).

*Dosing regimens are subject to discussion.

• When prescribing pharmacotherapy, it is recommended to aim for symptom control and reduction of future risks, i.e., COPD exacerbations and mortality (Table 6) [1, 16].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Table 6. Use of various pharmacological agents to achieve COPD therapy goals.

Comments: The decision to continue or discontinue treatment should be made based on the reduction of future risks (exacerbations).

Studies have demonstrated the superiority of LAMAs in reducing the risk of exacerbations compared to placebo and LABAs [47-50]. More extensive evidence proving a reduction in the risk of COPD exacerbations is available for fixed LAMA/LABA combinations compared to LAMA or ICS/LABA monotherapy [51-55], and for ICS/LAMA/LABA combinations compared to ICS/LABA and LAMA/LABA [56, 57]. Reliable data have been obtained on the reduction of mortality risk in COPD as a result of ICS/LAMA/LABA treatment [58-60].

Drugs for obstructive airway diseases (bronchodilators)

Bronchodilators include selective beta-2-adrenoreceptor agonists and anticholinergics, comprising short-acting (duration of effect 3–6 hours) and long-acting drugs (duration of effect 12–24 hours), Table 7.

Table 7. Pharmacokinetic characteristics of bronchodilators (drugs for obstructive airway diseases).

• All patients with COPD are recommended to be prescribed short-acting bronchodilators (drugs for obstructive airway diseases) for as-needed use [61].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: The use of short-acting bronchodilators (drugs for obstructive airway diseases) on an as-needed basis is also possible in patients receiving LABD treatment. At the same time, regular use of high doses of short-acting bronchodilators, including via a nebulizer, in patients receiving LABD is not justified and should be resorted to only in the most complex cases. In such situations, it is necessary to comprehensively assess whether the prescription of maintenance (baseline) therapy matches the severity of the disease and whether the patient is able to perform inhalations correctly.

Selective β2-agonists (ATC R03AC Selective beta-2-adrenoreceptor agonists).

• For the treatment of COPD, it is recommended to use the following long-acting β₂-agonists (LABAs): formoterol**, indacaterol**, (Table 7) [62-65].

GCR ALEL 1Grade of Recommendation A (Level of Evidence – 1)

Comments: In terms of their effect on FEV₁ and dyspnea, indacaterol** is at least not inferior to formoterol** and tiotropium bromide**. In terms of its effect on the risk of moderate/severe exacerbations, indacaterol** is inferior to tiotropium bromide** [66, 67].

• When treating COPD patients with comorbid cardiovascular diseases, it is recommended to assess the risk of cardiovascular complications before prescribing LABAs [68].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Activation of cardiac β-adrenoreceptors by β₂-agonists (selective beta-2-adrenoreceptor agonists) may theoretically cause ischemia, heart failure, arrhythmias, and increase the risk of sudden death. However, controlled clinical trials in COPD patients have not shown an increased incidence of arrhythmias, cardiovascular mortality, or all-cause mortality with the use of β₂-agonists (selective beta-2-adrenoreceptor agonists) [69, 70]. Unlike asthma, LABAs can be used without ICS in the treatment of COPD [69, 70].

Anticholinergics

• For the treatment of COPD, it is recommended to use the following long-acting muscarinic antagonists (LAMAs):

- tiotropium bromide** [71-73],

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

- aclidinium bromide**, glycopyrronium bromide** [74-77] (Table 7).

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: Tiotropium bromide has the strongest evidence base among LAMAs**. Tiotropium bromide** increases lung function, relieves symptoms, improves quality of life, and reduces the risk of COPD exacerbations [72, 73].

Aclidinium bromide** and glycopyrronium bromide** improve lung function and quality of life, and reduce the need for rescue medication [74-77].

In studies lasting up to 1 year, aclidinium bromide** and glycopyrronium bromide** reduced the risk of COPD exacerbations [74, 76], but long-term studies lasting more than 1 year, similar to those with tiotropium bromide**, have not been conducted to date.

Inhaled anticholinergics are generally well tolerated, and adverse events (AEs) occur relatively rarely with their use.

• In patients with COPD and comorbid cardiovascular diseases, the use of LAMAs is recommended [72, 73].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: While short-acting muscarinic antagonists (SAMAs) have been suspected of causing cardiac AEs, no reports of an increased incidence of cardiac AEs have been received for LAMAs [78]. In the 4-year UPLIFT study, patients treated with tiotropium bromide** experienced significantly fewer cardiovascular events and lower overall mortality compared to the placebo group [72]. In the TIOSPIR study (mean treatment duration 2.3 years), tiotropium bromide** delivered via a soft mist inhaler demonstrated high safety, with no differences from tiotropium bromide** in a dry powder inhaler regarding mortality, serious cardiac AEs, and COPD exacerbations [73].

LABA monotherapy may be prescribed as initial treatment to patients with mild COPD symptoms [1].

Bronchodilator combinations (drugs for obstructive airway diseases)

• In COPD patients with pronounced symptoms, as initial therapy, it is recommended to combine bronchodilators (drugs for obstructive airway diseases) with different mechanisms of action to achieve greater bronchodilation and symptom relief [79-81].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: The combination of a LAMA with a LABA improves FEV₁ to a greater extent than either monocomponent alone [79, 80].

• For the treatment of COPD, it is recommended to use fixed LAMA/LABA combinations: vilanterol + umeclidinium bromide**, glycopyrronium bromide + indacaterol**, olodaterol + tiotropium bromide**, aclidinium bromide + formoterol** [82-90].

GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)

Comments: These combinations have shown superiority over placebo and their individual monocomponents in their effect on trough FEV₁, dyspnea, and quality of life, while being comparable in safety [83-90]. When compared with tiotropium bromide**, all LAMA/LABA combinations demonstrated superiority in their effect on lung function and quality of life. Regarding the effect on lung hyperinflation (LH), only olodaterol + tiotropium bromide** was significantly superior to tiotropium bromide monotherapy [90].

At the same time, LAMA/LABA combinations showed no superiority over tiotropium bromide** monotherapy in terms of their effect on the risk of moderate/severe COPD exacerbations [83, 88, 91].

Combinations of inhaled corticosteroids (ATC: R03BA) and long-acting bronchodilators (ICS/LAMA/LABA – drugs for the treatment of obstructive airway diseases)

• If there are indications for prescribing ICS, it is recommended to prefer fixed ICS/LAMA/LABA combinations, which have proven advantages over ICS/LABA [1].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: before initiating ICS/LAMA/LABA therapy, it is advisable to perform a complete blood count (differential white blood cell count) (B03.016.003).

Three fixed ICS/LAMA/LABA combinations are registered in the Russian Federation (vilanterol + umeclidinium bromide + fluticasone furoate**, budesonide + glycopyrronium bromide + formoterol, and beclometasone + glycopyrronium bromide + formoterol).

• For COPD patients without signs of asthma who are receiving ICS/LABA therapy and have good control of symptoms and exacerbations, ICS/LABA therapy may be continued [1]. According to international COPD management guidelines, the threshold determining sensitivity to ICS is a peripheral blood eosinophil count of 100 cells per 1 µL.

The relationship between the effects of blood eosinophilia levels and ICS is consistent; no or minor effects are observed at lower eosinophil values, with an enhancement of effects at higher eosinophil counts. Patients with infectious exacerbations and/or an eosinophil count of less than 100 cells/µL are switched back to LAMA/LABA therapy, and the administration of mucolytic drugs, roflumilast, or azithromycin** is considered. In case of recurrent exacerbations and/or an eosinophil count ≥100 cells/µL, ICS/LAMA/LABA therapy should be continued. The baseline therapy must be reassessed at least once a year to confirm its rationale. At the same time, the blood eosinophil count cannot be used as an independent biomarker without considering the risk of disease exacerbation and the risk of adverse ICS effects [92].

The response of COPD patients to ICS treatment cannot be predicted based on the response to systemic (oral) GCS treatment [93, 94].

Adverse effects of ICS include oral candidiasis and dysphonia. There is evidence of an increased risk of pneumonia, osteoporosis, and fractures with the use of ICS and ICS/LAMA/LABA combinations. The risk of pneumonia in COPD patients is a class effect of ICS, manifested when using various drugs of this group [95]. Initiation of ICS treatment was accompanied by an increased risk of diabetes mellitus in patients with respiratory pathology [96].

In asthma, therapeutic and adverse effects of ICS depend on the dose used; a similar trend exists in COPD [97]. In long-term studies of the previous decade, medium and high doses of ICS were used [98], but in recent years, low doses of ICS are more frequently used for maintenance therapy in COPD patients, which is more rational from the efficacy/safety ratio perspective [57, 59, 99]. When using extrafine ICS (MMAD <2 µm), the risk of pneumonia is significantly reduced by 40% (p=0.011) compared to ICS with an MMAD of 2–4 µm [100].

A meta-analysis using data from 4 randomized clinical trials involving 21,809 COPD patients showed that the vilanterol + umeclidinium bromide + fluticasone furoate** combination has a better efficacy profile compared to the budesonide + glycopyrronium bromide + formoterol and beclometasone + glycopyrronium bromide + formoterol combinations; however, the best combined efficacy/safety profile was characterized by the beclometasone + glycopyrronium bromide + formoterol combination with an extrafine ICS delivery form [101, 102]. The results of this meta-analysis are inconsistent with 4 other network meta-analyses indicating comparable efficacy of triple therapy in COPD patients regarding the effect on exacerbation frequency [56].

• For COPD patients with a high risk of exacerbations and a peripheral blood eosinophil count >300 cells/µL, triple therapy with a fixed ICS/LAMA/LABA combination is recommended as the only pharmacotherapy shown to reduce mortality in COPD in clinical trials [58–60].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comment: Two large one-year randomized controlled trials (IMPACT and ETHOS) provided reliable evidence of reduced mortality in COPD as a result of treatment with fixed triple combinations of vilanterol + umeclidinium bromide + fluticasone furoate** and budesonide + glycopyrronium bromide + formoterol compared with fixed dual combinations of umeclidinium bromide + vilanterol by 28% and compared with glycopyrronium bromide + formoterol by 49%, respectively [58, 59]. The results of the pooled analysis of data from the TRILOGY, TRINITY, and TRIBUTE studies showed a trend towards a 29% reduction in overall mortality (without reaching statistical significance, p=0.066) in COPD patients as a result of one-year therapy with beclometasone + glycopyrronium bromide + formoterol compared with glycopyrronium bromide + indacaterol therapy, and a 35% reduction in non-respiratory (mainly cardiac) causes (p=0.037) compared with tiotropium bromide monotherapy and glycopyrronium bromide + indacaterol** [60].

Evidence supporting reduced mortality with pharmacotherapy and non-pharmacological treatment in COPD patients (Appendix B.5).

• Patients with mild COPD symptoms, a high risk of exacerbations, and no blood eosinophilia are recommended to be prescribed LAMA/LABA [1, 103].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

• COPD patients with reduced lung function and no history of repeated exacerbations are not recommended to use ICS [97].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: Therapy with ICS/LABA combinations does not affect the rate of FEV₁ decline or mortality in COPD [100, 104, 105].

Roflumilast

Roflumilast suppresses the inflammatory response associated with COPD by inhibiting the phosphodiesterase-4 enzyme and increasing intracellular cyclic adenosine monophosphate levels.

• Roflumilast is recommended for COPD patients with FEV₁ <50% of predicted, chronic bronchitis, and frequent exacerbations despite LABD use, to reduce the frequency of moderate and severe exacerbations [106, 107].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

• Roflumilast is not recommended to be prescribed for reducing COPD symptoms [106, 107].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: Roflumilast is not a bronchodilator (a drug for the treatment of obstructive airway diseases), although during long-term treatment in patients receiving tiotropium bromide**, roflumilast additionally increases FEV₁ by 50–80 ml [106, 107].

The effect of roflumilast on quality of life and symptoms is mild. The drug causes significant adverse effects, typical among which are gastrointestinal disorders and headache, as well as weight loss [107].

Systemic glucocorticosteroids (H02AB Glucocorticoids)

Comments: Although a high dose of systemic GCS (equal to ≥30 mg of oral #prednisolone** per day) improves pulmonary function in the short term, data on the benefits of long-term use of low, medium, or high doses of systemic GCS are lacking while the risk of adverse events is significantly increased [108]. However, this fact does not preclude prescribing a short course of systemic GCS during exacerbations.

Systemic GCS cause a number of serious adverse effects; one of the most important in relation to COPD is steroid myopathy, the symptoms of which include muscle weakness, decreased physical activity, and respiratory failure in patients with extremely severe COPD [110].

Theophylline

Disagreement remains regarding the exact mechanism of action of theophylline, but this drug possesses both bronchodilator and anti-inflammatory activity. Theophylline significantly improves pulmonary function in COPD and possibly improves respiratory muscle function, but at the same time increases the risk of adverse events [111]. There is evidence that low doses of theophylline (100 mg twice daily) statistically significantly reduce the frequency of COPD exacerbations [112].

• It is possible to prescribe theophylline for the treatment of COPD as add-on therapy in patients with severe symptoms [111-114].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: The effect of theophylline on lung function and symptoms in COPD is less pronounced than that of the LABA formoterol** [114].

The exact duration of action of theophylline, including modern slow-release formulations, in COPD is unknown.

• When prescribing theophylline, it is recommended to monitor its blood concentration and adjust the dose based on the results obtained, which is often not done in clinical practice [111].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: The pharmacokinetics of theophylline is characterized by interindividual variability and a tendency for drug interactions. Theophylline has a narrow therapeutic concentration window and can lead to toxicity. The most common adverse events include gastric irritation, nausea, vomiting, diarrhea, increased diuresis, signs of central nervous system stimulation (headache, nervousness, anxiety, agitation), and cardiac arrhythmias.

Antibacterial drugs (J01 Antibacterials for systemic use)

• The prescription of macrolides (#azithromycin**) as long-term therapy at 250 mg/day or 500 mg every 3 days/week is recommended for patients with COPD who have bronchiectasis and frequent purulent exacerbations [115, 116].

GCR ALEL 1Grade of Recommendation A (Level of Evidence – 1)

Comments: A meta-analysis showed that long-term treatment with macrolides (#erythromycin, #clarithromycin**, and #azithromycin**) in 6 studies lasting from 3 to 12 months reduced the frequency of COPD exacerbations by 37% compared with placebo. Additionally, hospitalizations were reduced by 21% [115, 116]. The widespread use of macrolides is limited by the risk of bacterial resistance and side effects (hearing loss, cardiotoxicity) [115].

Mucolytic drugs (R05CB)

This group includes several substances with different mechanisms of action. The regular use of mucolytic drugs in COPD has been studied in several trials with conflicting results [117].

• The prescription of #acetylcysteine** 600-1200 mg/day [1], erdosteine 600 mg/day, and carbocisteine 750 mg twice daily is recommended for patients with COPD with the bronchitic phenotype and frequent exacerbations, especially if ICS therapy is not administered [117, 118, 207, 209].

GCR ALEL 1Grade of Recommendation A (Level of Evidence – 1)

Comments: Acetylcysteine**, erdosteine, and carbocisteine can exhibit antioxidant properties and may reduce the number of exacerbations, but they do not improve lung function or quality of life in patients with COPD.

Advanced biological therapy

Comment: To date, compelling evidence has been obtained regarding the efficacy of #dupilumab** in COPD patients with signs of type 2 inflammation and blood eosinophilia >300 cells/µL.

Inhaler selection

Table 8. Main principles of inhalation device selection.

Note: Drug product supplied with an inhaler – medicinal product packaged with an inhaler; pMDI-BAI – breath-actuated pressurized metered-dose inhaler.

Comments: A significant proportion of patients make mistakes when using inhalers. When using a dry powder inhaler (DPI), coordination between actuation and inhalation is not required, but sufficient inspiratory effort is needed to generate an adequate inspiratory flow. When using a pressurized metered-dose inhaler (pMDI), generating a high inspiratory flow is not required, but the patient must be able to coordinate inhaler actuation with the start of inspiration. (Table 8).

• In patients with severe COPD, it is recommended to favor pMDIs (including with a spacer) or drug products supplied with an inhaler [121, 122].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: This recommendation is due to the fact that in patients with severe COPD, the inspiratory flow using a DPI is not always sufficient [121].

Management strategy for stable COPD

• All patients with COPD are recommended to implement non-pharmacological measures. Prescribing a short-acting bronchodilator (a medication for treating obstructive airway diseases) for as-needed use only, influenza and pneumococcal vaccination, and treatment of comorbidities [124, 199].

For a short-acting bronchodilator (a medication for treating obstructive airway diseases) for as-needed use and influenza vaccination – grade of recommendation B (level of evidence – 1), for pneumococcal vaccination – grade of recommendation C (level of evidence – 1).

Comments: Non-pharmacological measures include smoking cessation, instruction in inhalation technique and self-monitoring basics, influenza and pneumococcal vaccination, encouragement of physical activity, and assessment of the need for long-term oxygen therapy (LTOT) and non-invasive ventilation (NIV).

• All patients with COPD are recommended to receive a combination of LAMA/LABA or one of these drugs as monotherapy (Appendix B) [1].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• Initial monotherapy with a single long-acting bronchodilator (a medication for treating obstructive airway diseases) (LAMA or LABA) is recommended for patients with mild symptoms (mMRC <2 or CAT <10), with no or at most 1 exacerbation without hospitalization in the preceding year, and in the absence of contraindications to either component of the combination (Appendix B) [1].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: The advantage of LAMA lies in its more pronounced effect on the risk of exacerbations [81].

• Initial LAMA/LABA therapy is required for patients with prominent symptoms (mMRC ≥2 or CAT ≥10) regardless of exacerbation history in the preceding year immediately after establishing a COPD diagnosis, or if symptoms (dyspnea and reduced exercise tolerance) persist on monotherapy with a single LABD (Appendix B) [125, 126].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: Most COPD patients consult a doctor with prominent symptoms – dyspnea and reduced exercise tolerance. The prescription of the LAMA/LABA combination allows, through maximum bronchodilation, to alleviate dyspnea, increase exercise tolerance, and improve patients' quality of life.

If symptoms persist in patients receiving LAMA/LABA and there is no history of exacerbations in the preceding year:

- consider changing the device or molecule,

- implement or intensify non-pharmacological treatment methods,

- investigate (and treat) other causes of dyspnea.

- as initial therapy for patients with ≥2 moderate exacerbations or ≥1 severe exacerbation (hospitalization) if blood eosinophils (EOS) ≥300 cells/µL;

- for patients with exacerbations on LAMA or LABA monotherapy if EOS ≥300 cells/µL;

- for patients with ≥2 moderate exacerbations or ≥1 severe exacerbation while on LAMA/LABA treatment if EOS ≥100 cells/µL;

- in case of coexisting COPD and asthma.

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: the most convenient option for triple therapy is the use of a medicinal product containing all three components in a single delivery device. Using a single inhalation device helps improve treatment adherence and reduces the likelihood of critical errors in inhalation technique [128].

The use of the fixed-dose combination fluticasone furoate/umeclidinium/vilanterol compared with the LAMA/LABA combination (umeclidinium/vilanterol) resulted in a 25% reduction in the rate of moderate/severe exacerbations per year [57], and a 15% reduction compared with the ICS/LABA combination (vilanterol/fluticasone furoate) [92]. The annualized rate of COPD exacerbations as a result of treatment with the single-inhaler combination budesonide/glycopyrronium bromide/formoterol decreased by 52% compared with glycopyrronium bromide/formoterol treatment and by 13% compared with budesonide/formoterol treatment [56]; treatment with the fixed-dose combination beclometasone/glycopyrronium bromide/formoterol resulted in a 15% reduction compared with glycopyrronium bromide/indacaterol [129] and a 23% reduction compared with beclometasone/formoterol [130].

• If recurrent exacerbations occur while receiving LAMA/LABA therapy in a patient without eosinophilia (eos <100 cells/µL) and/or a history of asthma, or in case of relapse of exacerbations on triple therapy (ICS/LAMA/LABA), it is recommended to clarify the COPD phenotype and prescribe phenotype-specific therapy (roflumilast 250 or 500 mcg/day, acetylcysteine 600 or 1200 mg/day, #azithromycin 250 mg once daily or 500 mg once every 3 days/week, etc.) [106, 115, 116, 118].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

• It is not recommended to reduce the volume of bronchodilator therapy (LAMA/LABA) (in the absence of adverse events) even in the event of maximum symptom relief [1].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: this is due to the fact that COPD is a progressive disease, making complete normalization of lung function impossible.

Step-down therapy

• In stable COPD, it is recommended to:

- continue rather than discontinue ICS/LAMA/LABA combination therapy [1].

- perform step-down therapy in COPD patients receiving ICS/LAMA/LABA [131-134, 170-173]: when eosinophil levels are <100 cells/µL and/or adverse events associated with ICS occur (discontinuation of ICS and continuation of LAMA/LABA therapy, assessment of the COPD phenotype, and consideration of additional therapy) [132].

LoR CLoE 3Level of Recommendations C (Level of Evidence – 3)

Comments: if, in the physician's opinion, the patient does not need to continue ICS treatment, or adverse events from such therapy occur, ICS may be withdrawn. If symptoms persist in the absence of COPD exacerbations over the preceding year, patients are switched to LAMA/LABA therapy [1].

An FEV₁ <50% value was previously considered a risk factor for frequent COPD exacerbations and was regarded as an indication for prescribing an ICS/LABA or ICS/LAMA/LABA combination. Currently, this approach is not practiced, as it leads to adverse effects and unjustified costs [131].

The treatment algorithm for patients with chronic obstructive pulmonary disease is presented in Appendix B-1 [230].

3.4 Surgical treatment

• Patients with COPD with upper-lobe emphysema and low exercise tolerance are recommended to undergo lung volume reduction surgery [136].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comments: Lung volume reduction surgery is performed by removing a portion of the lung to reduce hyperinflation and achieve more efficient pumping work of the respiratory muscles. Currently, less invasive methods can also be used for lung volume reduction, such as occlusion of segmental bronchi using valves, special sealants, etc.

• Lung transplantation is recommended for a subset of patients with very severe COPD who have the following indications: BODE index ≥ 7 points (see Appendix G5) (BODE – B – body mass index, O – obstruction, D – dyspnea, E – exercise tolerance), FEV₁ <15% predicted, ≥3 exacerbations in the preceding year, 1 exacerbation with the development of acute hypercapnic respiratory failure, moderate-to-severe pulmonary hypertension (mean pulmonary arterial pressure ≥35 mm Hg), and age under 60 years [137].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Lung transplantation can improve quality of life and functional parameters in carefully selected COPD patients.

3.5 Other Treatment Methods

Long-term oxygen therapy

One of the most severe complications of COPD developing in its late (terminal) stages is chronic respiratory failure (CRF). The main sign of CRF is the development of hypoxemia, i.e., a decrease in the oxygen content in arterial blood (PaO₂).

LTOT is currently one of the few therapeutic methods capable of reducing mortality in COPD patients. Hypoxemia not only shortens the life of COPD patients but also has other significant adverse consequences: impaired quality of life, development of polycythemia, increased risk of cardiac arrhythmias during sleep, and the development and progression of pulmonary hypertension. LTOT helps reduce or eliminate all these negative effects of hypoxemia.

• COPD patients with CRF are recommended to undergo LTOT (for indications, see Table 9) [1, 138].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Table 9. Indications for long-term oxygen therapy.

Comments: It should be emphasized that the presence of clinical signs of cor pulmonale suggests earlier initiation of LTOT.

Correction of hypoxemia with oxygen is the most pathophysiologically sound method of treating CRF. Unlike a number of emergency conditions (pneumonia, pulmonary edema, trauma), the use of oxygen in patients with chronic hypoxemia must be continuous, prolonged, and generally carried out at home, which is why this form of therapy is called LTOT.

• Gas exchange parameters on which indications for LTOT are based are recommended to be assessed only during the stable state of patients, i.e., 3–4 weeks after a COPD exacerbation [139-141].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: This exact amount of time is required for the restoration of gas exchange and oxygen transport following a period of acute respiratory failure. Before prescribing LTOT to COPD patients, one should ensure that the potential of pharmacotherapy has been exhausted and that maximally tolerated therapy does not raise PaO₂ above threshold values.

• When prescribing oxygen therapy, it is recommended to aim for PaO₂ >60 mm Hg and SpO₂ >90% [142].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• LTOT is not recommended for COPD patients who continue to smoke; those not receiving adequate pharmacotherapy aimed at controlling COPD (drugs for obstructive airway diseases, ICS, etc.); and those insufficiently motivated for this type of therapy [141, 202].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• The majority of COPD patients are recommended to undergo LTOT for at least 15 hours a day with maximum breaks between sessions not exceeding 2 consecutive hours, at an oxygen flow rate of 1–2 L/min [142].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: LTOT (>15 hours per day) increases survival in patients with chronic respiratory failure and marked resting hypoxemia. Oxygen concentrators are nowadays mainly used for home LTOT. In the most severe patients, the flow rate may be increased up to 4–5 L/min. The LTOT algorithm in COPD patients is presented in Appendix B2.

Long-term home mechanical ventilation

Hypercapnia (i.e., an increase in the partial pressure of carbon dioxide in arterial blood – PaCO₂ ≥45 mm Hg) is a marker of decreased ventilatory reserve in terminal stages of pulmonary diseases and also serves as a negative prognostic factor for COPD patients. Nocturnal hypercapnia alters the sensitivity of the respiratory center to CO₂, leading to higher PaCO₂ levels during the daytime as well, which has negative consequences for cardiac, cerebral, and respiratory muscle function. Respiratory muscle dysfunction combined with high resistive, elastic, and threshold loads on the respiratory apparatus further exacerbates hypercapnia in COPD patients; thus, a "vicious circle" develops, which can only be broken by providing respiratory support (mechanical ventilation).

In stable COPD patients with CRF who do not require intensive care, long-term continuous respiratory support at home—the so-called long-term home mechanical ventilation (LTHMV)—can be performed.

The use of long-term non-invasive positive pressure ventilation (NPPV) in patients with COPD is accompanied by a number of positive pathophysiological effects, the main ones being improved gas exchange parameters—increased PaO₂ and decreased PaCO₂, improved respiratory muscle function, increased exercise tolerance, improved sleep quality, and reduced static lung hyperinflation. Recent studies have demonstrated that with appropriately selected parameters of non-invasive positive pressure ventilation (NPPV), a significant improvement in survival can be achieved in patients with COPD complicated by hypercapnic chronic respiratory failure [143, 144].

• Long-term NPPV is recommended for patients with COPD who meet the following criteria [145 - 147]:

- Presence of symptoms of chronic respiratory failure: weakness, dyspnea, morning headaches;

- Presence of one of the following parameters: PaCO2 >55 mmHg, PaCO2 50–54 mmHg and episodes of nocturnal desaturation (SpO2 <88% for more than 5 min during O2 therapy at 2 L/min), PaCO2 50–54 mmHg and frequent hospitalizations due to recurrent exacerbations (2 or more hospitalizations over 12 months).

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Portable ventilators are predominantly used in home settings. Common features of portable ventilators include their small size, low cost, ease of setup, and ability to effectively compensate for even high air leaks; however, these devices generally lack the monitoring and alarm capabilities found in "ICU-grade" ventilators. Most portable ventilators use a single circuit (inspiratory), and the exhalation volume is evacuated via an exhalation valve or special ports in the mask or circuit.

Ventilation parameters are usually selected in a hospital setting, followed by regular patient monitoring and equipment maintenance by specialists at home.

• During long-term NPPV, it is recommended to use ventilators at night and, optionally, for a few hours during the day [148].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: Some patients with COPD, especially in the presence of pronounced daytime hypercapnia, require supplemental oxygen delivery from an oxygen concentrator or from a portable liquid oxygen unit (code 113770). Oxygen titration criteria are the same as for long-term oxygen therapy (PaO₂ >60 mmHg and SpO₂ >90%).

• Long-term NPPV is not recommended for patients with COPD with severe swallowing disorders and inability to control coughing (for mask ventilation); poor motivation and inadequate compliance; severe cognitive impairment; requirement for continuous (approx. 24 h/day) respiratory support; insufficient financial or insurance resources; lack of medical institutional support for the patient [144, 203].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

3.4 Treatment of COPD Exacerbations

A COPD exacerbation is an event characterized by an increase in dyspnea and/or cough with sputum, worsening within ≤14 days, which may be accompanied by tachypnea and/or tachycardia, and is often associated with increased local and systemic inflammation caused by a respiratory tract infection, pollutants, or other airway injuries [1].

• Patients with a COPD exacerbation are recommended an initial outpatient appointment, examination, and consultation with a pulmonologist (Medical Services Research code – B01.037.001) or a general practitioner/therapist (Medical Services Research code – B01.047.001) [1].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with a COPD exacerbation are recommended to undergo a complete blood count (differential leukocyte count) (Medical Services Research code – B03.016.003) [1].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with a COPD exacerbation are recommended to undergo a chest X-ray (Medical Services Research code – A06.09.007) [1].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Hospitalization is recommended for patients with a COPD exacerbation in the presence of the following indications:

- a significant increase in intensity and/or appearance of new clinical symptoms (dyspnea on the visual analog scale (VAS) Borg scale ≥5 points,

- respiratory rate ≥24/min,

- heart rate ≥95/min),

- drop in SpO2 <92% and/or decrease in SpO2 >3% from baseline, if known,

- PaO2 ≤60 mmHg and/or PaCO2 >45 mmHg (if determination is available), inability to relieve the exacerbation with initial therapy [15].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• As a mandatory diagnostic minimum upon hospital admission, it is recommended to perform a complete blood count with differential, blood serum C-reactive protein assay, coagulopathy screening (coagulation profile) with blood D-dimer concentration determination (as clinically indicated), pulse oximetry, targeted chest X-ray, as well as electrocardiography [1, 149].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Inhaled bronchodilators (drugs for obstructive airway diseases)

The prescription of bronchodilators (drugs for obstructive airway diseases) is a key component of COPD exacerbation therapy.

• All patients with a COPD exacerbation are recommended to be prescribed inhaled bronchodilators—short-acting beta2-agonists (SABA) (salbutamol**, fenoterol) or short-acting muscarinic antagonists (SAMA) (ipratropium bromide**), or a fixed SABA/SAMA combination [150, 151].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)

Comments: The efficacy of β₂-agonists (selective beta2-adrenergic agonists) and ipratropium bromide** in COPD exacerbations is approximately equal; the advantage of β₂-agonists (selective beta2-adrenergic agonists) is a faster onset of action, while anticholinergic drugs offer high safety and good tolerability.

Increasing the dose of SABA and SAMA, especially when administered via a nebulizer, can additionally relieve dyspnea during a COPD exacerbation [151]. Adverse effects are usually dose-dependent.

R03BA Glucocorticoids

According to clinical trials on COPD exacerbations requiring hospital admission, systemic corticosteroids (H02AB) shorten the time to remission, improve lung function (FEV₁), and reduce hypoxemia, and may also decrease the risk of early relapse and treatment failure, as well as reduce the length of hospital stay.

• Patients with a non-infectious COPD exacerbation requiring hospital admission are recommended to be prescribed systemic (H02AB) or inhaled corticosteroids (R03BA) [152, 153].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comments: a course of therapy with oral #prednisolone ** at a dose of 30–40 mg/day for 5–7 days is usually administered [1, 15, 19, 152]. Inhaled corticosteroid formulations (R03BA)—budesonide** (R03BA02) administered via a nebulizer—are a safer alternative to systemic corticosteroids in COPD exacerbations.

Patients with a COPD exacerbation and blood eosinophilia >2% show the best response to systemic corticosteroids [154].

Antibacterial therapy

Since bacteria are the cause of far from all COPD exacerbations, it is important to determine the indications for antibacterial therapy when exacerbations develop.

• The prescription of antibacterial therapy may be recommended for patients with a COPD exacerbation if there is increased dyspnea, increased sputum volume and purulence, or the presence of two of the three listed signs if one of them is purulent sputum [155, 156].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comments: In patients with such COPD exacerbation scenarios, antibiotics are most effective because the cause of these exacerbations is a bacterial infection.

• Antibacterial therapy is also recommended for patients with severe COPD exacerbations requiring invasive or non-invasive mechanical ventilation [157].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

• To improve diagnostics and treatment approaches for COPD exacerbations, the use of biomarkers such as C-reactive protein (blood serum C-reactive protein assay) is proposed [149]. Patients with a COPD exacerbation are recommended to be prescribed antibacterial therapy if C-reactive protein levels are ≥40 mg/L in the presence of corresponding Anthonisen criteria [158, 159].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Criteria for a high risk of bacterial infection in a COPD exacerbation are a combination of clinical and laboratory parameters [160]:

• serum C-reactive protein >40 mg/L,

• duration of symptom progression greater than 1 day,

• neutrophil count (neutrophilic leukocytosis) in the blood >9,500/µL.

The putative spectrum of respiratory pathogens playing an etiological role in a COPD exacerbation, and consequently the choice of empirical antibacterial therapy, depends on the severity of bronchial obstruction in COPD and the presence of risk factors (Table 10).

Table 10. Most likely pathogens of infectious exacerbations and antibacterial therapy taking into account GOLD bronchial obstruction severity [161-165, 204, 205, 210-214, 229].

Note: Post-FEV1 – post-bronchodilator FEV1

PRSP – penicillin-resistant Streptococcus pneumoniae

*Risk factors: age ≥65 years, concomitant cardiovascular disease, frequent exacerbations (≥2 per year)

**Predictors of Pseudomonas aeruginosa infection:

• Frequent courses of antibiotics (≥2 per year);

• FEV₁ < 30%;

• Isolation of Pseudomonas aeruginosa during previous exacerbations, colonization with Pseudomonas aeruginosa;

• Frequent courses of systemic corticosteroids (>10 mg of prednisolone in the last 2 weeks);

• Bronchiectasis.

The optimal duration of antimicrobial therapy for a COPD exacerbation is 5–7 days [215].

Oxygen therapy

Hypoxemia poses a severe threat to the patient's life; therefore, oxygen therapy is a priority in treating acute respiratory failure (ARF) in COPD.

• All patients with COPD exacerbation and ARF are recommended to receive oxygen therapy to achieve a PaO₂ of 55–65 mmHg and an SpO₂ of 88–92% [166].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comments. Nasal cannulas or a Venturi mask are used for oxygen delivery. When administering oxygen via cannulas, a flow rate of 1–2 L/min is sufficient for most patients. The Venturi mask is the preferred method of oxygen delivery because it provides fairly accurate fractions of inspired oxygen (FiO₃) that are independent of the patient's minute ventilation and inspiratory flow.

• Pulse oximetry is recommended for patients to assess the need for supplemental oxygen therapy [27, 30].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comment: Oxygen therapy is indicated for patients with an SpO2 ≤92% [1, 202].

Non-invasive positive pressure ventilation

The development of a new approach to respiratory support—non-invasive ventilation (NIV), i.e., providing ventilatory assistance without an artificial airway—ensures safe and effective unloading of the respiratory muscles, restoration of gas exchange, and reduction of dyspnea in patients with ARF. NIV is the only proven therapy capable of reducing mortality in patients with COPD and ARF [167].

• Patients with ARF due to COPD are recommended to undergo NIV in the presence of the following signs [168]:

- Severe dyspnea at rest;

- Respiratory rate >24 breaths/min, participation of accessory respiratory muscles, abdominal paradox.

Signs of gas exchange impairment:

- PaCO2 >45 mmHg, pH <7.35;

- PaO2/FiO2 <200 mmHg.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: During NIV, patient-ventilator interaction is achieved using nasal or facial masks. The patient is conscious, and sedatives and muscle relaxants are generally not required. Another important advantage of NIV is the ability to quickly discontinue and immediately resume it if necessary.

• Following the initiation or modification of oxygen therapy, arterial blood gas analysis is recommended within 30–60 minutes to monitor PaCO₂ and pH levels [169].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• NIV is not recommended for patients with ARF who require emergency tracheal intubation and invasive respiratory support [170, 171].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Contraindications to NIV in ARF due to COPD:

• Respiratory arrest;

• Unstable hemodynamics (hypotension, uncontrolled arrhythmias, or myocardial ischemia);

• Inability to protect the airway (impaired cough and swallowing reflexes);

• Excessive bronchial secretions;

• Signs of altered mental status (agitation or depression), patient inability to cooperate with medical staff.

Invasive respiratory support

• Mechanical ventilation (MV) is recommended for patients with COPD and ARF in whom pharmacotherapy and NIV fail to improve their condition [172].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: Indications for mechanical ventilation must take into account not only the lack of response to conservative therapy and the severity of respiratory function impairment, but also the rate of their development and the potential reversibility of the process that caused the ARF. Typically, prescribing respiratory support involves a comprehensive clinical and functional status assessment of the patient.

• Mechanical ventilation for ARF due to COPD exacerbation is recommended in the presence of the following indications [173, 174]:

Absolute indications:

• Respiratory arrest;

• Severe impairment of consciousness (sopor, coma);

• Unstable hemodynamics (systolic blood pressure <70 mmHg, heart rate <50/min or >160/min);

• Respiratory muscle fatigue.

Relative indications:

• Respiratory rate >35/min;

• Arterial blood pH <7.25;

• PaO2 <45 mmHg despite oxygen therapy.

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• In patients with COPD, weaning from mechanical ventilation is recommended to be initiated as early as possible [174].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comments: Every additional day of invasive respiratory support significantly increases the risk of MV-related complications, especially ventilator-associated pneumonia.

Mucolytic agents (R05CB)

Patients with COPD exacerbation presenting with a productive cough are recommended to receive mucolytic drugs to liquefy and improve sputum clearance [117].

Level of Evidence: 5Level of Recommendation C (Level of Evidence – 5)

Comments: Mucolytic drugs (R05CB) are used in the presence of a productive cough – Ambroxol**, Acetylcysteine**, Erdosteine, Carbocisteine.

Methods of bronchial secretion mobilization and clearance

• During a COPD exacerbation, it is recommended to use special methods to improve airway drainage, such as high-frequency chest percussion ventilation or high-frequency chest wall oscillations, or vibroacoustic therapy [175, 176, 206].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comments: Hypersecretion and poor clearance from the airways can pose a serious problem for many patients with severe COPD exacerbations, so these methods can significantly improve their condition.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Physical activity decreases in COPD patients, and physical inactivity serves as a predictor of increased mortality [177]. Pulmonary rehabilitation is an important and essential component of COPD management with a high level of evidence.

• Pulmonary rehabilitation courses are recommended for COPD patients with persistent dyspnea despite the use of bronchodilators (drugs for the treatment of obstructive airway diseases), as well as for physically inactive patients with frequent exacerbations or exercise intolerance [178, 179].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comment: The effects of pulmonary rehabilitation include [178-180]:

• Improved exercise tolerance;

• Reduction in the sensation of dyspnea;

• Improvement in health-related quality of life;

• Reduction in the number and duration of hospitalizations;

• Reduction in COPD-related anxiety and depression levels;

• Improved survival;

• Improved outcomes of hospitalization for exacerbations;

• Enhanced effect of LABDs.

Rehabilitation is a multi-component intervention. In some cases, psychological support and management of depression, patient education, nutritional support, and individual physical therapy sessions should be included in the pulmonary rehabilitation program [181]. The duration of such a program has not been strictly established, but it is believed to range from 4 to 10 weeks [182].

Individual physical therapy sessions (exercise training)

• When conducting pulmonary rehabilitation in COPD patients, it is recommended to include individual physical therapy sessions (exercise training) in the program [183].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comments: Developing training programs requires an individualized approach and depends on the patient's baseline condition, severity of COPD, comorbidities, and motivation. If clinically indicated, various types of respiratory support should be used during training.

Individual physical therapy sessions (exercise training) may include treadmill or cycle ergometer workouts lasting 10 to 45 minutes per session at an intensity ranging from 50% of peak oxygen consumption to the maximum tolerance level [184]. In general practice, if resources for comprehensive rehabilitation are lacking, daily walks should be prescribed (e.g., 30 minutes, 4 km – depending on physical status), as well as Nordic walking training. Some programs include upper-extremity muscle training to improve their function and strength [185].

The effect of individual physical therapy sessions (exercise training) has a prolonged action.

Comments: Respiratory muscle training can have a positive effect, especially when combined with general training.

Climatotherapy can be effective in combination with pulmonary rehabilitation for COPD patients. Studies have shown that climatic factors enhance adaptive capacities and improve psychophysiological status indicators, making their widespread use advisable in the treatment and rehabilitation of COPD patients [187].

Comment: Pulmonary rehabilitation for COPD patients should be a continuous cyclic process aimed at correcting respiratory biomechanics, bronchial patency, preventing respiratory muscle fatigue, improving physical performance, and exercise tolerance under the supervision of the clinical and functional status of each patient.

In addition, the pulmonary rehabilitation program should include psychological support from medical and non-medical staff, patient counseling aimed at altering their attitude toward the disease, and management of existing risk factors.

Patient education

• Patient education is recommended to be included in the pulmonary rehabilitation program for COPD [188].

GCR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

Comments: Patient education is an effective means of achieving specific goals, including smoking cessation, understanding issues related to end-of-life events, and improving exacerbation outcomes. Multidisciplinary educational programs may be beneficial for elderly patients.

• When educating COPD patients, it is recommended to formulate an individualized written self-management action plan [189].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: Creating an individualized written self-management action plan leads to improved quality of life and shortens recovery time during an exacerbation due to a shorter delay in treatment initiation by the patient. Patient education along with self-management instructions and an individualized written action plan can improve exacerbation outcomes [190].

Main methods of pulmonary rehabilitation and their rationale (see Appendix A3.)

The pulmonary rehabilitation program requires proactive screening for frailty syndrome in elderly and senile COPD patients to identify high-risk groups with an unfavorable prognosis for life and disease progression, and to formulate an individualized management plan (see Appendix G-7).

5. Prevention and Dispensary Observation

• As preventive measures for COPD, it is recommended to identify, reduce, and control risk factors such as smoking, occupational hazards, and indoor air pollution [191, 192].

For smoking, the strength of recommendation is C (level of evidence – 1)

For indoor air pollution, the strength of recommendation is C (level of evidence – 2)

• All COPD patients are recommended to receive annual influenza vaccination to reduce the risk of exacerbations [123].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: In the general population, vaccination of individuals over 65 years of age against influenza has been shown to reduce the risk of pneumonia, hospitalization, and death by 50–68%.

• COPD patients are recommended to receive pneumococcal vaccination [1, 193].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Pneumococcal vaccination (PV) can reduce the incidence of pneumococcal pneumonia in COPD patients, although there is no evidence that vaccination reduces the risk of confirmed pneumococcal pneumonia, which is relatively rare. The efficacy of pneumococcal vaccination regarding other outcomes (risk of exacerbations, all-cause mortality) requires further study [201]. PV immunization can be carried out throughout the year. If a mass influenza vaccination program is planned, it is convenient to administer it simultaneously with PV immunization before the onset of the acute respiratory infection and influenza season, in accordance with WHO recommendations.

Clinical studies of bacterial lysates (OM-85 and PMDL) in COPD patients demonstrate a reduction in the number of disease exacerbations as well as the need for antibiotic therapy [217-222]. A meta-analysis of 12 studies on the efficacy and safety of bacterial lysates published in 2022 showed that they may benefit COPD patients by reducing exacerbations [RR = 0.83; 95% CI: 0.72–0.96], among which the chemical bacterial lysate subgroup [OM-85]: RR = 0.87, 95% CI 0.77–0.98; the mechanical bacterial lysate subgroup: RR = 0.70, 95% CI 0.41–1.20, while alleviating symptoms [223].

Comments: currently, further research results are needed to determine the role and place of bacterial lysates in COPD treatment regimens.

• Due to the increased risk of herpes zoster (HZ) and its related complications compared to the general population, COPD patients are recommended routine vaccination against herpes zoster with a recombinant adjuvanted vaccine (Vaccine for the prevention of herpes zoster [recombinant, adjuvanted]) [1].

Level of Evidence 5Strength of recommendation C (level of evidence – 5)

Comments: Currently, further research is needed to determine the role and place of shingles vaccines in COPD treatment regimens.

Dispenser surveillance of patients with chronic obstructive pulmonary disease

Dispenser surveillance of patients suffering from COPD is carried out by:

• general practitioner (district general practitioner, occupational health district general practitioner, general practitioner (family doctor));

• pulmonologist;

• physician (paramedic) of the medical prevention department (office);

• physician (paramedic) of the health center;

• paramedic of a feldsher-midwife station (feldsher health post) if assigned individual duties of the attending physician by the head of the medical organization.

Table 11. Dispenser surveillance of patients suffering from COPD [231].

The algorithm for managing a patient with an established COPD diagnosis is presented in Appendix B1.

6. Organization of Medical Care

Diagnosis and management of COPD patients are carried out by: a general practitioner or general practitioner (family doctor) [194], a pulmonologist. If necessary, consultation and treatment by specialists in other fields are provided.

The primary care physician performs a comprehensive assessment of symptoms, history of the disease, and the patient's life history. COPD risk factors (bad habits, occupational history, living conditions) are also assessed. Initial patient examination is carried out by the primary care physician: assessing the severity of patient complaints using mMRC and CAT scales, pulmonary function testing with a bronchodilator test, and chest radiography (A06.09.007) [195]. The general practitioner or general practitioner (family doctor) diagnoses COPD, prescribes LABA therapy and symptomatic therapy with SABA or SABA/SAMA [196].

The pulmonologist formulates the diagnosis in accordance with the current version of clinical guidelines, performs additional patient examination when indicated, determines the required treatment regimen for COPD and respiratory rehabilitation, including nutritional and respiratory support. The effectiveness of the prescribed treatment plan is evaluated at 1, 3, and 12 months in the first year, and annually thereafter [197]. An important aspect of the pulmonologist's work in the outpatient pulmonology office of a medical organization is conducting COPD schools for patients [198].

Indications for a pulmonologist consultation are [199]:

1. Clarification of the COPD diagnosis,

2. Differential diagnosis,

3. Selection of a patient management algorithm, including pharmacological and non-pharmacological treatment methods for COPD patients,

4. Change in therapeutic strategy in the absence of an effect from previously prescribed therapy (including low compliance with certain drug delivery devices).

Indications for hospitalization in the day hospital of a medical organization:

1. Increasing severity of symptoms for more than 3 days (increased dyspnea, increased sputum expectoration, increased purulence of sputum) [200],

2. Exacerbation meeting the criteria for a mild or moderate exacerbation,

3. Inefficacy of initial outpatient exacerbation therapy within 3 days,

4. Exacerbation of chronic comorbidities without vital organ dysfunction of grade 2 or higher,

5. Administration of pathogenetic therapy.

Planned hospitalization in an inpatient 24-hour facility for COPD patients is provided in the following cases:

1. For re-examination or determination of disability group in controversial cases,

2. For the selection of respiratory support methods.

Indications for emergency and urgent hospitalization in an inpatient 24-hour facility of a medical organization:

1. Significant increase in symptom severity (suddenly developed severe dyspnea),

2. Appearance of new symptoms (cyanosis, peripheral edema),

3. Inefficacy of initial exacerbation therapy within 3 days,

4. COPD exacerbation in patients with severe and extremely severe disease,

5. Onset of acute or exacerbation of chronic comorbid conditions,

6. COPD exacerbation in elderly patients.

Indications for discharging a patient from a medical organization:

1. The patient is able to take long-acting bronchodilators (selective beta2-agonists and/or anticholinergics) with or without inhaled corticosteroids,

2. The intake of short-acting inhaled β2-agonists (selective beta2-agonists) is required no more frequently than every 4 hours,

3. The patient is able (if previously managed on an outpatient basis) to move around the room independently,

4. The patient is able to eat and can sleep without frequent awakenings due to dyspnea,

5. Clinical stability of the condition for 12–24 hours,

6. Stable values of acid-base balance and arterial blood gas parameters for 12–24 hours,

7. The patient or home caregiver fully understands the correct medication regimen.

7. Additional Information

Occupational chronic obstructive pulmonary disease

Occupational chronic obstructive pulmonary disease is a disease characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar pathology caused by an abnormal inflammatory response of the lung tissue to harmful workplace particles or gases.

The etiological factor of occupational COPD can be any component of industrial aerosol that damages the airways and lung parenchyma and is present in the workplace for a prolonged period. The chemical composition, physical and biological properties of the aerosol, and the concentration of chemicals and dust in the work area air are significant for the development of the occupational disease [233, 234].

According to Order No. 417n of the Ministry of Health and Social Development of the Russian Federation dated April 27, 2012, "On Approval of the List of Occupational Diseases," the causes of occupational COPD include: chemicals with toxic action, with the exception of substances specified in paragraphs 1.1–1.51, irritants, tin and its compounds, beryllium and its compounds, nickel and its compounds, cobalt and its compounds, nitrogen oxides, chlorine gas, fluorine and its compounds. Additionally, occupational COPD can be a consequence of acute inhalation poisonings by chemicals specified in paragraphs 1.1–1.51 of the Order.

Concomitant exposure to other adverse factors of the working environment increases the likelihood of developing occupational COPD. For example, intense physical labor or a heating microclimate increases the minute ventilation and, consequently, the entry of pathogenic particles into the lungs. Simultaneous exposure to cigarette smoking and industrial pollutants increases the risk of COPD and disease severity.

Workers in mining, various manufacturing industries (metallurgy, oil refining, machinery and equipment production, plastics, chemicals, building materials, textiles), agriculture, construction, railway transport, and firefighters are at the highest risk for occupational COPD [235–240].

Occupational COPD can be viewed as the result of the interaction between the bronchopulmonary system, acting as a barrier organ, and harmful occupational environment factors. Prolonged exposure (for 5–10 years or more) of gases, vapors, dusts, and smokes to the airway epithelium initially leads to overloading of the mucociliary apparatus and subsequently to its damage with impaired mucociliary clearance. This facilitates the entry of aggressive components of industrial aerosols into the distal parts of the respiratory tract, where they damage epithelial cells and alveolocytes, and activate macrophages, initiating inflammation of the primary immune response type. The macrophage is the key inflammatory cell in the development of occupational COPD [241–243]. The probability of developing occupational COPD is higher under the action of fine aerosols consisting of particles 1–5 µm or less than 2.5 µm in size (PM_2.5) [233]. Such aerosols are more stable compared to coarse ones; their particles remain suspended for a long time, enabling them to penetrate the distal parts of the bronchial tree and lung parenchyma, bypassing the protective mucociliary barrier. The damaging effect of dust increases when the concentration of particles exceeds 10 mg/m³. Silicon dioxide, hydrocarbons, and organic dust have pronounced immunogenic properties; therefore, even a slight excess of the maximum allowable concentrations (MAC) of these substances in the work area air poses a risk of developing occupational COPD. Shift-average and maximum single concentrations of chemicals and dust, as well as cumulative indicators (dust load), are significant [234]. As a result, persistent inflammation develops in the small bronchi, bronchioles, and lung parenchyma. During the inflammatory response in occupational COPD, lung tissue damage occurs, forming a proteinase/matrix metalloproteinase imbalance responsible for the impairment of the elastic properties of lung tissue and the development of static hyperinflation, as well as smooth muscle cell hypertrophy and excessive connective tissue formation, which drive the remodeling of bronchiole walls and the development of bronchial obstruction at this level [241–243].

Occupational COPD accounts for about 10–19% of all COPD cases and 31% of COPD in non-smokers [236, 245]. Exposure to industrial pollutants increases the risk of death from COPD regardless of smoking status [246–248].

The occupational etiological factor influences the COPD phenotype. Thus, exposure to smoke and gas is associated with bronchitis, while inorganic dust is associated with greater symptom severity [249]; COPD caused by quartz or asbestos dust is always accompanied by significant pulmonary fibrosis [250]. Dyspnea severity is greater when the disease develops under conditions of toxic gas exposure, and lesser under the action of silicon-containing dust. Patients with COPD caused by toxic gases have fewer total exacerbations, but more severe ones compared to COPD caused by dust or tobacco smoking [251]. Cough in occupational COPD is non-productive or sparingly productive, often paroxysmal. Chronic atrophic bronchitis, tracheitis, laryngitis, and pharyngitis are characteristic [252]. Patients with occupational COPD frequently exhibit bronchial hyperresponsiveness syndrome, manifesting as episodes of wheezing, cough, and chest tightness upon inhalation of irritants or cold air. Furthermore, this syndrome may include post-exercise bronchoconstriction (bronchospasm occurring 5–6 min after cessation of physical exertion, not always associated with bronchial asthma). In the presence of upper respiratory tract irritation syndrome, the patient experiences a dry, paroxysmal cough accompanied by a "tickling" sensation in the throat [252]. Eosinophilic inflammation predominates upon exposure to toxic gases, while pauci-cellular inflammation predominates with inorganic dust [251].

Comments: The occupational history must contain data on work under conditions of exposure to industrial aerosols of various compositions—dust, gases, vapors, smokes throughout the entire occupational route. It is also necessary to collect data on exposure to other adverse occupational factors that may exacerbate the negative impact of industrial aerosols on the bronchopulmonary system, such as physical exertion and an unfavorable microclimate. The presence or absence of alternative COPD risk factors is also assessed, including smoking, domestic pollutants, low socioeconomic status, general respiratory, cardiovascular, and endocrine system diseases, overweight, etc. The occupational health physician studies the sanitary and hygienic characteristics data regarding the nature of the acting substances and the patient's occupational activity in detail, and draws conclusions about their possible impact on the development of COPD, taking tenure into account. The presence of industrial aerosols, gases, vapors, smokes in the workplace, as well as indicators of the intensity of these factors (at the level of established hygienic standards or above them) and, especially for factors with a predominantly cumulative action profile, the duration of exposure with the cumulative exposure level (dust load) over the entire period of occupational contact with the factor, are significant for the development of occupational COPD.

Comments: The simultaneous presence of asthma and COPD symptoms and documented exposure to sensitizing substances and/or irritants determines the need for examination in order to rule out/confirm bronchial asthma as a second occupational disease.

Early diagnosis

Comments: This approach is intended to ensure employee health and occupational longevity. For the purpose of early diagnosis of occupational COPD, spirometry is performed during periodic medical examinations in all individuals working in contact with industrial aerosols.

In occupational COPD when combined with cigarette smoking, the severity of ventilation disorders is expected to be higher than in the general COPD population [248, 253]; when COPD develops under conditions of exposure to toxic gases, a mild severity of bronchial obstruction but a significant degree of emphysema is expected; when COPD develops due to the action of dust containing silicon dioxide, the severity of bronchial obstruction is higher than in "chemical" COPD, but emphysema is less pronounced, with significant concomitant interstitial changes in the lungs [251].

When diagnosing occupational COPD, laboratory and instrumental research methods are carried out as outlined in the relevant sections of these guidelines.

The treatment of occupational COPD is carried out according to the same principles as COPD of other etiologies. The specific features include the importance of rational employment placement and consideration of phenotypic differences.

Comments. Ceasing the action of the exogenous etiopathogenetic factor helps to slow down the progression of bronchopulmonary system remodeling [238, 254].

Comment. One of the main features of occupational COPD is the development of respiratory tract mucosal atrophy. In this regard, the majority of patients require the prescription of mucolytic drugs [252].

In the treatment of patients with occupational COPD that has developed under the conditions of exposure to toxic gases, prescribing ICS may be considered [154].

The high frequency of eosinophilic inflammation in the development of occupational COPD under conditions of toxic gas exposure provides an additional rationale for prescribing ICS in this group of patients [251].

Expert Assessment of the Link Between COPD and Occupation

Since 2012, COPD has been included in the list of occupational diseases of the Russian Federation (Order of the Ministry of Health and Social Development of the Russian Federation No. 417n dated April 27, 2012, "On Approval of the List of Occupational Diseases", registered with the Ministry of Justice on May 15, 2012, Reg. No. 24168). The assessment of the occupational link is carried out in accordance with Russian legislation (Decree of the Government of the Russian Federation No. 1206 of July 5, 2022, "On the Procedure for Investigation and Registration of Occupational Disease Cases in Employees"; Order of the Russian Ministry of Health No. 36n of January 31, 2019, "On Approval of the Procedure for Conducting the Assessment of the Link Between a Disease and Occupation and the Form of the Medical Certificate on the Presence or Absence of an Occupational Disease").

Initially, the diagnosis of COPD is established by a pulmonologist, general practitioner (therapist), or occupational health physician holding an additional certificate in internal medicine or pulmonology.

The link between COPD and occupation, as well as the diagnosis of an occupational disease (occupational COPD), is established by a medical commission comprising occupational health physicians and specialists who hold a valid occupational health certificate. An analysis of the sanitary-hygienic characteristics of working conditions, a certified copy of the employment record book, and the submitted medical documentation is performed. The link between COPD is established given documentary confirmation of the following circumstances: the onset of the disease in the presence of occupational contact with industrial aerosols exceeding established hygienic standards (MAC) and, for dusts with a predominantly cumulative effect, total exposure doses (exceeding the critical exposure level for aerosol industrial fibrogenic dusts) over the entire period of occupational contact according to sanitary-hygienic data by 2.5–4 times or more [233–243]. Factors accelerating the development of occupational COPD include working under conditions of an unfavorable microclimate (cooling, alternating cooling-heating) and/or with significant physical exertion. The link between COPD and occupation may be established in workers who have worked for a significant period (20 years or more) under conditions of exposure to industrial aerosols moderately (1.1–2.5 times) exceeding the MAC [233–243] in the absence of other causes (such as smoking) that could cause COPD.

Additional factors pointing to the occupational genesis of COPD may include: phenotypic characteristics of the disease corresponding to its formation under the influence of a particular type of industrial aerosol, the presence of atrophic bronchitis and ENT organ lesions, and a history of an initial reaction to industrial aerosols in the form of bronchial hyperreactivity [243].

Importantly, when COPD is combined with bronchial asthma, the assessment of the occupational link is conducted separately for each disease.

Upon establishing a preliminary diagnosis of a chronic occupational disease (occupational COPD), the "Notice of Establishment of a Preliminary Diagnosis of an Acute or Chronic Occupational Disease" for the employee is sent within 3 days to the territorial department of Rospotrebnadzor, which, within 2 weeks from the date of receipt of the notice, submits the sanitary-hygienic characteristics of the employee's working conditions to the medical organization. The medical organization that established the preliminary diagnosis of occupational COPD is obliged to refer the patient within a month for outpatient or inpatient examination to a specialized medical and preventive institution or its subdivision (occupational pathology center, clinic, or department of occupational diseases of clinical research medical organizations, hereinafter referred to as the occupational pathology center) along with an extract from the outpatient and/or inpatient medical record, information on the results of preliminary (upon employment) and periodic medical examinations, sanitary-hygienic characteristics of working conditions, and a copy of the employment record book. The occupational pathology center, based on the clinical data of the employee's health status and the submitted documents, establishes the final diagnosis of a chronic occupational disease (including one that arose long after the cessation of work in contact with harmful substances or production factors), draws up a medical report, and within 3 days sends a notice of the establishment of the final diagnosis of a chronic occupational disease (COPD), its clarification or cancellation, to the territorial department of Rospotrebnadzor. The medical report on the presence of an occupational disease is issued to the employee and is also sent to the insurer and the referring medical organization.

2. Assessment of Occupational Fitness

The assessment of occupational fitness in patients with COPD is carried out based on the results of preliminary and periodic medical examinations and may also be conducted upon appropriate referral during the examination of patients in occupational pathology departments and centers. According to Order of the Ministry of Health of the Russian Federation No. 29n of January 28, 2021, "On Approval of the Procedure for Conducting Mandatory Preliminary and Periodic Medical Examinations of Workers Provided for by Part Four of Article 213 of the Labor Code of the Russian Federation, the List of Medical Contraindications to Performing Work with Harmful and (or) Dangerous Production Factors, as well as Work in the Performance of Which Mandatory Preliminary and Periodic Medical Examinations Are Conducted," patients with COPD (as well as other chronic respiratory diseases) have contraindications for work in contact with industrial aerosols (harmful chemical substances):

1. Diseases with grade III respiratory failure (general),

2. Recurrent forms of diseases with a frequency of exacerbations of 4 times or more per calendar year.

The specified regulatory act does not establish grounds for restricting the occupational capacity of patients with initial and moderately pronounced phenomena of COPD if the frequency of its exacerbations is less than 4 times per year. However, considering the importance of prompt cessation of the patient's exposure to harmful occupational factors that caused occupational COPD, after establishing the link between the disease and the occupation, the occupational center or department of occupational pathology recommends the advisability of placing the patient in jobs where exposure to working conditions that may contribute to disease progression is excluded.

The assessment of occupational fitness is carried out in accordance with Order of the Ministry of Health of Russia No. 282n of May 5, 2016.

1. Medical and Social Assessment

Patients with an established diagnosis of occupational COPD are eligible for medical, social, and vocational rehabilitation based on the results of the state medical and social expert evaluation at their place of residence or registration (MSE). Referral of the patient for rehabilitation is carried out following the MSE results in accordance with the degree of disability.

The MSE bureau indicates contraindications for continued work under the influence of harmful occupational factors that may contribute to the progression of COPD. The degree of loss of professional capacity for work is determined, along with the disability group (if criteria are met). The MSE bureau draws up a rehabilitation program for the affected individual, which specifies the need for drug therapy, sanatorium-resort treatment, and, if necessary, the provision of a nebulizer, an oxygen concentrator, as well as the need for vocational retraining.

In accordance with Order of the Ministry of Labor and Social Protection of the Russian Federation No. 585n dated August 27, 2019, "On Classifications and Criteria Used in the Implementation of Medical and Social Expert Evaluation of Citizens by Federal State Institutions of Medical and Social Expert Evaluation", these classifications determine the main types of persistent disorders of human body functions, the degree of their severity, as well as the main categories of human life activity and the severity of limitations in these categories. The Order provides a quantitative rating system for assessing the severity of persistent impairments of body functions in citizens aged 18 years and older caused by diseases, consequences of injuries, or defects (in percentages, applied to the clinical and functional characteristics of persistent impairments of human body functions).

Thus, for subsection 10.1 "Chronic diseases of the lower respiratory tract (excluding asthma)", the following is specified (Table 6).

Table 6. Assessment of the severity of persistent respiratory function impairments [Order of the Ministry of Labor and Social Protection of the Russian Federation No. 585n dated August 27, 2019].

Organization of the expert evaluation establishing the link between COPD and profession, and specific features of follow-up care for a patient with an occupational disease.

• If signs of a previously unestablished chronic occupational disease—occupational COPD—are detected in a patient, the specialist physician who identified these signs shall, within 24 hours from the moment of their detection, refer the patient for a consultation at the office of an occupational health physician of the medical organization at their place of residence or stay (taking into account the right to choose a medical organization). In case of suspected signs of a chronic occupational disease, the patient has the right to independently apply to the occupational health physician's office for consultation.

• In case of detecting signs of a previously unestablished chronic occupational disease, the occupational health physician establishes a preliminary diagnosis of a chronic occupational disease and refers the patient to a center for occupational pathology or another medical organization licensed to provide medical care, including work and services in the specialties "occupational medicine", "expert evaluation of the link between disease and profession", "expert evaluation of occupational suitability", for the provision of medical care if indicated, as well as for conducting an expert evaluation of the link between the disease and profession and an expert evaluation of occupational suitability.

• At the center for occupational pathology, the expert evaluation of the link between the disease and profession is carried out in the established manner.

• A patient with an established definitive diagnosis of a chronic occupational disease, after receiving medical care: is referred to the medical organization at their place of residence or stay (taking into account the right to choose a medical organization) for outpatient treatment and/or rehabilitation measures; is referred by the occupational health physician of the medical organization at their place of residence or stay (taking into account the right to choose a medical organization) for assessment at a medical and social expert evaluation institution; is registered and enrolled in the organizational and methodological department of the center for occupational pathology; is subject to follow-up monitoring by the occupational health physician at the place of residence or stay (taking into account the right to choose a medical organization).

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Conflict of interest:

The members of the working group declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. General practitioner (family physician);

2. Pulmonologist;

3. General practitioner (internist);

4. District general practitioner;

5. Occupational health physician.

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions).

Table 2. Scale for grading the levels of evidence (LoE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions).

Table 3. Scale for grading the levels of evidence (LE) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions).

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Current instructions for medicinal products mentioned in these clinical guidelines can be found at http://grls.rosminzdrav.ru.

1. Main methods of pulmonary rehabilitation and their rationale [259-262]

2. Methodology for conducting tests of unforced respiratory volumes and flows (spirometry)

When assessing unforced respiratory volumes and flows (spirometry), it is recommended to perform at least three technically acceptable forced vital capacity (FVC) maneuvers until reproducible results are obtained: the highest and the next highest FVC and FEV₁ values should not differ by more than 150 ml. When the FVC is 1000 ml or less, the maximum allowable difference for both FVC and FEV₁ must not exceed 100 ml.

If reproducible results are not obtained after 3 attempts, breathing maneuvers must be continued up to 8 attempts. A greater number of breathing maneuvers may lead to patient fatigue and, in rare cases, a decrease in FEV₁ or FVC. If values drop by more than 20% from baseline, further testing should be discontinued in the interest of patient safety, and the trend in values should be reflected in the report. The report must present graphical results and numerical values of at least the three best attempts. Results of technically acceptable attempts that do not meet the reproducibility criterion may be used in writing the conclusion with an indication that they are not reproducible.

The bronchodilator test is performed using a short-acting beta2-agonist (SABA) (salbutamol) at a single dose of 400 mcg via a metered-dose inhaler with a spacer. A repeat spirometry test should be performed 15–30 minutes after inhalation of the selective beta2-agonist.

The bronchodilator test is considered positive if, after inhalation of the bronchodilator (salbutamol), the bronchodilation response (BDR) in FEV₁ is at least 12% and the absolute increase is 200 ml or more.

Formula for calculating BDR:

where FEV_1basal is the value of the spirometric parameter before inhalation of the bronchodilator (salbutamol), and FEV_{1 post} is the value of the parameter after inhalation of the bronchodilator (salbutamol).

A mandatory functional criterion for documenting a COPD diagnosis is a post-bronchodilator FEV1/FVC ratio < 0.70.

When evaluating the bronchodilator test, adverse cardiovascular reactions (tachycardia, arrhythmia, increased blood pressure) as well as symptoms such as agitation or tremor must be taken into account.

Appendix B. Physician Action Algorithms

Appendix B1. Treatment Regimens for Patients with Confirmed COPD

¹ On the background of ongoing therapy, ≥2 exacerbations per year or 1 exacerbation requiring hospitalization.

² Reassessment of the number of exacerbations and symptom severity is performed at each patient visit; exacerbations are assessed against the prescribed therapy rather than at baseline.

³ If exacerbations or severe symptoms persist despite LABA/LAMA therapy, LAMA/LABA/ICS should be prescribed at this stage.

Appendix B2. Long-Term Oxygen Therapy Algorithm

Appendix B3. Evidence supporting the reduction in mortality with pharmacotherapy and non-pharmacological treatment in patients with COPD

^*RCT with pre-specified mortality outcome analysis (primary or secondary outcome); ^#Inconclusive results likely due to differences in pulmonary rehabilitation among a broad range of participants and across various settings.

Note: ICS – inhaled corticosteroids (R03BA), LABA – long-acting beta2-agonists (R03AC), LAMA – long-acting muscarinic antagonists (R03BB), HR – hazard ratio (ratio of events at a given time point); RR – relative risk (ratio of the probability of an event in exposed subjects compared to the control group), CI – confidence interval, QoL – quality of life, PaO₂ – partial pressure of oxygen in arterial blood, COPD – chronic obstructive pulmonary disease, mMRC (Medical Research Council) – dyspnea scale, NIV high IPAP level – non-invasive ventilation with high inspiratory positive airway pressure, mechanical ventilation – mechanical ventilation.

Appendix B4. Algorithm for Assessing Occupational Causality of COPD

Appendix C. Patient Information

Chronic obstructive pulmonary disease (COPD) is a condition characterized by obstructed airflow through the bronchi and impaired oxygen transfer from the lungs into the blood. This leads to respiratory failure, which manifests as dyspnea. Varying degrees of disease severity result in different intensities of dyspnea. Typically, it first appears when climbing stairs or walking uphill, then manifests during brisk walking on a flat surface, eventually forcing the patient to walk slowly and stop frequently. In very severe forms, dyspnea occurs at rest.

The primary cause of COPD is smoking. Tobacco smoke contains substances that cause inflammation, destroying lung and bronchial tissue. Less commonly, COPD is caused by occupational hazards, ambient air pollution, or indoor air pollution. The disease progresses slowly, so dyspnea—the primary symptom—becomes noticeable, i.e., interfering with daily life, after the age of 40.

COPD is diagnosed based on clinical symptoms (primarily dyspnea, as well as cough and sputum production), pulmonary function tests (spirometry, which records reduced airflow velocity through the bronchi), and several other examinations. For example, chest computed tomography (CT) may reveal pulmonary emphysema—one of the manifestations of COPD—and gas exchange tests help determine the presence and severity of respiratory failure. Additionally, cardiac evaluation can detect complications involving the heart. These examinations help refine the diagnosis, identify complications, and guide appropriate treatment.

COPD treatment begins with smoking cessation (or cessation of exposure to other inhaled harmful substances). Quitting smoking relieves symptoms and prolongs life. If a person is unable to quit smoking on their own, they may need pharmacological support to cope with nicotine addiction. The mainstay of such support is nicotine replacement therapy (NRT), where nicotine is administered via patches, chewing gum, or nicotine inhalers, thereby relieving the patient of the harmful components of tobacco smoke. Subsequently, the nicotine dose is gradually tapered off. This treatment requires medical consultation and supervision. Other pharmacological support methods prescribed by a specialist are also available.

The mainstay of pharmacological treatment for COPD is bronchodilators. Patients are typically prescribed an inhaler containing a rapid-acting bronchodilator for rapid relief as needed. Maintenance treatment relies on long-acting bronchodilators (12- or 24-hour duration). All of these are administered via inhalers, either dry powder or pressurized metered-dose. Usually, one or two bronchodilators are prescribed depending on symptom severity.

The physician may also prescribe inhaled corticosteroids (ATC code R03BA Corticosteroids), as they provide additional benefits in certain forms of COPD. Some types of COPD require the addition of specific medications—special anti-inflammatory agents targeting mucus, antioxidants, systemic antibiotics administered in special regimens, etc.

Some patients experiencing severe dyspnea due to respiratory failure may require oxygen therapy or specialized portable devices to assist with breathing. At home, oxygen is used via specialized concentrators that extract oxygen from ambient air, and various types of respiratory support machines are available depending on the patient's specific needs. A pulmonologist will provide guidance on using these devices if necessary.

Surgery is sometimes performed in COPD to reduce dyspnea in severe emphysema. In some cases, lung transplantation is possible. Patient selection for these procedures is very complex and requires consultations with multiple specialists.

A patient with COPD must stay physically active and engage in an appropriate level of exercise. Training on a treadmill or cycle ergometer should be done twice a week, along with light dumbbell exercises. Additionally, daily walks should be undertaken, trying to walk as far as dyspnea and general condition allow, with a general target of about 3–4 kilometers. Such activities improve physical conditioning and reduce the severity of dyspnea.

A patient with COPD must undergo regular clinical dispensary follow-up examinations, as COPD is frequently accompanied by other comorbidities, primarily cardiovascular diseases.

Therapeutic and preventive measures, when applied correctly and regularly, reduce disease manifestations, lower the risk of exacerbations and complications, and prolong life.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Dyspnea Assessment Using the mMRC Scale

• Russian title: Modified Medical Research Council Dyspnea Scale.

• Original title: mMRC (The Modified Medical Research Council Dyspnea Scale).

• Source (validated publication):

  - Nena Milačić, Bojan Milačić, Olivera Dunjic et al. Validity of CAT and mMRC – dyspnea score in evaluation of COPD severity. Acta Medica Medianae 2015, Vol.54(1) .

• Type (underline):

- rating scale

- index

- questionnaire

- other (specify)

• Purpose: To assess the severity of dyspnea experienced by a patient with COPD (chronic obstructive pulmonary disease).

• Content (template):

• Scoring key (interpretation): The patient is asked to choose one of five statements that best describes their severity of dyspnea: from 0 ("I only get breathless with strenuous exercise") to 4 ("I am too breathless to leave the house or I am breathless when dressing or undressing").

• Notes: The mMRC scale allows for a more precise assessment of a COPD patient's condition.

Appendix G2. COPD Assessment Test (CAT)

• Russian title: COPD Assessment Test.

• Original title: CAT (COPD Assessment Test).

• Source (validated publication):

- Mahler D.A., Faryniarz K., Tomlinson D. et al. Impact of dyspnea and physiologic function on general health status in patients with chronic obstructive pulmonary disease . Chest. 1992. Vol. 102, №2. P. 395-401.

- Gruffydd-Jones K., Marsden H.C., Holmes S. et al. Utility of COPD Assessment Test (CAT) in primary care consultations: a randomised controlled trial // Prim. Care Respir. J. 2013. Vol. 22, №1. P. 37-43.

- Online version available at www.CATestonline.org.

• Type (underline):

- rating scale

- index

- questionnaire

- other (specify)

• Purpose: To evaluate the impact of COPD on a patient's health-related quality of life.

• Content (template):

0 – 10 points – Little impact of COPD on the patient's life;

11 – 20 points – Moderate impact of COPD on the patient's life;

21 – 30 points – Severe impact of COPD on the patient's life;

31 – 40 points – Very severe impact of COPD on the patient's life.

• Scoring key (interpretation): The COPD Assessment Test (CAT) consists of 8 items, each scored on a 5-point scale and summed. It aims to assess cough, phlegm, chest tightness, breathlessness, limitations on home activities, confidence when leaving home, sleep, and energy.

0-10 points – little impact of COPD on the patient's life;

11-20 points – moderate impact of COPD on the patient's life;

21-30 points – severe impact of COPD on the patient's life;

31-40 points – very severe impact of COPD on the patient's life.

• Notes: The COPD Assessment Test (CAT) has a broad scope regarding its impact on the patient's daily life and well-being.

Appendix G3. COPD Diagnostic Questionnaire

• Russian title: COPD diagnostic questionnaire.

• Original title: COPD diagnostic questionnaire.

• Source (validated publication):

- S. DeWeerdt, L. Grouse. Chronic Airways Diseases: A Guide for Primary Care Physicians. 2005 - 28 pages.

• Type (underline):

- rating scale

- index

- questionnaire

- other (specify)

• Purpose: Differential diagnosis of the disease.

• Content (template):

• Key (interpretation):

17 points or more: COPD diagnosis is likely

16 points or less: consider other conditions, including bronchial asthma, or refer to a specialist.

• Notes: --

Appendix G4. BODE Index

• Russian title: BODE index.

• Original title: - BODE index.

• Source (validated publication):

- Celli B.R. Change in the BODE index reflects disease modification in COPD: lessons from lung volume reduction surgery. // Chest. 2006. -Vol.129, №4. -P.873-878.

• Type (underline):

- rating scale

- index

- questionnaire

- other (specify)

• Purpose: Predicting mortality rates (death) from chronic obstructive pulmonary disease (COPD).

• Contents:

- 4 factors in the BODE index

- B - Body mass index

- O - Airflow obstruction

- D - Dyspnea

- E - Exercise tolerance

- Values and ranges

- Mortality prediction

- Survival

- Life expectancy