Chronic bronchitis: clinical guidelines

List of Abbreviations

BP –                                       blood pressure

ACE –                                   angiotensin-converting enzyme

BA –                                       bronchial asthma

COAD – bronchial obstruction syndrome

WHO – World Health Organization

GCs – glucocorticosteroids

GERD – gastroesophageal reflux disease

RF – respiratory failure

VC – vital capacity

ICS – inhaled glucocorticosteroids

BLPs – beta-lactamase inhibitor-protected penicillins

SAMA – short-acting muscarinic antagonists

SABA – short-acting β2-agonists

CT – computed tomography

MSCT – multislice computed tomography

Chest – chest organs

FEV₁ – forced expiratory volume in 1 second

ADRs – adverse drug reactions

PEF – peak expiratory flow

PFT – pulmonary function testing

FVC – forced vital capacity

CB – chronic bronchitis

CLRD – chronic non-specific lung diseases

COPD – chronic obstructive pulmonary disease

RR – respiratory rate

HR – heart rate

ECG – electrocardiography

PaO₂ –                                                      arterial partial pressure of oxygen

PaCO₂ – arterial partial pressure of carbon dioxide

SpO₂ – capillary blood hemoglobin oxygen saturation determined by pulse oximetry

6MWT – 6-minute walk test

Terms and Definitions

Chronic bronchitis is clinically defined as a condition characterized by a cough with sputum production lasting for at least 3 months in two consecutive years.

Acute exacerbation of chronic bronchitis is defined as a condition associated with the worsening of a stable patient's status, characterized by increased sputum volume, purulent sputum, and/or worsening dyspnea.

Cough is a protective body reflex that helps restore airway patency and removes foreign particles, microorganisms, or pathological bronchial secretions, thereby cleansing the bronchi.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Definition. In these clinical guidelines, chronic bronchitis is defined as an independent disease unrelated to any other condition, accompanied by chronic bronchial hypersecretion for at least 3 consecutive months over 2 or more years, typically manifesting as a productive cough.

Commentary: Patients with a chronic productive cough lasting for at least 3 consecutive months over 2 or more years, unaccompanied by functional signs of bronchial obstruction, are recommended to be provisionally diagnosed with CB after ruling out alternative diagnoses.

Table 1. Standardized respiratory symptom questionnaire [1]:

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

Risk factors

Risk factors for the development and exacerbation of CB may include:

• bad habits (smoking),

• exposure to physical and chemical factors (inhalation of dust, smoke, carbon monoxide, sulfur dioxide, nitrogen oxides, and other chemical compounds),

• climatic factors (damp and cold climate),

• seasonality (autumn, winter, early spring),

• allergic diseases and immunodeficiency states,

• viral infection (typically significant as a cause of exacerbation),

• genetic factors, constitutional predisposition

Etiology of the disease

Exogenous and endogenous factors interact closely in the onset and development of CB. Among exogenous factors, irritating and damaging pollutants (both domestic and occupational) as well as non-inert dusts play a significant role, exerting a harmful (chemical and mechanical) effect on the bronchial mucosa. Tobacco smoke exposure should be considered the primary exogenous factor in terms of significance. CB morbidity is directly proportional to the number of cigarettes smoked. Cigarette smoke consists of a complex mixture of 4,000 particles and gases, and the specific etiological role of each of these components has not been established.

Several epidemiological studies have established a link between occupational hazards and the development of CB. The diagnosis is typically made by exclusion. This is difficult because many workers smoke or are passive smokers.

Although the prevalence of passive smoke exposure in the workplace is declining due to smoking bans in public places, it remains a problem in many countries worldwide. Nonsmokers are frequently exposed to cigarette smoke in domestic settings as well. Involuntary exposure to tobacco smoke is strongly associated with chronic cough and sputum production, even in young individuals who have been screened to rule out other risk factors. The risk increases significantly with the duration of daily exposure to tobacco smoke. Another important domestic exposure increasingly recognized as a cause of CB in underdeveloped countries is the inhalation of cooking fuel fumes, especially in poorly ventilated indoor spaces.

Workers exposed to organic dust may complain of chronic cough and asthma-like bronchial obstruction syndrome symptoms without airway eosinophilia, with reversible airflow obstruction or bronchial hyperresponsiveness. This occurs with chronic exposure to cotton, jute, hemp, flax, wood, and various types of grain, as well as coal dust, vitreous fibers, cement, silicon dioxide, silicates, vanadium, welding fumes, organic dust, engine exhaust, etc.

Air pollution and adverse climatic factors (hypothermia and overheating) are of great significance. Viral (influenza viruses, adenoviruses), mycoplasmal, and bacterial infections (S. pneumoniae, H. influenzae, M. catarrhalis) play a lesser role among etiological factors, but their significance increases sharply during exacerbations of chronic bronchitis [2].

Given that the disease does not develop in all individuals exposed to identical adverse exogenous factors, it is advisable to also consider endogenous factors contributing to the development of CB, such as nasopharyngeal pathology, altered nasal breathing with impaired clearance, humidification, and warming of inhaled air, as well as recurrent acute respiratory infections, acute bronchitis, focal upper respiratory tract infections, impaired local immunity, and obesity.

Pathogenesis of the disease

Structural airway changes have been described in healthy individuals, predominantly smokers, even at 20 to 30 years of age. Studies have shown an increased number of neutrophils and macrophages, which play a major role in the initiation and maintenance of the inflammatory process in CB.

Normally, about 100 ml of sputum is produced by the bronchial glands daily and generally goes unnoticed. Smokers with CB produce an average of 100 ml/day more than normal, which is the cause of cough and sputum production.

In chronic bronchitis (CB), the structural and functional properties of the mucous membrane and submucosa undergo changes, manifested by hyperplasia and hyperfunction of goblet cells and bronchial glands, hypersecretion of mucus, and alteration of its properties (mucous secretion becomes thick, viscous, and traps the cilia of the ciliated epithelium). All this leads to impaired mucociliary transport. The efficiency of bronchial mucociliary transport depends on two main factors: the mucociliary escalator, determined by the function of the mucosal ciliated epithelium, and the rheological properties of the bronchial secretion (its viscosity and elasticity), and is determined by the optimal ratio of its two layers—the outer (gel) and the inner (sol) [3].

Inflammation of the mucous membrane is caused by various irritants combined with infection (viral and bacterial). The production of secretory IgA decreases, and the content of lysozyme and lactoferrin in the mucus diminishes. Mucosal edema develops, followed by atrophy and epithelial metaplasia.

Chemical substances contained in the air cause damage to the respiratory tract, accompanied by mucosal edema and bronchospasm. This leads to impaired clearance and reduced barrier functions of the bronchial mucosa. Catarrhal contents are replaced by mucopurulent, and then purulent ones.

The spread of the inflammatory process to the distal parts of the bronchial tree disrupts surfactant production and reduces the activity of alveolar macrophages, which perform phagocytosis of bacteria and other foreign particles.

Impairment of the bronchial drainage function develops as a consequence of a combination of several factors:

• spasm of bronchial smooth muscles resulting from the direct irritating effect of exogenous factors and inflammatory changes in the mucous membrane;

• hypersecretion of mucus and changes in its rheological properties, leading to impaired mucociliary transport and bronchial obstruction by viscous secretion;

• metaplasia of the epithelium from columnar to stratified squamous and its hyperplasia;

• inflammatory edema and infiltration of the mucous membrane;

• allergic changes in the mucous membrane.

Various ratios of mucosal changes manifested by its inflammation determine the development of a particular clinical form of the disease.

In catarrhal bronchitis, superficial changes in the structural and functional properties of the mucosa predominate; in mucopurulent (or purulent) bronchitis, processes of infectious inflammation predominate. Transition from one clinical form of bronchitis to another is possible. Thus, catarrhal bronchitis, if protracted, may become mucopurulent due to a superimposed infection, etc.

When predominantly large-caliber bronchi are involved (proximal bronchitis), bronchial patency disorders are not pronounced. Affection of small and medium-caliber bronchi frequently proceeds with impaired bronchial patency, which, as a rule, is pronounced during exacerbations of CB.

Comment. All of the listed exogenous and endogenous factors, as well as pathogenetic mechanisms, are the cause of the development of other diseases, primarily COPD, which must be taken into account in clinical practice.

1.3 Epidemiology of the Disease or Condition

Modern studies on the prevalence of CB have not been published. Table 2 provides an overview of the prevalence of cough, sputum production, and CB in population-based studies.

Table 2. Prevalence of cough, sputum production, and CB in population-based studies

Comment. Most of the cited sources refer to the prevalence of cough and sputum production without specifying the diagnosis. In the Russian Federation, data from one study showed a CB prevalence ranging from 10% to 20% [14].

1.4 Features of Coding the Disease or Condition

• J40 Bronchitis, not specified as acute or chronic

• J41 Simple and mucopurulent chronic bronchitis

  - J41.0 Simple chronic bronchitis

  - J41.1 Mucopurulent chronic bronchitis

  - J41.8 Mixed, simple and mucopurulent chronic bronchitis

• J42 Chronic bronchitis, unspecified

1.5 Classification of the disease or condition

I. Functional characteristics:

• non-obstructive

• with obstructive syndrome

II. Nature of inflammation:

• catarrhal

• mucopurulent

• purulent

III. Severity of the course:

• mild

• moderate

• severe

IV. Phase of the disease:

• exacerbation

• unstable remission (fading exacerbation)

• clinical remission.

1.6 Clinical presentation of the disease or condition

The main and essential symptom of chronic bronchitis (CB) is a cough with sputum production. CB may coexist with any of the following conditions:

(a) localized lung diseases of any kind, such as tuberculosis,

pneumonia, cystic diseases, and bronchiectasis;

(b) generalized lung diseases (obstructive, granulomatous, and interstitial diseases, pneumoconioses);

(c) primary cardiovascular or renal diseases.

Some patients claim to have a chronic or recurrent cough without sputum production; however, sputum is present but swallowed by the patient. In cases where the cough is non-productive, it may be regarded as a "chronic dry cough" until the specific cause of the cough is determined.

Formulation of the clinical diagnosis of "chronic bronchitis"

• Clinical variant (non-obstructive, with obstructive syndrome)*

• Form of the disease (by the nature of inflammation: catarrhal, catarrhal-purulent, purulent)

• Phase of the process (exacerbation, fading exacerbation or unstable remission, remission)

• Complications

*When formulating the diagnosis of chronic non-obstructive bronchitis, the term "non-obstructive" may be omitted.

Comment. It is not recommended to indicate obstructive syndrome when formulating the diagnosis of CB, except for newly diagnosed exacerbation of the disease. The presence of obstructive syndrome requires clarification of the diagnosis and is not a manifestation of CB. Complications are not typical for CB.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Overdiagnosis of CB among patients and physicians is very common. In the United States, estimates from national surveys conducted by the National Center for Health Statistics show that statistical data underestimate the prevalence of COPD by 50%, because many patients are not critical of their symptoms and the disease remains undiagnosed. The overwhelming majority of people (88.4%) who reported a self-reported CB diagnosis or a diagnosis confirmed by a physician did not meet the standard criteria for CB.

Diagnostic criteria:

1. "Cough anamnesis" (minimally productive cough or cough with sputum production for 3 months for at least 2 years)

2. Absence of other bronchopulmonary pathologies (tuberculosis, bronchiectasis, pneumonia, bronchial asthma, lung cancer, etc.) that account for the "cough anamnesis"

3. Detection of airway obstruction (its reversible and irreversible components) during the differential diagnosis of COPD.

The diagnostic scheme for chronic bronchitis is presented in Appendix B1.

Differential diagnosis of chronic bronchitis is carried out with diseases accompanied by chronic cough syndrome (cough lasting more than 8 weeks) [22-24].

A thorough history taking, evaluation of clinical symptoms, and physical examination data make it possible to exclude serious, life-threatening diseases (see Table 3) [22].

Table 3. List of diseases accompanied by chronic cough [23]

Note: SI – smoking index

Taking into account the potentially wide range of diseases/pathological conditions, accompanied by a chronic cough, it is advisable to single out frequent, less frequent, and rare ones among them (see Table 4) [21].

Table 4. List of frequent and rare diseases accompanied by chronic cough

Given the kinship of risk factors, the similarity of pathomorphological changes at the level of the large airways, and, as a consequence, the resemblance of clinical manifestations (chronic productive cough), a practicing physician most often faces the need to differentiate between CB and COPD.

The simplest and most demonstrative test in this case is the measurement of unforced respiratory volumes and flows with a bronchodilator test. The formalized spirometric criterion for COPD is airflow limitation (FEV₁/FVC^[1] < 0.7), whereas in patients with CB outside of exacerbation, the studied parameters of external respiration function turn out to be close to the predicted values [21].

Cough as an adverse drug reaction (ADR) can develop in 5–20% of patients receiving ACE inhibitors^[2] and is associated with the accumulation of bradykinin and other cough mediators. It is important to emphasize that the onset of cough is not related to either the dose or the duration (from several days to several months) of drug administration. As a rule, after discontinuing the ACE inhibitor, the cough stops within the next 1 to 4 weeks. In contrast, angiotensin II receptor blockers (sartans) do not cause cough and are considered an acceptable alternative to ACE inhibitors if this ADR develops [25].

Cough associated with upper respiratory tract diseases (CAURTD) or "post-nasal drip" is often observed in patients with allergic (seasonal or perennial), non-allergic (vasomotor), and drug-induced ("rebound" effect after discontinuing long-term therapy with decongestants and other topical medications) rhinitis, chronic bacterial rhinosinusitis, and anatomical abnormalities (deviated nasal septum). In more than 20% of cases, the cough that develops in these conditions is "silent," i.e., not accompanied by prominent symptoms of the corresponding upper respiratory tract disease. The diagnosis of CAURTD can be considered established only after targeted examination (MSCT^[3] of the paranasal sinuses, otorhinolaryngologist examination) and achieving a therapeutic effect from subsequent treatment [26].

In a certain proportion of patients with asthma, the disease may manifest as a cough in the absence of other symptoms and any abnormalities during physical examination (the so-called cough-variant asthma). Among patients with chronic cough, cough-variant asthma accounts for up to 30%.

Exacerbation of chronic bronchitis

Patients with CB have a higher incidence of acute respiratory infections than patients without bronchitis, and symptoms of acute upper respiratory tract infection are more often combined with signs of lower respiratory tract infection in them than in healthy individuals. During an exacerbation, cough and sputum production increase, and the sputum may become purulent. Exacerbations can be a cause of shortness of breath. It has been proven that other conditions, such as heart failure or pulmonary embolism, can mimic a CB exacerbation.

Although there is no single universally accepted definition of a CB exacerbation, most researchers agree that this condition is associated with a deterioration in a stable patient's status, characterized by an increase in sputum volume, the appearance of purulent sputum, and/or dyspnea. Exacerbations are often preceded by symptoms of an upper respiratory tract infection. Evidence of viral infection is found in approximately one-third of episodes. Common viral infections in outpatient settings include rhinovirus, coronavirus, influenza B, and parainfluenza. Viral respiratory infections predispose to bacterial superinfection because they impair adequate mucociliary clearance and increase the risk of aspiration of secretions containing bacteria from the upper respiratory tract. The question of whether bacterial overgrowth is the cause of a CB exacerbation is controversial. During remission, many patients with CB, especially smokers, harbor their own opportunistic flora (Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae). These same microorganisms are found in patients during an exacerbation. At the same time, molecular sputum typing has shown that CB exacerbations are often associated with a new, exogenous strain. Most episodes of CB exacerbations respond well to therapy.

2.1 Complaints and Anamnesis

Symptoms:

Cough is the main complaint in patients with CB.

Characteristics of cough:

• by time of occurrence: morning, day, evening, night;

• by periodicity: frequent, intermittent, constant, paroxysmal, painful, painless;

• by character: non-productive (dry), productive (wet);

• by intensity: throat clearing, mild, severe;

• by timbre: silent, throat-clearing, harsh;

• by duration: episodic, short-term, or paroxysmal, constant;

• by course: acute cough up to 3 weeks, subacute from 4 weeks to 8 weeks, chronic more than 8 weeks.

History of present illness:

The onset of CB is gradual: morning cough with the discharge of mucous sputum, which gradually begins to bother the patient throughout the day, worsening in cold and damp weather, persisting on most days for a period of at least 3 months consecutively for 2 or more years, and becoming constant over the years [17].

CB symptoms should be identified using affirmative answers to all of the following questions, obtained from search data in the National Library of Medicine (PubMed) published in August 2004, starting from 1950 (Table 5) [16]. The search was limited to human studies using the search terms "cough", "postinfectious cough", "postviral cough", "Bordetella pertussis", "pertussis infection", and "pertussis" [16].

Table 5. Cough in chronic bronchitis. ACCP (American College of Chest Physicians) evidence-based clinical practice guidelines [16]

Positive answers to all questions indicate CB [16].

Questionnaires for cough assessment are presented in Appendices G1–G2.

LoE CGoE 5Level of Evidence C (Grade of Recommendation 5)

In the early stages of CB, cough is noted only in the mornings — the "morning toilet of the bronchi" with a small amount of sputum; cough may increase in cold, damp weather.

Over time, the frequency of the cough increases (morning hours, morning and daytime hours, throughout the day). It occurs as a result of irritation of vagus nerve receptors in reflexogenic cough zones located in the mucous membrane of the trachea and the branching sites of the main bronchi ("spurs").

There are no cough receptor zones in the small bronchi, so sputum-producing cough is the main manifestation of proximal bronchitis. With pronounced expiratory collapse of the trachea and large bronchi (sagging of the membranous part of the trachea into its lumen and collapse of the bronchi during exhalation), the cough takes on a "brassy" character and may be accompanied by syncopal states (brief loss of consciousness due to acute cerebral hypoxia).

2.2 Physical Examination

Physical pathological signs in patients with CB may be absent. Auscultatory changes, namely: scattered dry rales, predominantly in the posterior lower parts of the chest, harsh buzzing dry rales when large and medium bronchi are involved, as well as wheezes, especially well audible on exhalation, are characteristic of small airway disease, indicating bronchospastic syndrome.

Comment. The indicated lung auscultation pattern requires timely differential diagnosis with other respiratory diseases

The evolution of bronchitis, as well as associated complications, alters the findings obtained during direct physical examination of the patient.

Signs of hyperinflation, pulmonary emphysema, and respiratory failure point toward COPD.

• During the physical examination of patients, it is recommended to perform lung and bronchial auscultation during forced breathing, as well as in the supine position when establishing the diagnosis of "Chronic bronchitis" [20].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

2.3 Laboratory Diagnostics

In the initial period of the disease, as well as in patients during the period of chronic bronchitis (CB) remission, laboratory and instrumental parameters may show no changes. With the progression of CB, laboratory and instrumental diagnostic methods become essential. They are used to detect the activity of the inflammatory process, clarify the clinical form of the disease, identify complications, and perform differential diagnosis with diseases having similar clinical symptoms.

• For the purpose of diagnosing "chronic bronchitis" in patients with chronic productive cough lasting at least 3 consecutive months for 2 or more years, it is recommended to establish the diagnosis of CB after ruling out other possible respiratory or cardiac causes [2].

GCR CLOE 5Level of Evidence C (Level of Likelihood of Evidence 5)

• To identify risk factors for chronic bronchitis, all patients with chronic cough are recommended to undergo an assessment of direct exposure to respiratory irritants (various types of cigarette smoke); passive exposure to cigarette smoke at work and at home; evaluation of the smoking index (pack-years); adverse occupational and/or living conditions, as all of these are predisposing factors for the development of chronic bronchitis. An assessment of the frequency of CB exacerbations during the year must also be performed [2].

GCR CLOE 5Level of Evidence C (Level of Likelihood of Evidence 5)

Comments: The stable course of CB is not accompanied by systemic inflammation or biochemical disorders.

Comments: The course of CB is not accompanied by respiratory failure, and its presence indicates either COPD or another underlying disease.

2.4 Instrumental Diagnostics

Radiological methods

Comments: In the majority of these patients, chest radiographs show no pulmonary changes. In long-standing CB, a reticular deformation of the pulmonary pattern is observed, which is often combined with other signs of distal bronchitis. Chest radiography assists in diagnosing complications or other respiratory pathologies (pneumonia, bronchiectasis) and in differential diagnosis with conditions where symptoms of bronchitis may accompany the primary process (tuberculosis, tumors, etc.) [1, 2].

Computed tomography

Comments: Chest computed tomography is used not to confirm CB, but to detect other pathological changes in the respiratory organs (bronchiectasis, pulmonary emphysema, etc.).

Respiratory function testing

Comments: During a stable course of CB, pulmonary function test values remain within normal limits.

A stable course of CB (clinical remission phase) from a functional standpoint is accompanied by a post-bronchodilator FEV₁/FVC ratio of ≥ 0.7, while the bronchodilator test with salbutamol** 400 mcg is negative (an increase in FEV₁ of less than 12% and less than 200 ml from the baseline value). CB is not accompanied by bronchial obstruction syndrome (BOS) (Appendix G3) [9, 21].

Electrocardiography

Comments: Electrocardiography does not provide additional information in CB.

2.5 Other Procedures

Differential diagnosis of chronic bronchitis

Clinical symptoms and functional impairments determined by spirometry in patients with stable CB, indicating BOS with a negative bronchodilator test, require differential diagnosis, primarily with COPD (Table 6).

Table 6. Clinical and functional characteristics of patients with chronic bronchitis and COPD [32]

Note: ¹FEV1/FVC < 0.7 on spirometry

²Chronic cough for at least 3 months per year for 2 years

Comments: GERD is another very frequent cause of chronic cough (according to several studies, the detection rate of GERD in patients with long-standing cough reaches 70%), which may be caused by the reflux of gastric contents through a relaxed lower esophageal sphincter into the esophagus, larynx, and respiratory tract [28].

It is important to emphasize that in some patients, cough may be the only symptom of GERD in the absence of typical manifestations such as heartburn, regurgitation, or a sour taste in the mouth [28].

Stage 1

Detailed study of the medical history, physical examination of the patient.

Chest X-ray.

Smoking cessation (in smoking patients).

Discontinuation of ACE inhibitors or their replacement with angiotensin II receptor blockers.

Stage 2

Consider performing chest computed tomography (CT) in cases of:

• long-term smoking patients meeting lung cancer screening criteria (low-dose CT)

• pathological lung changes detected during a prior chest X-ray

• presence of symptoms such as anorexia, weight loss, hemoptysis, fever, chills, dyspnea, finger clubbing (osteoarthropathy of the terminal phalanges), bilateral crackles/crepitations in the basal lung fields

Stage 3

Empirical therapy with systemic antihistamines and/or decongestants and other topical medications for suspected upper respiratory tract disease.

Stage 4

Rule out bronchial asthma:

• pulmonary function testing with medication administration (bronchodilator test), eosinophil count in cytological examination of bullous fluid, peripheral blood eosinophil count,

• in case of parameters characteristic of bronchial asthma, trial therapy with inhaled glucocorticoids/systemic corticosteroids.

Step 5

Lifestyle modifications (weight loss, avoidance of fatty and acidic foods, alcohol, chocolate, coffee, and tea) for ≥8 weeks.

Step 6

Chest CT, if not previously performed

Step 7

Consider specialist consultations (pulmonologist, otolaryngologist, gastroenterologist) [24].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Exacerbation of bronchitis

Characteristic features of chronic bronchitis (CB) include the seasonality of exacerbations (early spring, late autumn), with the phases of exacerbation and remission in this variant of bronchitis being quite clearly demarcated.

Anamnesis reveals increased sensitivity to hypothermia, and many patients report a history of prolonged smoking.

In a number of patients, the disease is associated with occupational hazards; men are affected more often than women.

Comments: The presence of all three criteria in a patient is described as Type I, two of them as Type II, and one as Type III CB exacerbation. Assessment of the severity of CB exacerbation is based on the analysis of clinical symptoms.

Physical examination

• In all patients with CB exacerbation, it is recommended to perform a general physical examination, measure respiratory rate, heart rate, blood pressure, body temperature, and perform lung auscultation to screen for general pathologies and diagnose CB exacerbation [30, 31, 80].

GCR CLOCE 5Grade of recommendation C, level of evidence 5.

Comments: Physical signs of CB exacerbation heard during lung auscultation include harsh breathing, diffuse dry wheezes, and rhonchi. When secretion appears in the bronchi, moist rales may be heard. However, it should be noted that physical examination findings depend on many factors, including the patient's age, presence of comorbid conditions, etc.

• All patients with CB exacerbation are recommended to undergo a complete blood count (CBC) (B03.016.003) and serum C-reactive protein (CRP) level testing.

GCR CLOCE 5Grade of recommendation C (level of evidence 5) [2].

Comments: Blood test findings are not specific; however, along with clinical criteria, they help decide on the need for additional examination to rule out pneumonia and the prescription of systemic antimicrobial drugs. Leukocytosis > 10–12×10⁹/L and/or a band neutrophil shift > 10%, neutrophil-to-lymphocyte ratio > 20, and serum C-reactive protein level > 100 mg/L indicate a high probability of bacterial infection, which requires further evaluation of the patient to rule out pneumonia. In outpatient practice, microbiological tests aimed at verifying the etiological diagnosis during a CB exacerbation do not significantly impact treatment tactics.

Comments: Chest radiography is recommended to be performed in the anterior-posterior (posteroanterior) and lateral projections [30];

• All patients with CB exacerbation are recommended to undergo pulse oximetry with SpO2 measurement to detect signs of respiratory failure [16, 19–24, 64, 80].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Pulse oximetry is recommended as a simple and reliable screening method for detecting patients with respiratory failure. At the same time, the presence of respiratory failure in a patient with CB exacerbation should prompt the physician to search for another disease. CB exacerbation is typically not accompanied by a drop in SpO2.

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

The main goals of CB therapy should target various pathophysiological mechanisms underlying this disease:

• reduce excessive bronchial secretion formation;

• reduce the severity of inflammation in the airways;

• improve bronchial secretion clearance by enhancing ciliary transport and reducing mucus viscosity;

• modify cough. These goals can be achieved using a range of non-pharmacological and pharmacological agents.

3.1 Non-pharmacological therapy

Smoking cessation

• All patients with CB are recommended to quit smoking for the prevention of exacerbations and better control of disease symptoms [35, 81].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: The most effective means of achieving cough and sputum production control in patients with CB is the cessation of contact with known airborne irritants.

Patients with CB who are exposed to prolonged airborne irritants (tobacco smoke components, workplace airborne irritants) are recommended to avoid them. Thus, smoking cessation is accompanied by the cessation of cough or a substantial reduction in its intensity in 94–100% of patients, with this effect being persistent (> 1 month) in half of the cases [33]. The long-term effects of smoking cessation are equally striking: a 5-year follow-up study also indicated that the overwhelming majority of patients with CB who quit smoking (> 90%) showed regression or reduction in the severity of main disease symptoms, which persisted throughout the subsequent follow-up [34].

Routine physician advice leads to smoking cessation in 7.4% of patients (2.5% more than in controls), while a 3–10 minute counseling session brings the cessation rate to about 12% [34]. With greater time investment and more complex interventions including skills training, problem-solving education, and psychosocial support, the cessation rate can reach 20–30% [34].

• All smoking patients with CB, in the absence of contraindications, are recommended to be prescribed pharmacotherapy for nicotine dependence to support cessation efforts [35–38].

GCR BLOCE 2Grade of recommendation B (level of evidence 2).

Comments: Pharmacotherapy effectively supports smoking cessation efforts. First-line drugs for the treatment of tobacco dependence include varenicline and medications used for nicotine dependence (N07BA). The combination of physician advice, support groups, skills training, and nicotine replacement therapy leads to smoking cessation after 1 year in 35% of cases, with 22% remaining non-smokers after 5 years [39].

Medicines

Mucolytic agents

Comments: Observational and real-world clinical practice studies indicate that mucolytic agents alter the volume and composition of bronchial secretion, facilitating its elimination in upper and lower respiratory tract diseases, including chronic bronchitis (CB) [40]. Since modern guidelines for the pharmacotherapy of chronic cough view symptomatic treatment as one of the primary goals, it is evident that facilitating sputum expectoration and, indirectly, reducing cough make mucolytics an important component of therapy for patients with CB [41-44]. In turn, relieving cough contributes to the resolution of other associated symptoms: sleep disturbances, general malaise, chest pain, dyspnea, and other manifestations of respiratory discomfort.

It is important to emphasize that possessing both anti-inflammatory and antioxidant activity, some of them (ambroxol**, bromhexine, carbocisteine, acetylcysteine**) are capable of reducing the frequency and duration of CB exacerbations [44].

Antitussive drugs

Bronchodilators

• Patients with stable CB are recommended to receive bronchodilators (selective beta2-agonists, anticholinergics) to relieve cough [46, 48, 82].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comments: Short-acting beta2-agonists facilitate sputum expectoration by widening the airway lumen, increasing the ciliary beat frequency of the ciliated epithelium, and hydrating the bronchial mucosa, as well as reducing the viscosity of bronchial secretions [46]. Long-acting beta2-agonists (formoterol**, #indacaterol**) also increase the ciliary beat frequency of the bronchial mucosal epithelium while simultaneously increasing peak expiratory flow, which is a crucial component of effective cough [46].

Long-term administration of the short-acting anticholinergic ipratropium bromide** in patients with stable CB reduces the frequency of recurrent cough episodes, its severity, and also contributes to a significant decrease in the volume of expectorated sputum [47]. On the other hand, administration of the long-acting anticholinergic tiotropium bromide** failed to demonstrate an effect on cough severity and frequency [48].

Glucocorticosteroids

Antibiotics

Comments: Previous studies evaluating the efficacy of antibiotics prescribed prophylactically to patients with stable CB indicated a minimal, but statistically significant reduction in the duration of recurrent exacerbations of the disease

3.2. Other treatment methods

• To improve mucociliary clearance and facilitate sputum clearance, positive expiratory pressure is not recommended for patients with stable CB [48].

GCR CLOCE 5Grade of recommendation C (level of evidence 5).

Treatment of exacerbation of chronic bronchitis

Antibiotics

• Anthonisen criteria are recommended to be used as indications for antibacterial therapy in CB exacerbation [83].

GCR BLOCE 1Grade of Recommendation B (Level of Evidence 1)

Comments:

Anthonisen criteria used: A). 3 Anthonisen "major" criteria (increased dyspnea; increased volume of expectorated sputum; increased sputum purulence) or 2 Anthonisen "major" criteria (one of them being increased sputum purulence);

B). 1 "major" + ≥ 2 Anthonisen "minor" criteria (upper respiratory tract infection; fever; wheezing; increased cough; increased heart rate and/or respiratory rate by ≥ 20%).

Comments: The optimal duration of systemic antibacterial therapy during CB exacerbations is 5-7 days [59-62].

Table 7. Antibacterial therapy for acute exacerbation of chronic bronchitis

Comments: ¹—in case of intolerance to β-lactams (amoxicillin** or cephalosporins), it is recommended to prescribe new macrolides (azithromycin** or clarithromycin**) [84]. In addition to its main antibacterial action, clarithromycin** exhibits immunomodulatory and anti-inflammatory properties. An important advantage of clarithromycin** is the protection and normalization of ciliated epithelium functions, improvement of mucociliary clearance, inhibition of chemotaxis in the airways, and suppression of mucus production and release. Furthermore, clarithromycin** inhibits the production of pneumolysin, an important virulence factor of S. pneumoniae [85].

²—presence of ≥1 of the following risk factors for therapeutic failure: age > 65 years; serious comorbid conditions (diabetes mellitus, heart failure, chronic liver and kidney disease, malignant neoplasms); hospitalization for CB exacerbation within the last 12 months [55,56]

• During a CB exacerbation, it is recommended to prescribe inhaled short-acting selective beta2-agonists (salbutamol**), short-acting anticholinergics (ipratropium bromide**) [63], or their fixed combination for the effective treatment of CB exacerbation [89-91].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comments: The efficacy of SABA and SAMA in acute CB exacerbations is approximately equal; the advantage of SABA is a faster onset of action, while SAMA offers high safety and good tolerability.

Glucocorticosteroids

• Patients with an acute exacerbation of chronic bronchitis generally do not require corticosteroids. Bronchoobstructive syndrome during an acute exacerbation of chronic bronchitis requires clarification of its diagnostic category. To relieve bronchoobstructive syndrome, a short course (5 days) of systemic corticosteroids is recommended (e.g., oral #prednisolone** 30-40 mg daily, or nebulized budesonide** 4 mg daily for 5 days) in order to rapidly restore pulmonary function [2, 21, 86, 88, 92, 93].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: the expert community advises a 5-day course of systemic corticosteroid therapy for exacerbations of the disease with obstructive syndrome [92]. However, the optimal dose and duration of systemic corticosteroid administration are unknown [92].

Oxygen therapy

Mucolytic therapy and bronchial secretion clearance methods

• Clinical benefits of postural drainage and chest percussion in stable patients with chronic disease or during an exacerbation have not been proven, and the use of these treatment methods is not recommended [2].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• Pulmonary rehabilitation courses are recommended for physically inactive patients with chronic bronchitis and frequent exacerbations to improve their condition [68, 69].

GPP CLOE 5Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) level C (Level of Evidence 5)

Comments: Effects of pulmonary rehabilitation include [68, 69]:Improved exercise tolerance;

—    Reduction of dyspnea sensation;

—    Improvement of health-related quality of life;

—    Reduction in the number and duration of hospitalizations;

—    Reduction of anxiety and depression levels associated with chronic bronchitis;

—    Improvement of hospitalization outcomes regarding chronic bronchitis exacerbations.

• All patients with chronic bronchitis are recommended to include psychological support and depression management, patient education, nutritional support, and physical training in their rehabilitation program to comprehensively improve their condition [68].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Physical training

• For pulmonary rehabilitation in patients with chronic bronchitis, it is recommended to include physical training in the program [68].

GCR CLOCE 5Grade of Recommendation C (Level of Evidence 5)

Comments: The development of training programs requires an individualized approach and depends on the patient's baseline condition and comorbidities, as well as patient motivation.

Treadmill or stationary bicycle exercises lasting from 10 to 45 minutes per session with an intensity ranging from 50% of peak oxygen uptake to the maximum tolerated level can be used as physical training [68]. In general clinical practice, when resources for full-scale rehabilitation are lacking, daily walks (e.g., from 30 minutes to 60 minutes or more, depending on physical status and severity of comorbidities), as well as nordic walking training, should be recommended. Some programs include upper-extremity muscle training, which improves their function and strength [70].

The effect of physical training has a prolonged action.

• For pulmonary rehabilitation, it is recommended to include respiratory muscle training using various types of devices (respiratory trainers) in patients with chronic bronchitis [70].

LoR CLE 3Level of Recommendation C (Level of Evidence 3)

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

Patient education

• For pulmonary rehabilitation of patients with chronic bronchitis, it is recommended to include patient education in the program [71, 72].

LoR CLE 3Level of Recommendation C (Level of Evidence 3)

Comments: Patient education is an effective means of achieving specific goals, including smoking cessation. Multidisciplinary educational programs may be useful for elderly patients.

• For pulmonary rehabilitation of patients with chronic bronchitis, it is recommended to include an individualized written action plan aimed at self-management in the program [72].

LoR CLE 3Level of Recommendation C (Level of Evidence 3)

Comments: Creating an individualized written self-management action plan leads to improved quality of life and shortens recovery time during an exacerbation due to less delay in initiating treatment by the patient. Patient education along with self-management instructions and an individualized written action plan can improve exacerbation outcomes [72].

5. Prevention and Dispensary Observation

Secondary prevention measures are similar to those for primary prevention, but are aimed at preventing disease progression. An important measure of secondary prevention of chronic bronchitis is timely treatment of disease exacerbations if they occur, as well as sanitation of the nasopharynx and other foci of chronic infection.

Vaccination in chronic bronchitis

• Patients with chronic bronchitis are recommended to receive influenza and pneumococcal vaccination for the prevention of influenza, bronchopulmonary diseases, and their exacerbations [73-75].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: Influenza vaccination is included in the National Schedule of Preventive Vaccinations of Russia by Order No. 125n dated March 21, 2014.

• Meta-analyses and clinical studies have shown that OM-85 reduces the frequency, duration, and severity of chronic bronchitis exacerbations, and also decreases the number of antibiotic prescriptions with a well-tolerated safety profile in this population. The immunomodulation by OM-85 was noted by an increase in immunoglobulin (Ig)A and interferon-gamma (IFN-γ) concentrations, a decrease in IgE levels, an increase in the CD4/CD8 ratio, and enhanced alveolar macrophage activity, as observed in many of these studies [94-97]. Systematic reviews involving patients with chronic bronchitis and/or COPD have demonstrated the beneficial effects of OM-85 in reducing exacerbations [98-102].

LOE 5GRADE level C (Level of Evidence – 5).

Comments: Further research is currently needed to determine the role and place of bacterial lysates in chronic bronchitis treatment regimens.

6. Organization of Medical Care

Diagnosis and management of patients with chronic bronchitis are carried out by a general practitioner or family physician [76]. When necessary, consultation with specialists in other fields is also performed. The primary care physician performs a comprehensive assessment of symptoms, medical history, and the patient's lifestyle history. Risk factors for chronic bronchitis (bad habits, occupational history, living conditions) are also assessed. The patient's examination is performed by the primary care physician: pulmonary function testing with a bronchodilator test, chest radiography [76]. The general practitioner, primary care physician, or family physician (and a pulmonologist if necessary) formulates the diagnosis in accordance with the current version of clinical guidelines, conducts additional patient examinations if indications are present, and determines the required treatment regimen for a patient with chronic bronchitis. The effectiveness of the prescribed treatment plan is monitored at 1, 3, and 12 months in the first year, and annually thereafter [76].

Indications for a pulmonologist consultation are [76]:

• clarification of the diagnosis of chronic bronchitis,

• differential diagnosis,

• selection of a patient management algorithm, including pharmacological and non-pharmacological methods of treatment for patients with chronic bronchitis,

• change of therapeutic strategy in the absence of effect from previously prescribed therapy.

Treatment of patients for chronic bronchitis exacerbation is carried out on an outpatient basis [76].

Indications for referral to a day care facility of a medical organization [76]:

• need for differential diagnosis of chronic bronchitis when necessary examinations cannot be performed on an outpatient basis,

• inefficacy of initial outpatient exacerbation therapy within three days (increased sputum expectoration, increased purulence of sputum, persistent fever),

• exacerbation of chronic comorbidities without dysfunction of vital organs.

Scheduled and emergency admissions of patients with chronic bronchitis to an inpatient hospital are not provided [76].

Indications for completion of treatment for chronic bronchitis exacerbation [76]:

• establishment of the definitive diagnosis (exclusion or confirmation of chronic bronchitis),

• clinical stability of the condition for 12-24 hours,

• decrease in sputum expectoration and purulence, normalization of body temperature,

• the patient is aware of the need to quit smoking,

• the patient understands the need for treatment with mucolytic drugs,

• the patient has been trained and is able, if necessary, to correctly use short-acting inhaled selective beta2-agonists, anticholinergics, and their fixed combinations.

Indications for referral of patients with chronic bronchitis exacerbations to a day care facility are [30]:

• need for additional diagnostic methods and differential diagnosis,

• appearance of new symptoms not typical of chronic bronchitis (dyspnea and its progression, febrile body temperature when influenza and other acute viral infections are ruled out);

• absence of a positive response to outpatient therapy within 3 days;

• severe comorbidities and conditions (e.g., heart failure or arrhythmia, diabetes mellitus, obesity, etc.);

• advanced age in the presence of concomitant diseases.

7. Additional Information

No additional information available

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Conflict of interest:

The working group members declare no conflict of interest

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. general practitioner (family physician);

2. internist;

3. district general practitioner;

4. pulmonologist

Methods used for evidence collection/selection:

electronic database searching.

Description of methods used for evidence collection/selection:

the evidence base for the recommendations includes publications included in the Cochrane Library, EMBASE, and MEDLINE databases. The search depth was 10 years.

Methods used to assess the quality and strength of evidence:

• expert consensus;

• assessment of significance in accordance with the rating scheme.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of evidence (LE) for prevention, treatment and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Methods used for evidence analysis:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Description of methods used for evidence analysis:

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its validity. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations derived from it.

The subjective factor can undoubtedly influence the assessment process. To minimize potential errors, each study was evaluated independently, i.e., by at least two independent members of the working group. Any discrepancies in assessments were discussed by the full working group. If consensus could not be reached, an independent expert was involved.

Evidence tables:

Evidence tables were completed by the members of the working group.

Methods used to formulate the recommendations:

Expert consensus.

Table 3. Scale for assessing levels of recommendation persuasiveness (LRP) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Economic analysis:

Cost analysis was not performed, and pharmacoeconomic publications were not analyzed.

Method of recommendation validation:

• External peer review;

• Internal expert review.

Description of the guideline validation method:

The preliminary version of these guidelines was reviewed by independent experts, who were asked to comment primarily on how accessible the interpretation of the evidence underlying the recommendations is for understanding.

Comments were received from primary care physicians, general practitioners, and pulmonologists regarding the clarity of the presentation of the recommendations and their assessment of the importance of the recommendations as a working tool in everyday practice.

The preliminary version was also sent to a non-medical reviewer for comments from the patients' perspective.

Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and the resulting changes made to the recommendations were logged. If no changes were made, the reasons for refusing to make changes were logged.

Consultation and peer review:

The preliminary version was posted for wide discussion on the RSS website so that the professional community could have the opportunity to participate in discussing and improving the recommendations.

The draft recommendations were also reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

Working Group:

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

Key recommendations:

LRP ALEL 1The levels of recommendation persuasiveness (A–C) and levels of evidence reliability (1, 2, 3, 4, 5) are provided when outlining the text of the recommendations.

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

1. Current drug package inserts

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

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

When conducting the test of unforced respiratory volumes and flows (spirometry), it is recommended to perform at least three technically correct forced vital capacity (FVC) breathing maneuvers until reproducible results are obtained: the maximum and subsequent highest values of FVC and FEV₁ should differ by no more than 150 ml. In cases where the FVC value does not exceed 1000 ml, 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 bronchodilation test is performed with a short-acting beta2-agonist (salbutamol**) at a single dose of 400 mcg via a pressurized metered-dose inhaler with a spacer. A repeat test of unforced respiratory volumes and flows (spirometry) should be performed 15–30 minutes after inhalation of the β₂-agonist.

Formula for calculating BDR:

Absolute increase (ml) = FEV_{1 post}(ml) - FEV_{1 base}(ml),

where FEV_1base is the value of the spirometric parameter before bronchodilator inhalation, and FEV_{1 post} is the value of the parameter after bronchodilator inhalation.

When evaluating the bronchodilation test, it is recommended to consider adverse cardiovascular reactions (tachycardia, arrhythmia, increased blood pressure), as well as the appearance of symptoms such as agitation or tremor.

3. Chronic cough in chronic bronchitis. ACCP (American College of Chest Physicians) Evidence-Based Clinical Practice Guidelines

Title in Russian: Chronic cough in chronic bronchitis

• Original title: Chronic cough due to chronic bronchitis

• Source (validated publication):

Braman S.S. Chronic cough due to chronic bronchitis. ACCP evidence-based clinical practice guidelines. Chest 2006; 129(Suppl 1): 104S-115S.

Type (underline):

• rating scale

• index

• questionnaire

• other (specify)

• Purpose: assessment of respiratory symptoms

• Content (template):

Positive answers to all questions indicate CB.

Appendix B. Physician Action Algorithms

Appendix B1. Diagnostic flowchart for chronic bronchitis

Appendix C. Patient Information

• Consult a doctor. It is important to start treatment on time, based on evidence-based medicine principles

• Outpatient regimen.

• Indoor air should be sufficiently cool and humid. During the heating season, the air must be additionally humidified.

• Increase fluid intake, including the use of alkaline mineral water

• Do not take antibacterial drugs on your own

• Antipyretics (paracetamol, ibuprofen, combination dosage forms containing paracetamol/ibuprofen, or paracetamol and ibuprofen) may be used if the temperature exceeds 38°C

• Gargling, mustard plasters, pepper patches, and medical cupping are not advisable.

• Do not take antibacterial drugs on your own, as the cause of exacerbations is most often non-bacterial.

• Mustard plasters, pepper patches, medical cupping, electrophoresis, UHF therapy, and other physiotherapy procedures are strictly contraindicated

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

Appendix G1. Standardized Respiratory Symptoms Questionnaire

• Russian title: Standardized Respiratory Symptoms Questionnaire

• Original title: Definition and Classification of Chronic Bronchitis.

• Source (validated publication):

  Stuart-Harris C.H. (chairman), Crofton J., Gilson J.C., Gough J. et al. Definition and Classification of Chronic Bronchitis. Lancet 10 April 1965; 775-779.

Type (underline):

• rating scale

• index

• questionnaire

• other (specify)

• Purpose: assessment of respiratory symptoms

• Content (template):