Chronic obstructive pulmonary disease (COPD) is a major health and social problem in all industrialized countries. COPD is one of the most widespread diseases. It is a leader in the number of days of incapacity, causes of disability and, death and is associated with significant economic damage. Most epidemiological studies have shown that the incidence and mortality of the disease continue to grow. Experts predict that COPD will become the world’s third leading cause of death and the fifth leading cause of disability by 2020 (Juvelekian & Stoller, 2012). According to official statistics, the disease affects 329 million people worldwide although this number is much higher (Juvelekian & Stoller, 2012). The reason is that the disease is diagnosed at later stages when the most modern methods of treatment are not able to slow down its progression, which is the main cause of the high mortality of patients.
A special role in the pathogenesis of COPD belongs to chronic inflammation, which is a key element in the progression of the disease. The inflammation leads to the formation of main morphological manifestations, namely the pulmonary emphysema, airway remodeling, and peribronchial fibrosis. The slow and progressive course of the disease is an important feature of COPD. It complicates early diagnosis and leads to delayed treatment. The asymptomatic or blurred course of the disease during the first 10-15 years, when the therapy is the most promising, dictates the need for fundamentally new approaches to diagnosis, treatment, and prevention of the disease (Juvelekian & Stoller, 2012). The use of biomarkers and erdosteine in the treatment of COPD will help to improve early diagnosis and efficiency of treatment as well as reduce the incidence of hospitalization and death.
Brief Description of the Disease
The chronic obstructive pulmonary disease is a lung disease in which the person finds it difficult to breathe. It is caused by damage to the lungs for many years. COPD is often a combination of two diseases. The first one is chronic bronchitis. The airways are in a state of inflammation with a lot of mucus produced continuously during chronic bronchitis. The walls of the bronchi become thickened, which may cause narrowing of the lumen of the airways. It is extremely difficult to breathe in during this condition.
The second disease is emphysema. Alveoli walls are damaged and lose their elasticity in emphysema. As a result, the area of lungs decreases for exchanging gases (oxygen and carbon dioxide) between the blood and the inhaled air. The lack of oxygen in the blood results in shortness of breath.
Over time, COPD usually becomes more severe. The ongoing process of damaged lung tissue cannot be prevented. However, one can take steps to slow down the destruction of the alveoli in the lungs as well as to improve the state of health of a person suffering from COPD.
In most cases, COPD is caused by smoking. Over the years, the inhalation of tobacco smoke irritates the airways and destroys elastic fibers in the alveoli of the lungs. Passive smoking is also very bad. Other factors that may cause the occurrence of COPD include inhalation of the chemical vapors, dust, and air pollution for a long period. Typically, the process of destruction of the lung tissue takes many years before the first symptoms so that COPD is most common in people who are older than 60 years. This and other features of the chronic obstructive pulmonary disease are considered in the set of scientific works.
Review of the Current Literature
Currently, the study of COPD is conducted mainly in the international online research project EPOCA (Enfermedad Pulmonar Obstructiva Cr?nica en Acci?n) aimed at revealing features of COPD in different countries. The extent of studying the problem is so large that the risk of death after the admission of the patient with acute exacerbation of COPD may be predicted even on the basis of clinical evaluation in the emergency department.
Despite this progress, the increase in mortality from COPD continues (Takigawa et al., 2007). The rate of development of pathological changes characteristic of COPD is directly dependent on the age when the subject started smoking, the intensity, and the total length of smoking. Individuals with concomitant diseases occupy a special place in COPD patients. They can have a common etiology with COPD and arise as the iatrogenic factors in the treatment of COPD, complicating the treatment of COPD. About 15% of all cases of COPD are associated with hazardous working conditions of patients, namely the prolonged contact with dust, gases, and toxic substances (Chatila, Thomashow, Minai, Criner, & Make, 2008).
Development and Course of COPD
Dutch scientists examined 399 regular smokers with an average interval of 5.2 years (Geijer et al., 2006). The cumulative incidence was 8.3% while the average one was 1.6%. Severe obstruction did not develop in any case (Geijer et al., 2006). The risk of moderate COPD in smokers with initially mild COPD was five times higher than among people with normal spirograms. Age, smoking in childhood, cough, and a couple of episodes of lower respiratory tract infections were independent factors affecting the incidence of COPD of moderately severe flow (Geijer et al., 2006).
Spanish pulmonologists conducted a prospective analysis in a cohort of 596 patients with COPD who were observed for three years or until death. The ultimate goal was a rough estimate of mortality and its causes. It was concluded that the main causes of death from COPD were the following respiratory diseases: respiratory failure, pneumonia, and lung tumors (Celli, 2010).
In another study, 23% of the patients with COPD out of 985 patients who received standard treatment died within three years (Juvelekian & Stoller, 2012). The most important predictors of death were age and initial values of the forced expiratory volume (FEV1), but patients with low baseline values showed a relatively small decline in the future (Juvelekian & Stoller, 2012).
Analysis of the Causes and the Rate of Descent of FEV1
Publications indicate the importance of inflammation in COPD. One of the studies lasted two years and examined the role of the persistence of the respiratory syncytial virus. The authors noted that endobronchial inflammation is an independent factor in the annual decline in FEV1, but the conclusion about the importance of persistence of the virus in patients with COPD has not been made (Wilkinson, Donaldson, Johnston, Openshaw, & Wedzicha, 2006). In COPD, systemic inflammation and inflammation in the airways increase with time. High levels of these markers are associated with a more rapid decline in lung function (Wilkinson et al., 2006).
However, the above studies, as well as many others, did not consider the use of biomarkers in therapy for COPD. A review of several published studies enables to assume that some of the biomarkers may be used in non-pharmacologic treatment purposes.
The Use of Biomarkers in the Treatment of COPD
Currently, the risk of adverse events in patients with COPD is estimated on the basis of the history of exacerbations in the previous year as well as the degree of airway obstruction determined by spirometry. However, very few modern studies draw attention to biomarkers as predictors of COPD. System biomarkers in COPD were studied in several prospective studies. The identification of biomarkers that evaluate the regression of local and systemic inflammation in a short period of time can be regarded as a part of non-pharmacologic therapy for COPD.
The Lung Health Study included 4,803 patients with COPD of mild to moderate severity (Man et al., 2006). The study associated the increased C-reactive protein (CRP) with all-cause mortality, which had a relative risk (RR) of 1.79 (95% confidence interval (CI) 1.25 to 2.56) (Man et al., 2006). It was also associated with cardiovascular mortality (RR 1.51; 95% CI 1.20 to 1.90) and the cancer mortality (RR 1.85; 95% CI 1.10 to 3.13) (Man et al., 2006). It is important that the value of CRP level was the highest during the first year of treatment and decreased with time (RR of death in the first year was 4.03; 3.30 for 2-year mortality and 1.82 for mortality within five years).
The Copenhagen City Heart Study has shown that COPD patients with elevated CRP levels have a higher risk of hospitalization (hazard ratio (HR) 1.4; 95% CI 1.2 to 3.9) and lethal outcome (HR 2.2; 95% CI 1.2 to 3.9) associated with COPD (Kelly, Owen, Pinto-Plata, & Celli, 2013). The importance of CRP as a prognostic biomarker outcome of the disease was evaluated in a subsequent study. The results of the study suggested that CRP was not associated with survival of 218 patients with severe or moderate COPD observed for 36 months (Kelly et al., 2013). In this study, CRP levels were similar in survivors and patients who died (3.8, 95% CI 1.9 to 8.1 compared with 4.5, 95% CI 2.1 to 11.5 mg/L respectively, p = 0.22) (Kelly et al., 2013). The analysis of survivability found no differences between patients with CRP ? 3 and <3 mg/L (p > 0.05). According to the multivariate regression analysis, CRP did not become a predictor of mortality (HR 1.00, 95% CI 0.98 to 1.02, p = 0.56) in contrast to previously defined clinical predictors of mortality such as FEV1, tests with a six-minute walking, and PaO2 (Kelly et al., 2013).
Another Lung Health Study lasted for more than seven years and examined 4,787 individuals with mild to moderate COPD. The study explored the relationship of fibronectin to CRP as a biomarker of balance between reparative and inflammatory processes in the lungs (Man et al., 2008). The ratio of fibronectin with CRP in patients with COPD was correlated directly with the total mortality and mortality from cardiovascular diseases, but not from the respiratory diseases (Man et al., 2008). The same study evaluated the role of serum adiponectin as a predictor of outcome. It was found that serum adiponectin level correlated inversely with the frequency of hospitalization and death from coronary heart disease (HR 0.73; 95% CI 0.62 to 0.86) and cardiovascular diseases in general (HR 0.83; 95 % CI 0.73 to 0.94) (Man et al., 2008). It also found a direct correlation with mortality from respiratory causes (HR 2.09; 95% CI 1.41 to 3.11) (Man et al., 2008).
Cardiovascular disease is common in patients with COPD and associated with an increased rate of hospitalization and high mortality. Several studies have evaluated cardiac dysfunction biomarkers as predictors of mortality in patients with COPD. In particular, the scientists examined the level of brain natriuretic peptide (BNP) in 208 patients admitted to the emergency department with acute exacerbation of COPD (Mannino, Thorn, Swensen, & Holguin, 2008). BNP level was an independent predictor of the need for intensive care (HR 1.13; 95% CI 1.03 to 1.24) but was not a predictor of death in the immediate or long-term period.
Another study examined the high-sensitivity cardiac troponin T (hs-cTnT) as a biomarker of myocardial injury in 99 patients with COPD in the first days of hospitalization due to exacerbation of the disease during 1.9 years (Stolz et al., 2008). The study revealed that the level of hs-cTnT in 74% of patients was above the upper limit of normal (?14.0 ng/L) and an increase in this marker was associated with an increased risk of death (Stolz et al., 2008).
Thus, the identification of biomarkers can be regarded as a part of non-pharmacologic therapy for COPD because they identify new treatment opportunities and new biological mechanisms involved in the pathogenesis of COPD.
These studies emphasize the importance of cardiovascular mechanisms in the development of outcomes of severe COPD exacerbations. The results of studies conducted over the past years with the participation of a large number of COPD patients provided information about the relationship of biomarkers with clinically important endpoints, including hospitalization and death. The data will help to improve the efficiency of the treatment of the disease and reduce the incidence of hospitalization and death.
Inclusion of Erdosteine in the Treatment of COPD
One of the key tasks in the treatment of exacerbations of COPD is not only stabilization and gradual reduction of the occurrence of exacerbations, but also prevention of recurrence of the disease in the future and improvement of the quality of the patient’s life.
Mucolytic medicines such as erdosteine change the rheological properties of sputum, impact its consistency, change the saliva formation, and normalize the biochemical composition of the mucus. They are appointed if there is a viscous, mucous, mucopurulent or purulent sputum. Pathogenetic substantiation of the application of mucolytics in treating patients with acute exacerbation of COPD is beyond doubt, along with the use of antibiotics, bronchodilators, and anti-inflammatory medicines (Cazzola, Floriani, & Page, 2010).
The stable clinical effect in the treatment with mucolytic medicines observed by 2 to 4 days depending on the nature and severity of the disease (Cazzola et al., 2010). It has a significant beneficial effect on further treatment. The effectiveness of mucolytic therapy is obvious when assessing its positive impact on health, reduction of dyspnea on exertion, cough decrease, and improvement of the rheological properties of the sputum, as well as improvement of respiratory function. In addition, the use of mucolytic expectorant medications in the treatment of COPD could have a significant economic effect via the reduction of the number of exacerbations as well as the duration and number of antibiotics used (Cazzola et al., 2010).
Antibiotic treatment is effective in exacerbation of the disease, but at the same time, it does not prevent its development. The antioxidant and mucolytic therapy facilitates the course of the disease, but does not prevent the development of infectious exacerbations and does not slow the progression of decline in lung function. However, erdosteine is able to stop the progression of COPD due to the unique set of pharmacological properties that combine multiple mechanisms.
More than 50 clinical studies involving 5,500 patients with various diseases, including COPD exacerbation and COPD in remission, act as proof of the clinical efficacy of erdosteine (Cazzola et al., 2010). The comparative studies with other mucolytics also confirm the fact that the erdosteine has a number of positive properties such as mucoregulatory, antioxidant, anti-inflammatory, and anti-adhesion effects.
Erdosteine improves the rheological properties of sputum through its active metabolite that contains a free SH-group. It breaks disulfide bonds of sputum glycoproteins and significantly decreases the flexibility of sputum and concentration of glycoproteins in it. Besides, it improves mucociliary clearance due to the indirect and direct influence on the movement of the cilia of the epithelium of the respiratory tract and reduces the hypersecretion and the amount of sputum (Moretti, 2009).
Reactive oxygen species (ROS) have a direct cytotoxic effect on the cellular structure of the respiratory epithelium and induce mechanisms of chronic COPD. In particular, they increase the number of neutrophils and other cells of phagocytosis, triggering an autoimmune inflammatory process. ROS also activate and collagenase, as well as inactivates antiprotease such as ?1-antitrypsin and similar (Moretti, 2009). Reactive oxygen species shift the protease-antiprotease balance towards proteolysis, causing the alveolar destruction. Chronic pulmonary inflammation caused by oxidative stress leads to lung fibrosis and remodeling of lung tissue. Oxidative stress is also characterized by a decrease in the threshold of the cells' sensitivity to the damaging effect of oxidants and the reduction of endogenous antioxidant capacity. Patients with COPD have an imbalance of the oxidant-antioxidant potential with a violation of the antioxidant defense mechanisms (e.g., glutathione) (Moretti, 2009). Thus, the use of medicine with antioxidant properties in patients with COPD is pathogenetically justified.
Erdosteine has a proven direct neutralizing effect on free radicals. It also increases the concentration of endogenous antioxidants. Moreover, erdosteine demonstrated a direct antioxidant effect at a number of in-vitro experiments. The neutralizing effect is manifested in the reduction of ROS production such as hypochlorous acid, hydrogen peroxide, superoxide anion, and peroxynitrite (Moretti, 2014).
Erdosteine showed a local anti-inflammatory activity in a number of studies. The activity included a reduction of the markers of bronchial inflammation and ROS production and e-NO starting from the fourth day of therapy, which was associated with the decreased levels of pro-inflammatory cytokines IL-6, IL-8, and TNF-alpha (Moretti, 2014). It also increased the FEV1 in response to the inhalation of salbutamol in smokers with COPD (Moretti, 2014).
COPD exacerbation caused by infection is one of the main factors of disease progression and poor outcome. Up to 70% of the exacerbations are associated with infection (Cazzola et al., 2010). Bacterial colonization would have been impossible without the adhesion of bacteria to the cell. Erdosteine has proven its anti-adhesion activity. Anti-adhesion effects of the drug are implemented at the level of formation of the blockade of connecting bridges between the receptors of the cell membrane and the microfilaments of bacteria. The active metabolite of erdosteine results in a significant reduction of bacterial adhesion to the epithelial cells of a human (Cazzola et al., 2010).
Thus, the efficiency of erdosteine is reduced to a reduction in the frequency and duration of exacerbations; reduction of the need for antibiotic treatment of COPD exacerbations; and improvement of the life quality in patients with COPD.
In addition, it should be noted that erdosteine is characterized by an excellent safety profile. All undesirable effects of light or moderate degree or any other severe reactions have not been reported. This is due to the presence of blocked sulfhydryl groups (Cazzola et al., 2010). Besides, erdosteine perfectly combines with a variety of antibiotics such as ampicillin, amoxicillin, bakampitsillin, and cotrimoxazole without increasing the risk of side effects (Cazzola et al., 2010). Furthermore, there are no registered side effects during the erdosteine therapy in combination with theophylline or ?2-agonists (Cazzola et al., 2010). These advantages are particularly important for COPD patients who are on long-term therapy with mucolytics and elderly patients with concomitant diseases.
A comprehensive approach to the prevention of frequent exacerbations of COPD via the use of biomarkers and erdosteine in the treatment leads to a significant reduction in the frequency and duration of exacerbations and the need for antibiotic treatment of exacerbations of COPD. Besides, such an approach improves control of the disease and reduces hospital admissions and the number of days spent on disability in patients with acute exacerbation of COPD. Diagnostics and therapy with biomarkers and erdosteine contribute to more pronounced positive dynamics of clinical-instrumental and medical-economic indicators in patients with acute exacerbation of COPD. This fact can be one of the benefits when choosing treatment tactics for COPD patients.