**3. Results and discussion**

During the study period, 423 patients were admitted to the therapeutic department for COPD exacerbation. Of these, 276 were hospitalized once in a calendar year (control group), and 147 cases of hospitalization occurred in 60 patients who were hospitalized 2 or more times in a year (38 patients (63.33%)—2 times, 17 (28.33%)—3 times, 5 (8.33%)—4 times in a calendar year). Thus, 14.2% of patients required repeated hospitalizations due to an exacerbation of the disease (the main group). Men prevailed among the single-time hospitalized patients with a male/female ratio of 2.6:1, and among theх re-hospitalized patients with a ratio of 11:1. Belonging to the male sex increased the risk of repeated hospitalizations by 3.5 times (RR 3.49; 95% DI 1.45–8, 43). The mean age of patients in the control group was 69.49 ± 0.64 years (men: 67.68 ± 0.75 years, women: 74.28 ± 1.1 years). The average age of patients in the main group was 70.48 ± 1.22 years (men: 69.53 ± 1.24 years, women: 81 ± 1.84 years). (p>0.05). It was found that the age over 70 years increases the risk of repeated hospitalizations by 1.2 times (RR 1.21; 95% CI 0.74–1.86). The average bedtime in the control group was 8.98 ± 0.22 days, and in the main group—9.3 ± 0.33 days (*p* < 0.05). In the main group, the average bed-day in the first hospitalization was 9.32 ± 0.45 days, in the second—9.02 ± 0.6 days, in the third—9.9 ± 0.78 days, and in the fourth—10.2 ± 2.71 days (the number of bed-days during repeated hospitalizations in the main group did not distinguish, *p* > 0.05). There is a tendency to increase the duration of hospitalization, which may be associated with an increase in the severity of the condition of patients requiring repeated hospitalizations during the year.

Unfortunately, not all medical records contained data on the duration of the disease. Information about the duration of COPD was indicated only in 60.66% of cases in the control group. It was found that the average duration of the disease in patients in the control group was 8.51 ± 0.77 years. About 33.7% (93) of patients hospitalized once, were diagnosed with COPD for the first time, while 15 out of 93 patients had a history of chronic bronchitis. Data on the duration of COPD in patients hospitalized repeatedly were also available only in 54.42% of medical records. It turned out that

*The Risk Factors of Frequent Exacerbations of COPD DOI: http://dx.doi.org/10.5772/intechopen.107969*

the average duration of COPD in the main group was 11.34 ± 1.33 years (*p* < 0.05). Three patients were diagnosed with COPD for the first time in the first of repeated hospitalizations, and before that, they had a history of chronic bronchitis. The duration of COPD for more than 10 years increases the risk of repeated hospitalizations by 3.5 times (HR 3.48, 95% CI 2.27–5.34).

About 16.3% (45) of patients in the control group, as well as 23.33% (14) of patients in the main group, had a history of occupational hazards (working as a miner, welder, painter, bricklayer, grinder, milling machine, etc.), which could have an impact on the increased risk of frequent COPD exacerbations by almost 1.5 times (RR 1.4–3, 95% CI 0.84–2.42).

Medical records did not provide sufficient data on the fact, duration of smoking, and the number of cigarettes smoked. Only in 30.4% (84) of cases was it possible to determine the average smoking experience in "pack-years." In the control group, the average smoking experience was 37.9 ± 1.7 packs/year. Taking into account the possibility of obtaining information about smoking from several medical records of re-hospitalized patients, the average smoking experience was determined at 50% (30). It was 42.2 ± 3.44 packs/year (*p* < 0.05). Smoking duration of 40 years or more increased the risk of repeated hospitalizations by 1.6 times (RR 1.6, 95% CI 0.87–3.0, *p* < 0.05). Among the control group patients, 35.5% (98) and 29.9% (44) of the main group patients continued to smoke at the time of hospitalization. Only 43% (42) of the once-hospitalized patients and 36.36% (16) of the repeatedly hospitalized patients were recommended to quit smoking at discharge. Recommendations for quitting smoking after the first hospitalization were received by 25% of smokers, after the second hospitalization—by 50% of patients, after the third—by 80% of patients, and after the fourth hospitalization—by 100%. Following the recommendations for quitting smoking,3.3% of patients reported that they had quit smoking at the time of their next hospitalization for COPD exacerbation, half of them—after the second hospitalization.

It should be noted that the largest number of hospitalizations of patients in the control group occurred in the winter and spring months, during this period 63% (173) of patients were hospitalized, which is significantly higher than in the summer and autumn months. No such pattern was found in the main group of patients. On the contrary, the number of hospitalizations during the calendar year remained at the same level (**Figure 1**). Based on the data obtained, it can be assumed that the frequency of hospitalizations of patients in the main group may be more affected by the severity of the underlying disease and the general condition of patients.

All hospitalizations for acute COPD were carried out on an emergency basis. Moreover, 51.45% (142) of single-time hospitalized patients were delivered to the hospital by ambulance teams, 28.26% (78) of patients were referred by local therapists, 12.68% (35)—were delivered by ambulance teams from the polyclinic, 7.61% (21)—went to the hospital on their own. Re-hospitalized patients were also significantly more often delivered to the hospital by ambulance teams: 61.67% (37) of patients were admitted to the first hospital, 63.33% (38) to the second, 86.36% (19) to the third, and 80% (4) to the fourth.

At admission to the hospital, the condition of patients in the control group was assessed as severe in 11.59% (32) of cases, and in the main group—in 10.2% (15) of cases (*p* < 0.05). And due to the severity of respiratory failure 11.96% (33) once hospitalized patients were treated in the intensive care unit (ICU). At the same time, 60.6% (20) of them were admitted to the ICU from the emergency room, and 39.4% (13) were admitted to the ICU from the emergency room—they were

#### **Figure 1.**

*Dynamics of hospitalizations for exacerbation of chronic obstructive pulmonary disease from January 1, 2015 to December 31, 2018 by month.*

transferred from the Department of therapy. Re-admitted patients were admitted to ICU in 10.88% (16) cases, of which 56.25% (9)—were from the emergency room, and 43.75% (7)—were from the therapeutic department. Average bed-day in ICU of patients in the control group was 3.56 ± 0.62 days, and in the main group—4.38 ± 1.39 days (*p* < 0.05). Only 68.75% (22) of patients in the control group and 66.67% (10) of patients in the main group, whose condition was assessed as severe during hospitalization, received intensive care in the intensive care unit.

Mortality in the control group was 3.26%, and in the main group—4.76% (*p* < 0.05). It was found that the proportion of fatal cases among patients hospitalized in ICU from the emergency department, in the control group was 10% (2 out of 20), and in the main group—11.1% (1 out of 9). At the same time, the proportion of deaths among patients transferred to ICU from the therapeutic department was significantly higher in both once-admitted and re-admitted patients and amounted to 53.85% (7 out of 13) and 85.7% (6 out of 7), respectively. The revealed trend may indicate an insufficient assessment of the severity of the patient's condition upon admission to the hospital and untimely provision of intensive care for severe patients, which may be one of the reasons for more frequent deaths in this group of patients.

When evaluating the anamnesis data on outpatient treatment, it was found that 4.4% (8) of patients in the control group did not use inhalers on an outpatient basis, and 19.7% (36) of patients used only emergency medications. Among patients in the main group, 21.3% (23) also did not receive basic therapy (*p* < 0.05). When comparing these recommendations at discharge from the hospital and the history of outpatient therapy during subsequent hospitalization, it was found that 44.6% (29 out of 65) of patients in the main group did not follow the recommendations given to them at discharge. On an outpatient basis, patients were more likely to receive combination therapy with inhaled glucocorticoid steroids (ICS) and long-acting beta-2-agonists (LABA) (31.2% (57) of patients in the control group and 39.8% (43) in the main group), as well as a combination of ICS, LABA and long-acting anticholinergic drugs (13.1% (24) of patients in the control group and 23.1% (25) in the main group).

#### *The Risk Factors of Frequent Exacerbations of COPD DOI: http://dx.doi.org/10.5772/intechopen.107969*

In none of the cases in the medical records were there data on monitoring the correct inhalation technique and training in the correct use of inhalers, despite the fact that many large studies have shown that training and regular monitoring of inhalation techniques increases the effectiveness of therapy.

As it is known, infectious agents and, in particular, bacteria are not always the cause of COPD exacerbations, so the indications for antibiotic therapy remain rather narrow and include increased shortness of breath, an increase in the amount sputum, and an additional marker confirming the need for antibiotic therapy is an increase in the level of C-reactive protein (CRP) 10 mg/l. In accordance with these recommendations, when patients are admitted to a hospital, it is necessary to conduct a number of laboratory and instrumental research methods to select the correct patient management tactics.

Determination of the C-reactive protein level at admission was performed in 81.5% (225) of cases in the control group. At the same time, in 64% (144) cases, the level of CRP was higher than normal, but in dynamics, the analysis was repeated only in 62.5% (90) of them. It was also found that 10% (5) of patients who underwent CRP analysis only before discharge had elevated levels of C-reactive protein. In the main group of patients, the study of the level of CRP was conducted in 74.2% (109) cases, in half of which (54 cases) it turned out to be higher than normal, but in dynamics only 33.33% (18 out of 54) patients were analyzed. In patients of the main group, the CRP level was determined only before discharge, the indicator was normal. In 13.4% (37) of patients hospitalized once, and у in 21.8% (32) patients who were hospitalized repeatedly the level of C-reactive protein during hospitalization was not determined.

The result of sputum analysis was found in 80% (221) of hospitalizations in the control group, as well as in 83% (122) cases of hospitalizations in the main group. A possible reason for the absence of sputum analysis in 6.5% of patients in the control group and in 3.4% of cases in the main group may be the presence of an unproductive cough.

Bacteriological examination of sputum was performed during hospitalization in 80.4% of patients in the control group, but the result of the study in the medical record was only 9.4% of them. Streptococcus pneumoniae (38.5%), Klebsiella pneumoniae (23%), Pseudomonas aeruginosa (11.5%), Escherichia coli (7.7%), and Haemophilus influenzae (11.5%) were most frequently detected—11.5%. Phlegm bacteriological examination was performed in 76.2% of patients who were hospitalized again, but the result of the study was only in 9.5% of cases. Streptococcus pneumoniae (42.9%), Klebsiella pneumoniae (14.3%), and Pseudomonas aeruginosa (14.3%) were most frequently detected. In more than 90% of cases, etiologically significant growth of microflora was not obtained, which makes it possible to assume inadequate or untimely collection of material for the study.

Hypoxia and subsequent hypoxemia are threatening conditions for the body. One of the most screening diagnostic methods is pulse oximetry [5]. It was revealed that pulse oximetry was performed in the emergency department of the hospital in 81.88% (226) of patients in the control group and 91.8% (135) of patients in the main group. In dynamics, the level of blood oxygen saturation was determined in 82.6% (228) of single-time hospitalized patients and 83.7% (123) re-hospitalized patients.

In the control group, 28.6% (64) of patients had a blood saturation of more than 95%, 45.1% (101) had a saturation of 90–94%, 22.7% (51) had a saturation of 75–89%, and 3.6% (8) had a saturation of less than 75%. In the main group at admission, 21.6% (29) had a blood saturation of more than 95%, 44.1% (59) had a blood saturation of more than 95%. About 90–94%, 32.1% (43)—75–89%, 2.2% (3)—less than 75%.

When analyzing the level of saturation at each subsequent hospitalization separately, it was found that among patients who were hospitalized three times at the time of the first hospitalization, the proportion of patients with blood saturation of more than 95% was 2.25 times higher than at the third hospitalization (23.6% vs. 10.5%). At the same time, there was a tendency to increase in the number of patients with a saturation of 90–94% from the first to the third hospitalization (from 43.6% to 57.9%), as well as with a saturation of 75–89% from the first to the fourth hospitalization (from 30.9% to 60%). There were no significant differences in blood saturation between the first and second hospitalizations.

Spirometry is one of the main methods for determining the degree of air flow restriction, which is necessary for making a diagnosis of COPD and verifying the severity of ventilation disorders. Spirometry is not recommended for acute COPD patients, but it is possible to study the function of external respiration as patients stabilize closer to hospital discharge [3]. Spirometry is especially important for patients who have not previously been diagnosed with COPD, and they accounted for 33.7% (93) patients in the control group and 2% (3) of patients in the main group. When studying medical records it was found that only 38.4% (106) of patients in the control group and 37.4% (55)—the main group, had Spirometry data. Thus, only slightly more than half of the patients in the main group (53.3%) underwent ERF testing in at least one of the hospitalizations. Data were obtained that among single-time hospitalized patients, 10.38% (11) had mild obstructive disorders, 30.2% (32)—medium-heavy, 40.56% (43)—severe, 18.86% (20)—extremely severe. Among the re-hospitalized patients, 28.13% (9) of patients had moderate obstructive disorders, 37.5% (12)—severe, 34.37% (11)—extremely severe. Thus, it was found that the proportion of patients with extremely severe obstructive disorders in the main group was almost twice as high as in the control group.

Chest radiography (CHR) is recommended for all patients with severe COPD to a greater extent for differential diagnosis with other diseases that may be accompanied by increased dyspnea or cough. In accordance with the obtained data , an X-ray examination of the chest was performed in 93.8% (259) of patients in the control group and 84.35% (124) of patients in the main group who were hospitalized. Four patients who were hospitalized once, and three patients who were hospitalized repeatedly were not prescribed radiography of the chest by a general practitioner due to the presence of fluorography results for the last year, which cannot be a reason for refusing the study. It should be noted that all rehospitalized patients underwent radiography of the chest during at least one of their hospitalizations per year.

The revealed defects in laboratory and instrumental diagnostics of patients during COPD exacerbation can lead to underestimation of the severity of the patient's condition, the choice of inadequate management tactics and the amount of therapy.

The main component of COPD treatment in the acute phase is inhaled bronchodilators, the most popular of which are short-acting beta-2-adrenomimetics in possible combination with m-cholinolytics. About 95.65% of patients in the control group and 97.28% of patients in the main group received combined inhaled therapy (fenoterol/ ipratropia bromide) via a nebulizer.

According to federal clinical guidelines, the use of systemic glucocorticoids (SCS) during acute disease reduces the time of remission, improves lung function (FEV1), and reduces hypoxemia. It is recommended to use prednisone in a daily dose of 40 mg for 3–5 days with rapid withdrawal of the drug due to the frequent development of side effects, especially in elderly patients. In severe exacerbations of COPD, it is possible to prescribe SGS parenterally [3, 6]. It was found that 65.2% (180) of patients in the control group and 77.55% (114) of patients in the main group received SGS in the hospital. About 61.23% (169) of patients hospitalized once, prednisone was administered parenterally at an average daily dose of 63.55 ± 0.97 mg lasting from 1 to 12 days. At the same time, 14.2% (23) of them were transferred to oral administration of the drug at an average dose of 25 ± 1.5 mg per day for an average of 5.7 ± 0.4 days. Patients of the main group received prednisone parenterally in 74.83% (110) of cases at an average dose of 64.9 ± 2.24 mg/day lasting from 1 to 11 days. About 20.9% (23) of patients after parenteral administration were transferred to oral administration at a dose of 24.35 ± 1.86 mg with an average duration of 5.83 ± 0.52 days. Initially, oral prednisone was administered only in 4% (11) of patients in the control group and in 2.7% (4) of patients in the main group.

It is noted worthy that 12.7% (35) of patients in the control group and 1.4% (2) of patients in the main group did not receive glucocorticoids during hospitalization, which may question the severity of exacerbation and the validity of hospitalization, or be considered a defect in the choice of therapy for COPD exacerbation, which could prolong the time of remission. At the same time, the proportion of patients receiving glucocorticoids both systemically and inhaled was significantly higher: 82.46% (94) of patients in the main group and 55.43% (153) of patients in the control group. At the same time, in 9.78% (27) of cases in the control group and in 6.8% (10) of cases in the main group, when prescribing glucocorticoids, SGS was preferred over inhaled ones, despite the fact that for patients with comorbid pathology budesonide nebulization is a safer alternative to prednisone administration.

Since methylxanthines have a relatively weak bronchodilating effect (compared to beta-2agonists and m-cholinolytics), a small therapeutic range, and pronounced side effects, they are considered second-line drugs in COPD exacerbation and are recommended for patients with poor response to inhaled bronchodilator therapy [7]. However, it was found that theophylline was administered parenterally from the first day in 18.8% of patients in the control group for an average of 4.27 ± 0.29 days, and in 14.3% of patients in the main group—for an average of 4.43 ± 0.37 days. At the same time, 2 patients of the main group a and 2 patients of the control group received theophylline therapy if they had a permanent form of atrial fibrillation.

Oxygen therapy in the hospital was prescribed to patients in the control group only in 21.38% (59) of cases, of which in 11.86% (7) of cases, blood oxygen saturation was more than 95% in air, and in 13.56% (9) of cases, pulse oximetry was not performed. About 29.25% (44) of patients in the main group received oxygen therapy. There were no indications in 11.36% (5) of these cases, and pulse oximetry was not performed in 4.5% (2). At the same time, in the presence of absolute indications, only 56.5% (35) of the medical records of patients in the control group and 54.35% (25) of the main group have data on the appointment of oxygen inhalation.

Based on a comprehensive assessment of the results of the study, in 9.4% (26) of cases in the control group and in 11.5% (17) in the main group, the validity of prescribing antibiotic therapy can be questioned. In 1.8% (5) of cases in the control group and 4.1% (6) of cases in the main group, patients did not receive antibiotics reasonably. In the control group ceftriaxone was prescribed in most cases: in 55% (152) cases—as monotherapy, in 17% (47)—in combination with azithromycin. In all cases of dual antibiotic therapy, community-acquired pneumonia was suspected at the initial examination by a general practitioner, but the diagnosis was confirmed only in 5 out of 47 patients. At the same time, in 10% (25) of cases, an antibiotic replacement was performed, in a third of cases (8) it was not justified according to the medical history. When studying the data of medical records of patients hospitalized repeatedly,

it was found that ceftriaxone was prescribed as the starting therapy in 62% of cases, and in 11% of cases (16)—ceftriaxone with azithromycin, of which in a third of cases there was no justification for prescribing dual antibiotic therapy. In almost half of the cases of repeated hospitalization (29 out of 60 patients), patients received the same antibiotic as in the previous one. It was also found that the same antibiotic was prescribed in 38.3% (23) of two consecutive hospitalizations, in 8.3% (5)—three consecutive hospitalizations, and in 1.6% (1)—four times. In addition, it was found that in 9 more cases after ceftriaxone monotherapy, a combination of ceftriaxone with azithromycin or levofloxacin was subsequently prescribed in the previous hospitalization. Thus, we can assume that in 63.3% (38) of cases, when prescribing an antibiotic, therapy in the previous hospitalization was not taken into account.

Comorbidity in COPD plays an important role in its progression and affects the survival of patients with exacerbation of the underlying disease. It was found that patients in the control group had an average of 2.7 ± 0.1 concomitant diseases, and patients in the main group—3.27 ± 0.18. The presence of 3 or more comorbidities increased the risk of repeated hospitalizations by 2 times (RR 2.0; 95% CI 1.23–3.4).

There were no significant differences in the incidence of concomitant diseases such as coronary heart disease (46.6% and 44.6%, respectively) between patients in the main and control groups, diabetes mellitus (13.3% and 12.3%), atrial fibrillation (10% and 10.1%), in 25% and 26.8% of cases, respectively, an increase in pulmonary artery pressure was detected.

COPD itself has significant systemic effects on the body, including weight loss, eating disorders, and skeletal muscle dysfunction. However, it was found that in the control group, the number of patients with body mass deficiency was 2 times higher than in the main group (13.4% vs. 6.7%) (*p* < 0.05). At the same time, the number of overweight and obese patients was the same in both study groups (51.7% and 51.8%). Patients in the main group were significantly more likely to have a history of hypertension (88.3% vs. 72.1%), stage 2 chronic heart failure (CHF 2А) (35% vs. 23.5%), and gastroesophageal reflux disease (GERD) (23.3% vs. 5.8%). When analyzing the data, it was found that the presence of hypertension increased the risk of repeated hospitalizations by 3.5 times (RR 3.55, 95% CI 1.47–8.57, *p* < 0.05), the presence of CHF stage 2A—by 1.5 times (RR 1.5–6, 95% CI 0.98–2, -8–2.5, *p* < 0.05), the presence of GERD increased 3-fold (HR 3.1, 95% CI 1.95–4.95, *p* < 0.05).

In addition, the number of patients with verified bronchiectasis was significantly higher in the main group compared to the control group (6.7% vs. 1.8%). A history of clinically significant bronchiectasis increased the risk of frequent COPD exacerbations by more than 2.5 times (HR 2.59, 95% CI 1.2–5.6, *p* < 0.05). This, in turn, confirms the literature data that in the presence of bronchiectasis, COPD occurs with a greater severity of symptoms, more frequent chronic bronchial infections and exacerbations, as well as a poor prognosis [8].

The risk of community-acquired pneumonia in patients with COPD increases as the severity of the disease increases, while pneumonia itself on the background of COPD is characterized by a more severe course with frequent development of acute respiratory failure [9]. It was found that during the period of COPD exacerbation, community-acquired pneumonia was observed in 1.8% (5) of patients in the control group and in 8.3% (5) of patients in the main group. It was found that the development of pneumonia increased the risk of COPD exacerbation by almost в 1.5 times (HR 1.45, 95% CI 0.771–2.741, *p* < 0.05).

Recommendations given to patients at discharge from the hospital were studied in detail. Despite the fact that smoking remains the main cause of COPD development and progression, and smoking cessation is considered very significant for patients,

#### *The Risk Factors of Frequent Exacerbations of COPD DOI: http://dx.doi.org/10.5772/intechopen.107969*

only 42.8% of patients in the control group and 36.4% of patients in the main group received recommendations for quitting smoking at discharge.

In 74% (199) of cases in the control group, inhaled glucocorticoids (ICS) were prescribed as monotherapy or in combination with bronchodilators on an outpatient бронходилататорамиbasis. СAccording to current clinical guidelines, only 44.7% (89) of such prescriptions could be considered justified. In the main group, IGCS in combination with bronchodilators were prescribed in 77.1% (108) of cases, of which only 49.1% (53) met current clinical recommendations.

Despite the fact that the majority of patients had both hypertension and diabetes mellitus, в 2.6% (7) in the control group and 5% (7) in the main group were recommended to continue taking prednisone at an average dose of 17.86 ± 2.86 mg per day and 19.64 ± 4.64 mg per day on an outpatient basis, respectively, with a gradual reduction in the dose and discontinuation of the drug.

Most patients with severe COPD develop hypoxemia and chronic respiratory failure, which can lead to a decrease in the quality of life, cognitive impairment, and decompensation of the pathology of the cardiovascular system. Long-term oxygen therapy (LTOT) on an outpatient basis using an oxygen concentrator was recommended in 4.5% of patients in the control group and 5% of patients in the main group. Despite this, half of the patients in the control group and 66.7% of the patients in the main group who had indications for LTOT were not recommended to use an oxygen concentrator on an outpatient basis.

To obtain more reliable data on the dynamics of the severity of ventilation disorders, it is necessary to study Spirometry during remission of the disease, but only in 51.2% (87) in the control group and 31.2% (29) in the main group, outpatient spirometry was recommended.

Seasonal influenza vaccination was recommended in 15.7% (42) of cases in the control group and 19.2% (27) of cases in the main group, while pneumococcal vaccination was recommended in only 11.2% (30) and 15.7% (22) of cases, respectively.

Chronic hypoxia in patients with severe COPD may affect adherence to therapy, lead to refusal of physical activity, and changes in the inhalation technique [10]. Nondrug therapy and rehabilitation have the greatest impact on the frequency of exacerbations, but in practice they are not used enough. When analyzing medical records, it was found that only 11.2% (30) of patients in the control group and 9.3% (13) of patients in the main group were given recommendations for maintaining physical activity and respiratory gymnastics.
