Severe Asthma Management, Patient Pathway, and Disease Burden in Russia: Country Results From Multi-Country Retrospective Cross-Sectional Study

Severe asthma is a poorly controlled disease in Russia which leads to signicant healthcare resource use and costs. However, little is known about its burden and management in a real clinical practice in Russia. Here we report the results obtained in the Russian population during an international cross-sectional study. The study comprised two phases: in Phase I data were collected retrospectively from medical records, while Phase II was a cross-sectional collection of patient-reported outcomes and up-to-date data. For Phase I, adult patients with severe asthma according to ERS/ATS criteria were enrolled. Phase I patients were enrolled into Phase II if they signed a written consent form. Data on demographics, history of asthma and comorbidities, treatment approach, and healthcare resource utilization were obtained in both phases. In Phase II, asthma control and health-related quality of life (HRQoL) were also evaluated.

Many patients with asthma can be adequately controlled by use of treatment recommendations as described by the Global Initiative for Asthma (GINA) guidelines (1). However, for some asthma patients, despite attempts to control their disease following these recommendations, asthma control is not achieved. Landmark studies have shown that uncontrolled asthma remains a worldwide problem (2).
This group of subjects with frequent exacerbations, uncontrolled symptoms and impaired health-related quality of life (HRQoL) has been de ned as severe asthma patients (3). Severe asthma has been de ned by the American Thoracic Society (ATS) and the European Respiratory Society (ERS) as "asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids [SCS]) to prevent it from becoming 'uncontrolled' or which remains 'uncontrolled' despite this therapy" (4). Severe asthma patients experience considerable morbidity (5) and are responsible for approximately 50% of the total health costs associated with asthma (6, 7).
Evidence shows that patients with severe asthma are comprised of complex, overlapping phenotypes, including severe eosinophilic asthma (8, 9). Early identi cation of patients with eosinophilic asthma in clinical practice is important because these patients are at risk of poor asthma outcomes (10). For these reasons, there is a need to assess severe asthma management and the patient care depending on asthma phenotypes. However, little is known about the burden and management of severe asthma patients in real clinical practice in Russia, and it is unclear what asthma phenotypes are present in those with severe asthma in Russia. Thus, the primary objective of this study was to describe the patient care pathway, disease management and patient/disease characteristics, including patient demographics, clinical characteristics, and healthcare resource use in severe asthma patients.

Study design
This study was an observational, descriptive, retrospective cross-sectional conducted in Russia, Saudi Arabia, Kuwait, and the United Arab Emirates. This manuscript focuses on the Russian population. The study consisted of two phases. At Phase I retrospective data on severe asthma patients was collected. Investigators from 12 sites in Russia screened site medical records dated from 01 January 2016 until site initiation visit (SIV, start at 31 May 2018, nish on 10 August 2018). Any patients aged 21 years or older with severe asthma diagnosis according to ERS/ATS de nition have been included in the registry. Known participants of a clinical or cohort study were ineligible. The number of patients to be enrolled was not limited. Medical records of eligible patients were reviewed by investigators for extraction of data including, but not limited to clinical data, disease and treatment history, laboratory tests, including eosinophil and immunoglobulin E (IgE) level measurements, spirometry results during 12 months prior to SIV, number of exacerbations, and number of hospital admissions.
Asthma exacerbation was de ned as an event that required use of systemic corticosteroids (SCS) or led to hospital admission, emergency room (ER) visit, mechanical ventilation, or doubling the oral corticosteroids (OCS) dose for patients receiving maintenance OCS.
Eligible patients enrolled in Phase I of the study, and who presented at the site for a routine visit, were invited to participate in Phase II of the study. Patients who refused to sign informed consent, or who presented a severe mental illness or other disease that could, in an investigator's opinion, alter participation in the study, were ineligible. The recruitment period for Phase I and II lasted 14 weeks. Participants were asked to complete the Asthma Control Test (ACT) and the Five level EuroQol vedimension (EQ-5D-5L) HRQoL questionnaires. Investigators also extracted relevant data from the medical records, as done during Phase I.

Statistical analysis
Data were analyzed using descriptive statistics. Categorical and ordinal variables are presented as frequency and counts. Continuous variables are presented as mean values with standard deviation (SD).
Analyses conducted to meet the primary objective (to describe the patient pathway, in terms of disease management and patient/disease characteristics) were also strati ed by the last available eosinophil count. Analyses conducted to meet the secondary objectives (to describe the burden of severe asthma in terms of healthcare resource utilisation, impact of disease on HRQoL for overall, controlled, and uncontrolled severe asthma patients in specialised sites) involved frequencies, and two-tailed 95% con dence intervals (CIs) were presented for selected variables.
Categorical variables were compared using chi-square test, Student's t-test or analysis of variance (ANOVA) were used for continuous variables. Two-sided signi cance level of 0.05 was accepted for all statistical tests.
All statistical analyses were performed using SAS 9.4 (SAS Institute, North Carolina, USA) software.

Study population
Patient disposition is presented at Figure 1. A total of 392 patients screened for Phase I, 315 were enrolled, and 77 were excluded as ineligible. Of 315 patients, 106 visited sites during the enrollment period and gave consent for study participation.
Characteristics of patients included in the study are presented in Table 1. There were numerically more female (n=211, 67.0%) than male patients (n=104, 33.0%) in the study. Majority of patients were older than 50 years. Most enrolled patients were Caucasians (n=257, 84.3%) and were either obese with a body mass index (BMI) ≥30 kg/m 2 (n=103, 39.8%) or overweight with a BMI between 25 and < 30 kg/m 2 (n=94, 36.3%). More than half of the patients were non-smokers (n=193, 64.5%); the remaining patients were either past smokers (n=66, 22.1%), current smokers (n=38, 12.7%), or passive smokers (n=2, 0.7%). Among the current and past smokers, the mean (SD) number of cigarettes smoked per day was 17.7 (7.9), and the mean (SD) pack-years was 25.4 (17.7). The overall mean (SD) number of years as a smoker among past and current smokers was 27.7 (12.6) years. Asthma history data is presented in Table 2. Among the 315 patients, the median (range) age at diagnosis of asthma or severe asthma was 45.0 (1.0-79.0) and 55.5 (15.0-82.0) years, respectively. The median (range) age at the rst symptoms of asthma was 42.0 (1.0-76.0) years. The mean (SD) time between asthma diagnosis and severe asthma diagnosis was 10.1 (11.1) years. Most patients did not have a familial rst-degree history of asthma (n=150, 62.0%).  The most reported frequencies of nighttime awakenings due to severe asthma in the last 12 months were once a week (n=55, 23.9%), twice a week (n=40, 17.4%), and once per fortnight (n=39, 17.0%) ( Figure 2).
There were 268 (85.1%) patients who experienced at least one asthma exacerbation during the last 12 months, the majority of them had 1 exacerbation during the past 12 months (n=209, 66.3%) ( Figure 3). Retrospective spirometry data are shown in Figure 4.
Note FEV1 -forced expiratory volume in rst second; last FVC -forced vital capacity; data represent mean for 279 patients.
Among the 279 patients with available data on lung function examinations in the last 12 months, the majority had only one lung function examination (n=202, 72.4%   Note: SABA -short-acting β-agonist; * -excluding SABA; SD -standard deviation. Among the 315 patients, 199 (63.2%) patients received OCS treatment in the past 12 months. The mean (SD) overall daily dose of OCS in the last 12 months was 2.9 (5.1) mg (n=199). The mean (SD) daily dose of OCS for controller/maintenance treatment in the last 12 months was 6.1 (4.1) mg (n=16). The mean (SD) daily dose of OCS for exacerbation treatment in the last 12 months was 2.5 (4.9) mg (n=194).
Among the 250 patients who experienced at least one exacerbation within the prior 12 months, physician consultation was the most frequent intervention (n=227, 75.4%). A total of 30 (10.6%) patients experienced at least one exacerbation which required an ER visit, and 200 (67.1%) were hospitalized with a mean (SD) of 12.3 (6.0) nights spent in hospital in the last 12 months.

Patient-Reported Outcomes
Questionnaires were completed by the patients who participated in Phase II (n=106). Most patients had an ACT score of ≤15 and fell in the category "asthma may not be under control" (n=79, 74.5%); there were 22 (20.8%) patients with an ACT score of ≥16 to ≤19 and fell in the category "asthma partially or not well controlled"; and 5 (4.7%) patients with an ACT score of ≥20 and fell in the category "asthma may be under control". The mean (SD) ACT score was 11.4 (4.7).
The mean (SD) EQ-5D-5L utility score was 0.5 (0.3), and the mean (SD) EQ-5D visual analogue scale (VAS) score was 51.8 (20.2). The mean (SD) number of school or workdays patients reported missing due to severe asthma was 17.6 (21.8) days. The mean (SD) number of school or workdays with less productivity due to severe asthma was 44.6 (45.2) days. Overall, higher quality of life was associated with better asthma control.

Limitations
Most of the sites selected in this study were public hospitals (hence the results show that almost all patients were covered by public/social security healthcare), and thus the generalizability of the results is limited to patients treated in public healthcare settings. Physician participation in Phase I/II and patient participation in Phase II were on a voluntary basis; this may have resulted in selection bias, thereby impacting the representativeness of the nal sample of participating physicians and patients. Missing data, which is a known disadvantage of observational studies, could reduce the statistical power of analyses and may potentially bias estimates. There was very limited data captured on blood eosinophil measurements in this study. Finally, it is important to consider the reliability of certain variables, e.g., smoking status may be impacted by reporting bias, due to the reluctance of patients to report smoking behavior to their doctor.

Discussion
This retrospective cross-sectional study conducted in Russia collected and analysed real-world data on patients with severe asthma, including patient care pathway, disease management and patient/disease characteristics (demographics, clinical characteristics, healthcare resource utilisation and HRQoL).
In the Russian population included in the current study, most of the patients were female, which is in line with the previously reported data on asthma epidemiology (11,12). The majority of patients were aged >50 years. Similar was reported by the International Severe Asthma Registry (ISAR), where 52.1% were aged 55 to 69 years (12).
Previous studies have shown that other respiratory disease, such as cardiovascular disease, gastrointestinal disease, allergies and diabetes are prevalent in patients with asthma (13)(14)(15). In this study, on average, patients had approximately three comorbidities and the most common comorbidities were cardiovascular disease (71.4%) and chronic respiratory disease (68.8%). It is of interest to note the high proportion of patients with concomitant COPD (31.5%) observed in this study, it is known that asthma represents a signi cant risk factor for COPD (16). On the other hand, there might be a high proportion of COPD patients in Russia misdiagnosed with asthma due to di culties in differential diagnosis and/or intention to receive better therapies refunded by healthcare system. Another possible explanation for this nding is the relatively high rate of smoking in patients with severe asthma.
Median age for asthma diagnosis was 45.0 years and 55.5 for severe asthma. In a US-based survey (n=12,216) the average age of asthma onset among adults was 38 years (17). Another study has shown that in asthma patients the risk of subsequent development of severe asthma increases by around 7% each year until age 45 years (18).
The majority of patients had at least one exacerbation in the last 12 months, highest exacerbation frequency was in spring, followed by winter, summer, and autumn. Seasonal peaks in asthma exacerbations are well described in the literature, with variations according to the geography and climate (19). In this study u/cold was the major trigger for exacerbation (46.2%), which has also been identi ed by the other studies (20).
Mean blood eosinophil levels remained consistently elevated over consecutive measurements. It was observed in other study that elevated eosinophils are related to poorer asthma control (21). Sites that participated in this study did not routinely record eosinophil levels, despite blood eosinophil counts being part of the complete blood count (CBC) measurement. This may be because the clinical practice at the time of the study observation period (2016-2018) did not require routine measurement of blood eosinophil counts to assess patients' eligibility for phenotype-guided biologic therapy. Previously published data from Russia (27) as well as the results of this study suggest that biologics were infrequently used to treat severe asthma in Russia, and so this may also partly explain the limited measurement of eosinophil counts observed in this study considering eosinophil counts are used to guide biologic therapy. Furthermore, approximately one-third of patients visited general/family practice physicians for the treatment of severe asthma. Since eosinophil counts are not routinely measured in general/family medicine, this may also explain the limited data on eosinophil counts.
Despite clinical signi cance implied by some authors, especially for uncontrolled asthma patients, IgE levels were not measured in most patients (22). FEV1 values in this study should be considered as moderately severe lung impairment (23). It was shown in one study that low FEV1 I may be a risk factor of future exacerbation of asthma (24).
The most common treatment prescribed in the last 12 months was controller/maintenance treatment (99.4%). This is to be expected considering the study inclusion criteria -for patients to be included in the study, they must have been treated with high dose ICS plus a second controller (and/or systemic corticosteroids). The next most frequently used treatments were reliever treatment (96.8%), and exacerbation treatment (SABA excluded) (79.0%), and other medication (77.8%). The use of SABA, corticosteroids, and oxygen as treatment for exacerbations complies with guidelines for the management of exacerbations (25). However, use of SAMA for treatment of exacerbations, as observed in this study, is unusual and does not follow management guidelines (26), but combinations of SABA and SAMA is recommended to use in severe asthma exacerbation by GINA. The high proportion of other unspeci ed exacerbation treatments is also of scienti c interest; this warrants further investigation to elucidate the speci c other exacerbation treatments used.
Use of anti-IgE was very low (2.9%), the same was also reported for severe asthma patients in Russian Severe Asthma Registry (RSAR) (27). Biologics are recommended when they are available/affordable in cases of severe asthma where patients are prescribed with high dose ICS treatment and ful l the criteria for residual Type 2 airway in ammation (28). Therefore, drug availability/affordability may partly explain the low use of biologics in Russia during the study.
Most patients experienced at least one exacerbation in the last 12 months which required an intervention. Rates of hospital admission and duration of in-hospital stay were notably high, which can re ect standard of care in Russia during the study period (2016-2018). ISAR data indicated 12-month admission rates of 26.8% (12). Similarly, results from a study (n=3,619) conducted among asthmatic patients across ve European countries (France, Germany, Italy, Spain, and UK, observation period: 2008) reported a hospitalization rate of 27.3% over a 6-month (29).
The mean (SD) ACT score was 11.4 (4.7) and is corresponded to uncontrolled asthma. This mean score is in line with ndings from other research; one study conducted in Brazil among severe asthmatic patients (n=74) in an outpatient clinic reported a similar mean (SD) ACT score of 11.7 (4.5) (30).
Moreover, disease course signi cantly affected patient's quality of life.
Overall, the ndings of this study suggest an unmet medical need among severe asthmatic patients in Russia. The majority of patients in the study sample used medium/high dose ICS/LABA (along with a second therapy). However, most patients had uncontrolled asthma, according to the ACT; and experienced at least one exacerbation in the past 12-months. In addition, most patients reported a reduction in the quality of their life due to their severe asthma.

Conclusion
The results of this study showed that alongside elevated eosinophil levels, most patients in the study sample had uncontrolled asthma, and most patients experienced at least one severe exacerbation within the past year. Additionally, most patients reported at least moderate limitations in their usual activities due to asthma. In line with these ndings, healthcare resource use among patients was high. Most patients experienced at least one severe exacerbation during the last 12 months which required an intervention, some patients experienced two; and most patients experienced at least one exacerbation in the last 12 months which required hospitalization. Overall, the ndings of this study suggest an unmet medical need among severe asthmatic patients. Although most patients used medium/high dose ICS/LABA (along with a second therapy), which is the preferred treatment option for uncontrolled asthma, most patients remained uncontrolled. This highlights a need for alternative or additional treatment options for severe asthma.
In recent years, new biological agents that block eosinophil speci c interleukins (IL) such as anti-IL5 have become available (31). Research has shown that treatment with these new biologics result in a marked reduction in exacerbations and a signi cant improvement in HRQoL (10,32). To capitalize on the newly available biologics, it is important to diagnose severe eosinophilic asthma at an earliest convenience.  Frequency of nighttime awakenings due to severe asthma during 12 months prior to data entry  Last available spirometry measurement