Health-related quality of life of COPD patients aged over 40 years

Background: Chronic obstructive pulmonary disease (COPD) is the fourth most frequent disease globally, and its worldwide prevalence is projected to increase in the following decades. Health-related quality of life (HRQOL) of COPD patients depends on multiple factors. Objective: The aim of this study was to identify the most important risk factors affecting HRQOL of COPD patients and to measure how specific clinical parameters can predict HRQOL. Methods: A questionnaire-based cross-sectional study combined with clinical data was conducted among patients diagnosed with COPD ( n 5 321, 52.6% females, mean age 66.4 ± 9.5) at the National Koranyi Institute for Pulmonology, Budapest in 2019 – 2020. The inclusion criteria were age ≥ 40 years and existing COPD. Multivariate linear regression analyses were conducted on three components of the COPD-speci ﬁ c Saint George ’ s Respiratory Questionnaire (SGRQ-C) and on the physical (PCS) and mental component scales (MCS) of the 36-Item Short Form Health Survey (SF-36). Multiple linear regression analysis was performed to evaluate the effects of patient and disease characteristics on COPD Assessment Test (CAT) scores. Results: We found that frequent exacerbations, multiple comorbidities and tobacco smoking were associated with worse HRQOL. Engaging in more frequent physical activity and better 6-minute walking distance results were associated with better HRQOL. Conclusions: Our results indicate that the complex therapy of COPD should focus not only on improving lung functions and preventing exacerbation, but also on treating comorbidities, encouraging increased physical activity, and supporting smoking cessation to assure better HRQOL for patients.


INTRODUCTION
HRQOL. In the next decades, COPD is projected to increasingly affect the HRQOL of the global population. Therefore, the goals of our study were (1) to identify risk factors influencing HRQOL of COPD patients and (2) to measure how specific clinical parameters are associated to HRQOL.

Participants and procedure
A cross-sectional study was performed among COPD patients at an inpatient department of the Hungarian National Koranyi Institute for Pulmonology, Budapest in 2019-2020. Inclusion criteria were age ≥40 years and recognized COPD (post-bronchodilator FEV 1 /FVC<70%). Exclusion criteria were simultaneous asthma, malignant diseases, and/or autoimmune diseases in terms of ICD-10 definitions. Participation was voluntary, and before signing the consent document, all patients were informed verbally and in writing about the study and its purpose. An appointed coordinator conducted the questionnaire-based interviews and filled out the questionnaires according to the patients' answers in a timeframe of 30 minutes. Clinical examination of patients followed the completion of the questionnaire, generally on the same day. Altogether 321 patients were approached and all of them agreed to participate in the study. The study protocol and the study were approved by the Ethical Committee of the National Koranyi Institute for Pulmonology (25/2017) and the Institutional Review Board of Semmelweis University (TUKEB 44402-2/2018/EKU) in compliance with the Helsinki Declaration.

Measurement
Our questionnaire contained items exploring the patients' socio-demographic, lifestyle, and disease-specific characteristics. Specific items included age, gender, COPD exacerbation in the past year (yes/no), body mass index (BMI), current smoking status (yes/no), frequency of physical activity (≤1 time a week/≥2 times a week), and number of comorbidities. Exacerbation was defined as an acute and significant change of the patient's daily symptoms resulting in change of therapy. As noted by Guo et al., BMI for COPD is more consistent if BMI is categorized as ≤21, 21.1-29.99, and ≥30 compared to the traditional categories of <18.49, 18.5-25.0, and >25.1 [20]. To be able to include BMI in our analysis, we used two separate dummy variables to examine the effect of obesity (BMI≥30 vs. reference BMI≤29.9) and underweight (BMI≤21 vs. reference BMI≥21.1) as risk factors. Regarding comorbidities, cardiovascular diseases, diabetes, immunological diseases, osteoporosis, musculoskeletal diseases, psychiatric diseases, allergies, hypersensitivities, and gastrointestinal diseases were included in the analysis. Data on comorbidities, lung function values, and BMI were collected from the latest medical records from the past month. Presence of exacerbation was examined from medical records dating back one year. All other data were collected with questionnaires. HRQOL was measured by SGRQ-C, COPD Assessment Test (CAT) and Short Form Health Survey (SF-36) instruments. The SGRQ-C instrument consists of 40 questions divided into three separate components. The symptoms component describes the frequency and severity of symptoms over the past three months, the activity component measures the impact of breathlessness on activities, whereas the impact component describes the effect of the disease on social Physiology International functioning and mental health of patients [17]. Scores range from 0 to 100 with higher scores indicating more severe symptoms/limitations [17]. CAT is a unidimensional tool, consisting of eight items with six response options for each question [18]. Scores range from 0 (best) to 40 (worst) [18]. Finally, SF-36 contains 36 questions measuring eight separate components related to quality of life (physical functioning, role limitation-physical, role limitation-emotional, vitality, mental health, social functioning, pain, and general health) [16]. Results range from 0 (worst) to 100 (best) [16]. We decided to calculate two subscales derived from the SF-36 scale, namely the physical (PCS) and mental (MCS) component scales to decrease the number of concurrent comparisons. Therefore, we standardized each of the eight components of SF-36 with a Z-score transformation. Individual Z-scores were calculated by subtracting the population mean from the respondents' score and dividing it by the standard deviation. For both the PCS and MCS scales, scores were multiplied by weighting coefficients calculated from a USA population and standardized to a T-score with means set at 50 and standard deviation set at 10 [21].
Patients were assigned to one of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages based on their FEV 1 results, as measured after the completion of the questionnaire according to the following specifications: FEV 1 ≥80% as stage 1, 50-80% as stage 2, 30-50% as stage 3, and ≤30% as stage 4 [22]. The FEV 1 , FVC (forced vital capacity), and FEV 1 /FVC values were measured by spirometry [23]. Exercise capacity was assessed by the 6-minute walking distance (6MWD) test [24,25]. We requested patients to walk up and down a hallway with predefined turning points for a total of 6 minutes. Results were measured in meters.

Statistical analysis
Socio-demographic characteristics and HRQOL scores by gender were analyzed with Pearson's Chi-square test, independent samples t-tests, and Mann-Whitney U-test. Normality was assessed by Shapiro-Wilk's normality test. Bivariate correlational analyses were performed for the three components (symptoms, activity, and impact) and for the total score of SGRQ-C, CAT, and the PCS and MCS scales of SF-36 by including individual variables in our models one at a time. This was followed by multivariate linear regression analyses for different components of the SGRQ-C and SF-36 questionnaires and multiple linear regression analysis for the unidimensional CAT questionnaire by including all variables in each respective model. Multivariate regression analysis was used for SGRQ-C and SF-36 as both are multidimensional tools and are comprised of more than one dependent variable, whereas multiple linear regression analysis was used for CAT as it is a unidimensional instrument with a single dependent variable. Maximum likelihood estimation with robust standard error was used to calculate regression coefficients. Results of the correlation matrices of each analysis were presented as well. We evaluated the effect of gender, age, smoking, physical activity, BMI, exacerbations, comorbidities, FEV 1 /FVC, and 6MWD results on HRQOL scores in our linear regression analyses. For each model, R 2 values were calculated to describe the proportion of explained variance. Significance was set at P < 0.05. All analyses were conducted in R statistics (lavaan package). Table 1 shows the descriptive characteristics of the sample. Compared to males (47.4%), females (52.6%) had significantly higher BMI, greater number of comorbidities, and lower 6MWD results. Regarding HRQOL, females reported poorer HRQOL according to the activity and impact components, and total scores of SGRQ-C. Furthermore, the mean score of the PCS of SF-36 was also significantly lower among them than among males, whereas their mean score of CAT was significantly higher.

RESULTS
In the multivariate analysis of SGRQ-C (Table 2), we found that current smokers had higher scores on the symptom subscale (b 5 0.11, P < 0.05), more comorbidities correlated with higher activity scores (b 5 0.13, P < 0.01) and total scores (b 5 0.09, P < 0.05). The occurrence of exacerbations in the past year was associated with an increased score on the symptoms Note: *P < 0.05; **P < 0.01; ***P < 0.001. Multivariate regression. b: standardized regression coefficient; FEV 1 : forced expiratory volume in the first second, FVC: forced vital capacity; 6MWD: 6-minute walking distance; R 2 : proportion of explained variance; r: Pearson's correlation.
When we examined the correlations of individual HRQOL indices with each other, they were significant except that between MCS and PCS. In the correlation matrix, SF-36 (PCS, MCS) scores were inversely related to both SGRQ-C and CAT questionnaires because of the opposite scoring methods employed (Table 5).

DISCUSSION
Our study established that the occurrence of COPD exacerbations, simultaneous comorbidities, and smoking were the most important factors negatively affecting the COPD patients' HRQOL, whereas the frequency of physical activity and better results on the 6MWD test were positively associated with their HRQOL. The correlation between SGRQ-C, CAT and SF-36 questionnaires was fair, indicating that these questionnaires examine slightly different aspects of HRQOL.
Our sample revealed poorer results as measured by the SGRQ-C, CAT, and SF-36 instruments compared to the results of other studies measuring the HRQOL of COPD patients [26][27][28]. According to the OECD, Hungary ranks in the bottom 20% in health and life satisfaction [29]. Additionally, smoking rates are among the highest in Europe, along with higher rates of alcohol consumption and overweight/obesity, and somewhat poorer performance in terms of physical activity [30]. These factors, both individually and overall, may affect HRQOL while offering a possible explanation for our results and also explaining why mortality of COPD in Hungary ranks the highest in Europe [31]. In our study, the number of exacerbations and comorbidities were strongly related to worse HRQOL. Severe manifestations of COPD are often associated with more frequent exacerbations, which may have a strong impact on the day-to-day functioning of patients [12]. According to Miravitlles et al., HRQOL decreases substantially just after an exacerbation, but it tends to improve fairly quickly within days of the event [12]. However, negative effects of exacerbations on HRQOL seem to accumulate over time, explaining why patients with more exacerbations tend to have a lower HRQOL compared to stable patients with fewer events. As for comorbidities, patients with COPD are often aged individuals and are affected by a plethora of other conditions as well, such as cardiovascular diseases, malnutrition, depression, and anxiety, that may also affect their activities and functioning [32]. A previous study identified psychiatric disorders and peripheral artery diseases as the most important comorbidities with negative impact on HRQOL of COPD patients [33]. Our results highlight that effective tertiary prevention along with treatment of any comorbid conditions may be essential for the improvement of HRQOL.
Regarding lifestyle factors, we found that HRQOL was significantly affected by physical activity and smoking. Studies indicate that the improvement of physical fitness during rehabilitation leads to improved functional parameters of COPD patients [34][35][36]. In our study, physical activity improved all dimensions of HRQOL and also had a positive effect on the mental health of patients. According to the WHO, 150 minutes of moderate-intensity aerobic physical activity or at least 75 minutes of vigorous-intensity aerobic physical activity is advised per week for the maintenance of health between ages 18 and 65 [35,37]. For patients over 65, counseling should focus more on the importance of leisure time physical activity, transportation, household chores, and gardening for the same amount of time as specified above [37]. Regarding smoking, physicians offering smoking cessation support for COPD patients should emphasize that quitting will positively impact the severity of symptoms, which in turn will also improve their overall HRQOL.
In our study the FEV 1 /FVC index did not correlate with HRQOL, suggesting that it is independent of lung capacity values to a certain extent. This is corroborated by other studies which detected only modest association between FEV 1 or FEV 1 /FVC values and changes in health status and other disease outcomes [15,38], such as rate of exacerbations [39]. The results are, however, often inconsistent [6]. Namely, in the bivariate model we found that higher FEV 1 / FVC values were associated with improved outcomes on the activity component and total scores of SGRQ-C, although this association disappeared when we controlled for additional factors. The 6MWD results were positively associated with all components of HRQOL. Since physical activity is strongly associated with 6MWD [40], the latter can be used to assess patients' level of fitness and also give an insight for physicians in the HRQOL of their patients [41,42].
One of the strengths of our study is that we measured HRQOL with three different methods, and we compared them with clinical/diagnostic test outcomes. Having included all variables in the models, R 2 values were relatively high. This indicates that these variables explain the variance in our study population fairly well, suggesting that exacerbations, physical activity, and number of comorbidities affect the HRQOL of COPD patients to a greater extent.
Finally, we must also take into consideration certain limitations of our study, for example the relatively small sample and the single-center involvement. Since we examined hospitalized Physiology International in-patients, our study sample may have contained a higher proportion of patients with more severe forms of COPD and thus, worse health-related quality of life. The role of selection bias cannot be ruled out since the participation was voluntary, which explains the better HRQOL outcomes of the sample. It may also have been useful to evaluate comorbidities with a multidimensional comorbidity index rather than the total number of comorbidities. An additional limitation was that in the calculation of MCS and PCS scores, weighting coefficients calculated from the Hungarian general population were not available, therefore we had to rely on coefficients calculated from the general USA population. This may have led to biased results for SF-36 even though certain studies suggest that this is a viable option when lacking populationspecific estimates, as it produces similar results [43].
COPD is a progressive, multi-organ disease that requires a more complex treatment strategy due to its diverse effects on the body and the health-related quality of life of the patients. In this study, the most important factors negatively affecting HRQOL were frequent exacerbations, number of comorbidities, the lack of physical activity, and current smoking. Regarding clinical parameters, we found a consistent positive effect between 6MWD and all components of HRQOL. The treatment model of patients should focus not only on lung function improvement and the prevention of exacerbations but also on the management of comorbidities, complemented with suggesting physical activity and smoking cessation.