COPD , metabolic syndrome , respiratory symptoms , and functional incapacity in smokers , ex-smokers , and never-smokers aged 40-59 in Almaty , Kazakhstan : a cross-sectional study

No study has reported the relationship between smoking status Background: with chronic obstructive pulmonary diseases (COPD) and metabolic syndrome (MetS) in Kazakhstan. The aim of this study was to assess the associations between health outcomes, including COPD, MetS, respiratory symptoms, and functional incapacity, with the cigarette smoking status. The cross-sectional study recruited 500 smokers, 200 ex-smokers, Methods: and 200 never-smokers aged 40-59 in Almaty, Kazakhstan. Questions assessed socio-demographic, clinical characteristics, and smoking behavior. Blood glucose and lipid profiles were determined after overnight fasting. COPD was defined according to the GOLD 2017 statement. Respiratory symptoms and functional incapacity were assessed by the COPD Assessment Test (CAT) and 6-min walk test (6MWT), respectively. Logistic regression models were used to assess the associations. The prevalence of COPD among smokers, ex-smokers and Results: never-smokers were 5.5%, 3.0% and 3.0%, respectively. Respiratory symptoms based on CAT were more prevalent among smokers (42.8%) as compared to ex-smokers (42.8% vs 17.0%; aOR 3.43, 95% CI 2.25–5.23) and never-smokers (42.8% vs 12.5%; aOR 5.44, 95% CI 3.42–8.65). Current smokers were more likely to walk less than 450 meters during 6MWT as compared to never-smokers (16.5% vs 5.0%; aOR 3.72, 95% CI 1.86–7.44). No significant association was found between the smoking status with COPD and MetS. Respiratory symptoms are common among the current smokers, Conclusions: even if most of them had preserved pulmonary function defined by spirometry.


Introduction
Tobacco smoking is the greatest preventable cause of death and illness in the world that attributed to more than 7 million deaths in 2015 1 . Smoking is associated with elevated risk of mortality from lung and other cancers, heart disease, stroke, chronic obstructive pulmonary disease (COPD) and other respiratory diseases, and other conditions 2 . The Global Adult Tobacco Survey (GATS) conducted in Kazakhstan in 2014 found that 19.1% of the study population were daily smokers (36.9% of males and 3.2% of females) (http://apps.who.int/tobacco/surveillance/survey/gats/kaz_countryreport_en.pdf?ua=1). COPD accounted for 3.2 million deaths worldwide in 2015 3 and is the fourth leading cause of death globally 4 . In Kazakhstan, an expected 1.4 million people might have COPD based on estimations from neighboring countries 5 .
Metabolic syndrome (MetS), or the set of specific cardiovascular risk factors, is also identified as a significant public health challenge that increases risk of developing type 2 diabetes, cardiovascular disease and several cancers 6,7 . MetS is prevalent among patients with COPD 8 . It was shown that cardiovascular disease, hypertension and diabetes in patients with COPD are associated with higher hospitalization and mortality rates 9 .
The presence of respiratory symptoms prompts to recognize and diagnose respiratory disease including COPD 10 and is often used to evaluate a severity of disease 11 .
Smoking cessation has proven to have significant health benefits, including reduction in cardiovascular and COPD morbidity and mortality [12][13][14][15] , and decrease in outset of respiratory symptoms 14 . Some studies demonstrated that smoking is associated with metabolic syndrome and quitting smoking is recommended for the prevention and management of metabolic syndrome 16,17 .
Assessment of the associations between several health outcomes, including COPD, respiratory symptoms, MetS and functional incapacity, and cigarette smoking status has not been done in Kazakhstan.
This study investigated these associations by comparing prevalence of these outcomes in smokers, ex-smokers, and neversmokers aged 40-59 in Almaty City, Kazakhstan.

Study design
The design of the study was described in detail in the study protocol published earlier 18 .
The study included three groups of male and female residents of City of Almaty between the ages of 40 and 59 (inclusive), those who: 1) currently smoke cigarettes (current smokers); 2) quitted smoking between 1 and 5 years ago (ex-smokers); 3) have never smoked regularly (never-smokers) 19 . Smokers and ex-smokers were individuals with a minimum of 10 packyear smoking history. Pack-years were calculated by taking the average number of cigarettes smoked per day divided by 20 and multiplied by the number of years smoked. The actual sample size was 900 including 500 smokers, 200 ex-smokers, and 200 never-smokers. The data was collected from September 2017 to April 2018.
Outcome measures COPD. COPD is defined according to the Global strategy for the diagnosis, management, and prevention of COPD (COPD Gold) as a post-bronchodilator ratio of forced expiratory volume in one second (FEV 1 ) to forced vital capacity (FVC) less than 70% detecting by spirometry testing 11 . Respiratory symptoms. The COPD Assessment Test (CAT) is a quick and useful tool to weigh impact of COPD symptoms on health-related quality of life 20 . Participants with a CAT score of 10 and more are considered having more severe respiratory symptoms 11 .

Functional incapacity.
The six-minute walk test (6MWT) determines functional exercise capacity in patients with moderate-to-severe heart or lung disease 21 . There are several reference systems predicting distance of 6MWT in healthy subjects 22 . They take into account subject's gender, age, height and weight. However, no study has been conducted so far to develop such a system for the Kazakh population. Therefore, we consider the distance of 450 meters as a cut-off level to define functional incapacity because distances less than this value is highly correlated with maximal oxygen capacity 23 .

Statistical analysis
Data were analyzed using R, a language and environment for statistical computing, version 3.3.1 (https://www.R-project. org/). Logistic regression analyses were utilized to measure the crude and adjusted associations between the smoking status and the four health outcomes. Crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. For adjustment, logistic regression models included gender (categorical), age (continuous), ethnicity (categorical), level of education (categorical), secondary smoking (for the 'ex-smokers vs neversmokers' comparison, categorical), pack-year (for the 'smokers vs ex-smokers' comparison, continuous). An alpha-level of 0.05 was chosen to test statistical significance. The Bonferroni Correction of the significance level was applied to account that three associations (smokers vs ex-smokers, smokers vs never-smokers, and ex-smokers vs never-smokers) were studied for each health outcome. Therefore, a P-value<0.017 (0.05/3) was considered significant.

Results
Basic characteristics and smoking patterns of study participants by study group are summarized in Table 1. The study participants were approximately equally distributed as those who were younger than 50 years and older than 50 years of age. There were about twice as many participants of Kazakh ethnicity (Asian origin) compared to Russians (European origin). Most of the participants had higher education. Majority of those who were smoking had more than 20 pack-years of smoking (61%).
Data on COPD prevalence, CAT-test, functional capacity based on 6MWT and prevalence of MetS are shown in Table 2. The prevalence of COPD among smokers, ex-smokers and neversmokers were 5.5%, 3.0% and 3.0%, respectively. Respiratory symptoms based on CAT were more prevalent among smokers (42.8%) as compared to ex-smokers (17.0%) and never-smokers (12.5%). Proportion of participants with MetS varied across the study groups from 28.6% among never-smokers to 37.5% among currents smokers. Current smokers were more likely (16.7%) to walk less than 450 meters during the 6MWT as compared to never-smokers (5.0%).
Mean scores of CAT components are show in Figure 1. Smokers had significantly worse mean scores in all CAT components

Figure 1. Components of the COPD Assessment Test (mean score and 95% confidence interval).
than ex-smokers and never-smokers except in the sleeping category. There were statistically significant (p<0.017) differences between mean scores of ex-smokers and never-smokers for cough, phlegm, and chest tightness.
The relationship between the smoking status and the prevalence of metabolic syndrome components is presented in Table 3. The prevalence of reduced levels of high-density lipoproteins was significantly higher for the group of current smokers than for ex-smokers and never smokers. No significant relationship was found between the prevalence of other components and the smoking status (P>0.017).
Crude and adjusted odds ratios (aOR) between COPD, respiratory symptoms, MetS, functional incapacity and the smoking status are presented in Table 4. Current smokers were significantly associated with increased prevalence of functional incapacity (6MWT<450 meters) while comparing with neversmokers (aOR 3.72, 95% CI 1.86-7.44). Current smokers had more prevalent respiratory symptoms than ex-smokers (aOR 3.43, 95% CI 2.25-5.23) and never-smokers (aOR 5.44, 95% CI 3.42-8.65). No significant association was found between the smoking status and prevalence of COPD and MetS in all three pairwise comparisons. The main data are provided for 900 subjects who completed the study (500 smokers, 200 ex-smokers, and 200 never-smokers). Missing data were not replaced.

Discussion
This study was the first in Kazakhstan to assess prevalence of COPD, respiratory symptoms, MetS, functional exercise incapacity in adults aged 40-59, those who smoked cigarettes, quit smoking and never smoked. The study demonstrated that at least 3% of the study population were affected by Table 3. Prevalence of metabolic syndrome and is components by study group.
Two of four health outcomes assessed in the study, respiratory symptoms and functional exercise incapacity, were significantly worse among current smokers than among those participants who never smoked cigarettes. Two other study outcomes, COPD and MetS, were more prevalent in current smokers, but the study couldn't demonstrate statistically significant association with the smoking status.
The presence of all symptoms and signs of respiratory disease that are used as CAT components were significantly lower among ex-smokers compared to those who continued smoking. This study is in line with other studies, suggesting that respiratory symptoms improve after smoking cessation, however remain worse or at least similar to those found in never-smokers 19 . One may assume that respiratory symptoms may be a significant reason for smoking cessation in a number of cases.
It is important to notice that a substantial proportion of the current smokers or 42.8% had respiratory symptoms, even if most of them had preserved pulmonary function defined by spirometry. It was shown that high CAT scores in current or ex-smokers are associated with exacerbation-like events, i.e. that symptomatic smokers with preserved pulmonary function have evidence of airway disease even when they do not meet the current definition for COPD 24 . Exacerbation-like events in individuals without COPD raise the burden of respiratory disease and are associated with considerable health outcomes 25 . Thus, even proper diagnosis of COPD based on the spirometric criterion substantially underestimates the effect of smoking on the individual with smoking history.
The study has several limitations. This was cross-sectional study that was not designed to determine causal relationship. Second, although we adjusted for the known potential confounders, residual bias attributable to uncontrolled confounding variables may exist and cannot be estimated. Third, we used a quota sample which may have affected the generalizability of the study results to the study population. Fourth, our study participants were adults aged 40-59 from Almaty city, and further assessment is needed to determine whether the results are applicable to the other population groups.

Data availability
Dataset 1. Raw data behind the results of this study.
The main data are provided for 900 subjects who completed the study (500 smokers, 200 ex-smokers, and 200 never-smokers).
Missing data were not replaced.

○
The article is not consistent within itself: ○ -Conclusions of the study reflecting only one aspect of the aim, and it is only respiratory symptoms.
-There is no data presented on spirometry of patients from 3 groups. It is not clear if it was performed in all groups.
-In the protocol of this study published earlier, it was mentioned that there was laboratory testing of serum: its not clear if alfa1antitripsin was tested.
-The same for chest computed tomography: any data from the smoking group? -There is surprisingly low prevalence of COPD in the smoker group! -In the discussion, the data from the current study must be compared with the data from other studies.
Conclusions are not corresponding to the aim of the study.
We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above.
The benefits of publishing with F1000Research: Your article is published within days, with no editorial bias • You can publish traditional articles, null/negative results, case reports, data notes and more • The peer review process is transparent and collaborative • Your article is indexed in PubMed after passing peer review • Dedicated customer support at every stage • For pre-submission enquiries, contact research@f1000.com