ERJ OPEN RESEARCH ORIGINAL RESEARCH ARTICLE M. MIRAVITLLES ET AL. Respiratory symptoms and their determinants in the general Spanish population: changes over 20 years Marc Miravitlles 1,2, Juan José Soler-Cataluña2,3, Joan B. Soriano 2,4, Francisco García-Río 2,5, Pilar de Lucas6, Inmaculada Alfageme7, Ciro Casanova8, José Miguel Rodríguez González-Moro9, Guadalupe Sánchez10, Julio Ancochea2,4 and Borja G. Cosío 2,11 1 Pneumology Dept, Hospital Universitari Vall d’Hebron/Vall d’Hebron Institut de Recerca, Barcelona, Spain. 2CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. 3Servicio de Neumología, Hospital Arnau de Vilanova-Lliria, Valencia, Spain. 4 Servicio de Neumología, Hospital Universitario La Princesa, and Universidad Autónoma de Madrid, Madrid, Spain. 5Servicio de Neumología, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain. 6Servicio de Neumología, Hospital General Gregorio Marañon, Madrid, Spain. 7Unidad de Gestión Clínica de Neumología, Hospital Universitario Virgen de Valme, Universidad de Sevilla, Seville, Spain. 8Servicio de Neumología, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain. 9Servicio de Neumología, Hospital Universitario “Príncipe de Asturias”, Alcalá de Henares, Universidad de Alcalá, Madrid, Spain. 10Departamento Médico, GSK, Madrid, Spain. 11Servicio de Neumología, Hospital Universitario Son Espases-IdISBa, Palma de Mallorca, Spain. Corresponding author: Marc Miravitlles (marcm@separ.es) Shareable abstract (@ERSpublications) Approximately half of the adult Spanish population has some respiratory symptoms and this prevalence has remained quite stable over the last 20 years https://bit.ly/37uGRT7 Cite this article as: Miravitlles M, Soler-Cataluña JJ, Soriano JB, et al. Respiratory symptoms and their determinants in the general Spanish population: changes over 20 years. ERJ Open Res 2022; 8: 00067- 2022 [DOI: 10.1183/23120541.00067-2022]. Abstract Copyright ©The authors 2022 Background Few large epidemiological studies have analysed the prevalence of respiratory symptoms and their determinants in the general adult population. We investigated the prevalence and determinants of This version is distributed under the terms of the Creative respiratory symptoms and compared their prevalence with that of two previous studies conducted in 1999 Commons Attribution Non- and 2009. Commercial Licence 4.0. For Method EPISCAN II was a multicentre, cross-sectional, population-based epidemiological study in commercial reproduction rights individuals older than 40 years. and permissions contact Results A total of 9092 individuals were included. Up to 47.5% reported at least one respiratory symptom, permissions@ersnet.org being more frequent in women than in men (49.4% versus 45.5%, p=0.0002) and with wheezing being the Received: 3 Feb 2022 most frequent (33.7%) followed by dyspnoea (26.8%). The presence of any symptom was associated with Accepted: 1 April 2022 female sex, higher body mass index (BMI), lower forced expiratory volume in 1 s (FEV1 % pred), reduced physical activity, a higher Charlson index and the presence of anxiety and depression. Smoking was also significantly associated with having at least one respiratory symptom in a dose–response fashion (OR: 1.415, 1.916, 2.192 and 2.987 for 0–10, 10–20, 20–30 and >30 pack-years, respectively, all p<0.0001). The prevalence of symptoms remained quite similar over the last 20 years (wheezing 40%, 36% and 33.7% and dyspnoea 10.4%, 9.9% and 13.1% in 1999, 2009 and 2019, respectively). Conclusions Approximately half of the adult Spanish population have respiratory symptoms and this prevalence has remained quite stable over the last 20 years. Smoking remains the main factor associated with respiratory symptoms, but female sex, comorbidities, high BMI and low FEV1 and low physical activity are also significantly associated with respiratory symptoms. Introduction Acute and chronic respiratory symptoms are one of the most frequent causes of consultation to the health system. In fact, cough is the second cause of consultation to primary care physicians [1]. Although some respiratory symptoms may be benign and self-limited, others persist and significantly impair patients’ quality of life [2]. Chronic respiratory symptoms in adults may be the manifestation of several respiratory diseases, which are more frequently airways diseases such as asthma, COPD or bronchiectasis. However, https://doi.org/10.1183/23120541.00067-2022 ERJ Open Res 2022; 8: 00067-2022 ERJ OPEN RESEARCH ORIGINAL RESEARCH ARTICLE | M. MIRAVITLLES ET AL. other non-respiratory diseases, particularly, but not exclusively, cardiovascular diseases and anaemia, can also present with chronic respiratory symptoms. A previous epidemiological study conducted at the end of the last century in Spain in +4000 adults between 40 and 69 years of age showed that 48% reported at least one respiratory symptom, being more frequent in men than in women and with a clear relationship with smoking habits [3]. During the last 20 years significant social changes have occurred in Spain, including more restrictive legislations against smoking, with a reduction in smoking rates in males, but not in females [4]. Moreover, spirometry has become more widely available in primary care, and treatments for asthma and COPD have improved. It is not clear whether these and other aspects may have changed the prevalence of respiratory symptoms and their determinants in the adult population. The EPISCAN II (in Spanish: Epidemiology of COPD in Spain) is a population-based epidemiological study designed with the main objective of determining the prevalence of COPD in Spain through the analysis of a representative sample of adults from all the Spanish regions (autonomous communities) [5]. This article presents the results of a secondary objective which was to assess the prevalence and determinants of respiratory symptoms in the general adult population. The EPISCAN II study used a similar methodology and the same questionnaires as the IBERPOC study conducted in 1999 [3] and the EPISCAN study conducted in 2009 [6]; therefore, a comparison of the prevalence of respiratory symptoms in these three studies conducted over a period of 20 years was also conducted. Methods Study design and population The EPISCAN II study was a national, multicentre, cross-sectional, population-based epidemiological study aimed at investigating the prevalence of COPD in Spain. The fieldwork was conducted from April 2017 to February 2019 in 20 teaching hospitals from the 17 Spanish autonomous communities. Subjects from the general population who were resident in the postal code areas nearest the participating hospitals were selected. A list of random telephone numbers was obtained, stratified according to these postal codes and quotas for sex and age groups. The inclusion criteria were as follows: men or women aged 40 years or more with no physical or cognitive difficulties that would prevent them from completing spirometry or any of the study procedures. The protocol, the fieldwork and all the methods have been described previously [5, 7]. In this article we present the results of one of the secondary outcomes, the prevalence and determinants of respiratory symptoms in the general Spanish adult population. The study was approved by the ethics committees of each of the participating centres, and all participants provided informed consent. The EPISCAN II protocol is registered at https://clinicaltrials.gov (NCT03028207) and at www.gsk-clinicalstudyregister.com/study/205932. Variables and procedures Demographic information on sex, age, level of education, comorbidities, weight, height and smoking were collected. A smoker was defined as an individual who smoked at least one cigarette, cigar or pipe a day, and an ex-smoker was defined as an individual who had discontinued using any form of tobacco at least 6 months before the study visit. Comorbidities were assessed with the Charlson index [8]. Forced spirometry pre- and post-bronchodilation was performed using a pneumotachograph (Vyntus Spiro, Carefusion, Germany), according to standardised procedures as previously described [5, 9]. For the diagnosis of respiratory symptoms, the answers to the European Community for Coal and Steel Questionnaire (ECSC) were used [10]. The diagnosis of cough was considered when the participant answered yes to any of the following questions: Do you usually cough when you get up? Do you usually cough during the day or during the night? Chronic expectoration was considered when there was an affirmative answer to: Do you usually cough up phlegm during the day or during the night? Dyspnoea was diagnosed when a positive answer was given to: Do you get breathless when going up one flight of stairs at your normal pace? Wheezing was evaluated by the question: Have you ever had wheezing or whistling in your chest? Chronic bronchitis was diagnosed when the answer was yes to the question: Do you cough up phlegm most days or nights for 3 months each year? A diagnosis of asthma was accepted when the participant answered yes to: Has a doctor ever told you that you have asthma? The degree of dyspnoea was evaluated by the modified Medical Research Council (mMRC) dyspnoea scale, that ranges between 0 – I only get breathless with strenuous exercise – to 4 – I am too breathless to leave the house, or I get breathless when dressing [11]. https://doi.org/10.1183/23120541.00067-2022 2 ERJ OPEN RESEARCH ORIGINAL RESEARCH ARTICLE | M. MIRAVITLLES ET AL. Health status was assessed by the COPD Assessment Test (CAT) questionnaire. The CAT is a disease-specific questionnaire consisting of eight items: cough, expectoration, chest tightness, difficulty going up hills/stairs, confidence leaving home, activity limitations at home, quality of sleep and levels of energy, each presented as a 5-point scale, providing a total score of 0 (floor) to 40 (ceiling) indicating the impact of the disease [12]. Depression was identified through a clinical interview using the Hospital Anxiety and Depression Scale (HADS), which is a tool validated for use in Spanish and used for the assessment of symptoms and the identification of cases of anxiety and depression in patients with chronic disease [13]. This questionnaire includes seven items of depression (depression subscale or HADS-D) and seven of anxiety (anxiety subscale or HADS-A). In each subscale the scores range from 0 to 21. Possible depression or anxiety was classified in patients scoring >8 in the respective HADS subscales. Physical activity was measured by the Yale Physical Activity Questionnaire (YPAS) validated for the Spanish population and the elderly population. This questionnaire reflects the amount, frequency and intensity of physical activity that can be used to estimate the effects of physical activity as a continuous parameter, even at the low levels of activity that might be expected in COPD patients [14, 15]. Statistical analysis Categorical variables were presented as numbers with percentages, and continuous variables as mean±SD. The characteristics of the population and the prevalence of symptoms according to sex and smoking status were compared using the t-test, or χ2 test. The prevalence of symptoms among the different surveys was compared with the χ2 test for trend. Univariate and multivariate linear regression analyses were used to investigate factors associated with respiratory symptoms. Only variables with a level of significance <0.1 in the univariate analysis were included in a stepwise multivariate linear regression model. The R2 coefficient of determination was calculated for the model. Data were analysed with the Statistical Analysis System (SAS) Enterprise Guide 7.15, considering a statistical significance ( p) of 0.05 for all the statistical tests performed. Results Population characteristics Overall, a total of 12 825 subjects were initially contacted by phone, and 9092 (70.9%) agreed to be seen in the hospital and performed a valid spirometry and constituted the population of our study. The characteristics of the population are described in table 1. TABLE 1 Demographic and clinical characteristics of the study participants by sex and smoking Global Men Women p-value Smokers Never-smokers p-value Subjects n 9092 4311 4781 4910 4182 Age years 60.2±11.1 60.1±10.8 60.4±11.3 0.1553 59.4±10.2 61.2±12.0 <0.0001 BMI kg·m−2 27.5±5.0 28.1±4.4 27.01±5.4 <0.0001 27.4±4.8 27.6±5.1 0.0706 Active smoker % 19.8 21.6 18.1 <0.0001 36.6 Ex-smoker % 34.2 39.9 29.1 63.4 Never-smoker % 46.0 38.5 52.8 100 Pack-years 26.3±22.9 30.0±24.8 21.9±19.6 <0.0001 26.3±22.9 FVC L 3.7±1.0 4.32±0.9 3.1±0.7 <0.0001 3.8±0.9 3.2±1.1 <0.0001 FVC % 101.0±14.9 100.5±14.9 101.5±14.9 <0.0001 100.9±14.5 101.2±15.4 0.2152 FEV1 L 2.9±0.8 3.34±0.8 2.4±0.6 <0.0001 2.9±0.8 2.8±0.9 <0.0001 FEV1 % pred 100.6±17.1 99.64±17.7 101.5±16.5 <0.0001 98.8±17.2 102.7±16.8 <0.0001 FEV1/FVC 78.2±7.8 77.08±8.5 79.12±7.04 <0.0001 76.9±8.5 79.7±6.7 <0.0001 Charlson comorbidity index 0.36±0.87 0.42±0.97 0.30±0.77 <0.0001 0.40±0.94 0.30±0.78 <0.0001 COTE index 1.01±2.25 0.64±1.72 1.34±2.59 <0.0001 1.06±2.29 0.95±2.20 0.0256 Possible depression % 11.1 9.5 12.6 <0.0001 11.0 11.2 0.9141 Possible anxiety % 26.6 19.7 32.8 <0.0001 26.4 26.8 0.1447 YPAS 50.0±23.8 52.7±25.1 47.7±22.5 <0.0001 50.0±23.9 50.1±14.0 0.8135 Values are mean±SD, unless otherwise specified. BMI: body mass index; FVC: forced vital capacity; FEV1: forced expiratory volume in 1 s; COTE: COPD specific comorbidity test; YPAS: Yale Physical Activity Questionnaire. https://doi.org/10.1183/23120541.00067-2022 3 ERJ OPEN RESEARCH ORIGINAL RESEARCH ARTICLE | M. MIRAVITLLES ET AL. Prevalence of respiratory symptoms Up to 47.5% of the population reported at least one respiratory symptom, being more frequent in women than men (49.4% versus 45.5%, p=0.0002), and the most frequent was wheezing (33.7%) followed by any dyspnoea (26.8%) and cough (15.9%). The different respiratory symptoms were significantly more frequent in women except for wheezing and chronic bronchitis (table 2, figure 1a). However, the prevalence of airflow limitation by both fixed ratio and lower limit of normal (LLN) was significantly more frequent in men (table 2). The mean±SD CAT score was 6.4±5.8, being higher in women than men (6.8±6.1 versus 5.8±5.4; p<0.0001), and up to 22.8% of women had a CAT >10 compared with 16.2% of men ( p<0.0001). Up to 55.4% of smokers had at least one respiratory symptom compared with 38.3% of never-smokers ( p<0.0001). All individual respiratory symptoms were significantly more frequent in smokers compared to never-smokers, except for dyspnoea evaluated either as dyspnoea at one floor, as any dyspnoea or as the mMRC degree of dyspnoea (table 2, figure 1b). The prevalence of airflow limitation by both definitions, the CAT scores and the proportion of subjects with CAT >10 were also higher in smokers compared with never-smokers (table 2). However, the presence of asthma was significantly lower in smokers compared with never-smokers (6.6% versus 9.4%; p<0.0001). Prevalence of comorbidities and level of physical activity The population included had a low prevalence of comorbidities, with a mean±SD Charlson score of 0.36±0.87, which was significantly higher in men than in women and in smokers than in never-smokers. Up to 11.1% of participants had a HAD score consistent with possible depression and 26.6% of possible anxiety, both of which were higher in women than in men, but without differences between smokers and never-smokers. The mean±SD YPAS score was 50±23.8, being higher in men, but with no differences between smokers and never-smokers (table 1). Factors associated with respiratory symptoms In the multivariate analysis, dyspnoea was significantly and strongly associated with female sex (odds ratio (OR) 3.056, 95% CI 2.597–3.597; p<0.0001) and comorbidities, and especially with anxiety and depression. There was also an association with increasing age and the body mass index (BMI) and with a smoking consumption of >30 pack-years and a significant negative association with forced expiratory volume in 1 s (FEV1 % pred) and the YPAS score (table 3). TABLE 2 Prevalence of respiratory symptoms and chronic airflow obstruction in the study participants by sex and smoking Global Men Women p-value Smokers Never-smokers p-value Subjects n 9092 4311 4781 4910 4182 Chronic cough 15.9 14.9 16.8 0.0146 19.5 11.6 <0.0001 CMH 13.0 15.0 11.2 <0.0001 17.0 8.3 <0.0001 Wheezing 33.7 33.6 33.8 0.7927 41.4 24.7 <0.0001 Dyspnoea one floor 13.1 8.3 17.5 <0.0001 13.4 12.8 0.4333 Any dyspnoea 26.8 22.0 31.1 <0.0001 27.0 26.5 0.6041 Dyspnoea mMRC <0.0001 0.9011 0 73.2 78.0 68.9 73.0 73.5 I 21.8 18.1 25.1 21.9 21.6 II 3.8 2.9 4.7 3.8 3.9 III 1.1 1.0 1.2 1.2 1.0 IV 0.1 0.1 0.1 0.1 0.1 Chronic bronchitis 4.7 5.0 4.3 0.1387 6.7 2.3 <0.0001 Any symptom 47.5 45.5 49.4 0.0002 55.4 38.3 <0.0001 CAT score, mean±SD 6.4±5.8 5.8±5.4 6.8±6.1 <0.0001 6.8±5.8 5.9±5.7 <0.0001 CAT >10 19.6 16.2 22.8 <0.0001 21.5 17.5 <0.0001 Asthma 7.9 6.2 9.4 <0.0001 6.6 9.4 <0.0001 Chronic airflow limitation (FR) 11.8 14.6 9.4 <0.0001 16.0 7.0 <0.0001 Chronic airflow limitation (LLN) 6.0 7.1 4.9 <0.0001 8.8 2.7 <0.0001 Values are % unless otherwise specified. CMH: chronic mucus hypersecretion; mMRC: Modified Medical Research Council dyspnoea scale; CAT: COPD Assessment Test; FR: fixed ratio; LLN: lower limit of normal. https://doi.org/10.1183/23120541.00067-2022 4 ERJ OPEN RESEARCH ORIGINAL RESEARCH ARTICLE | M. MIRAVITLLES ET AL. a) 60 50 40 30 Global % Men Women 20 10 0 Any Cough CMH Wheezing Dyspnoea Chronic CAT >10 Asthma symptom (one floor) bronchitis b) 60 50 40 30 % Smokers Never-smokers 20 10 0 Any Cough CMH Wheezing Dyspnoea Chronic CAT >10 Asthma symptom (one floor) bronchitis FIGURE 1 Prevalence of respiratory symptoms in the general population over 40 years of age by a) sex and b) smoking habit. CMH: chronic mucus hypersecretion; CAT: COPD Assessment Test. Wheezing was significantly associated with smoking, with increasing odds ratios at different levels of consumption (OR 1.627, 1.930, 2.138 and 2.659 at 0–10, 10–20, 20–30 and >30 pack-years, respectively, all p>0.0001). It was also associated with increasing BMI and increasing comorbidities, including anxiety but not depression (table 3). Regarding chronic bronchitis, there was an association with increasing smoking consumption starting at 10–20 pack-years with OR 1.803 (95% CI 1.223–2.657; p=0.0029), which increased to OR 3.069 and 4.808 for 20–30 and >30 pack-years, respectively (both p<0.0001). It was also significantly associated with depression (OR 1.388, 95% CI 1.040–1.852; p=0.0259) and anxiety (OR 2.457; 95% CI 1.940– 3.110; p<0.0001) and negatively associated with FEV1 % pred (table 4). The presence of any symptom was associated with female sex (OR 1.435; 95% CI 1.302–1.582; p<0.0001), a higher BMI, having at least a Charlson score of 1 compared to 0, and the presence of anxiety and depression. Smoking was also significantly associated with having at least one respiratory symptom in a dose–response fashion with increasing odds ratios for increasing smoking consumption (OR 1.415, 1.916, 2.192 and 2.987 for 0–10, 10–20, 20–30 and >30 pack-years, respectively, all p<0.0001). Having any respiratory symptom was negatively associated with FEV1 % pred and physical activity measured by the YPAS (table 4). https://doi.org/10.1183/23120541.00067-2022 5 ERJ OPEN RESEARCH ORIGINAL RESEARCH ARTICLE | M. MIRAVITLLES ET AL. TABLE 3 Unadjusted and adjusted association between patients’ characteristics and the presence of dyspnoea and wheezing Variables Dyspnoea Wheezing Unadjusted analysis Adjusted analysis Unadjusted analysis Adjusted analysis OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) p-value Sex Male Ref Ref Ref Female 2.355 (2.062–2.691) <0.0001 3.056 2.597–3.597) <0.0001 1.012 (0.927–1.105) 0.7928 Age years 1.039 (1.033–1.045) <0.0001 1.029 (1.022–1.036) <0.0001 0.997 (0.993–1.001) 0.2092 BMI kg·m−2 1.111 (1.098–1.124) <0.0001 1.093 (1.078–1.107) <0.0001 1.054 (1.045–1.064) <0.0001 1.043 (1.033–1.052) <0.0001 Smoking pack-years 0 Ref Ref Ref Ref 0–10 0.775 (0.632–0.951) 0.0145 1.162 (0.919–1.470) 0.2107 1.448 (1.263–1.661) <0.0001 1.627 (1.409–1.879) <0.0001 10–20 0.748 (0.598–0.935) 0.0107 1.076 (0.835–1.386) 0.5704 1.818 (1.575–2.099) <0.0001 1.930 (1.659–2.245) <0.0001 20–30 0.930 (0.748–1.158) 0.5175 1.252 (0.972–1.612) 0.0815 2.154 (1.857–2.499) <0.0001 2.138 (1.828–2.502) <0.0001 >30 1.593 (1.362–1.864) <0.0001 1.529 (1.262–1.854) <0.0001 3.242 (2.870–3.662) <0.0001 2.659 (2.334–3.029) <0.0001 FEV1 % 0.966 (0.963–0.970) <0.0001 0.973 (0.969–0.977) <0.0001 0.972 (0.970–0.975) <0.0001 0.978 (0.975–0.981) <0.0001 Charlson comorbidity index 0 Ref Ref Ref 1 2.503 (2.147–2.919) <0.0001 1.700 (1.420–2.036) <0.0001 1.780 (1.578–2.009) <0.0001 1.372 (1.203–1.566) <0.0001 >1 3.409 (2.826–4.112) <0.0001 2.341 (1.873–2.926) <0.0001 1.665 (1.417–1.957) <0.0001 1.211 (1.015–1.446) 0.0335 Depression 4.167 (3.582–4.847) <0.0001 1.945 (1.606–2.356) <0.0001 1.543 (1.349–1.765) <0.0001 Anxiety 3.050 (2.685–3.464) <0.0001 2.302 (1.956–2.709) <0.0001 1.762 (1.599–1.942) <0.0001 1.769 (1.595–1.963) <0.0001 YPAS 0.975 (0.972–0.978) <0.0001 0.986 (0.983–0.989) <0.0001 0.995 (0.993–0.997) <0.0001 The analysis was adjusted for the following variables: body mass index (BMI); forced vital capacity (FVC); forced expiratory volume in 1 s (FEV1); Hospital Anxiety and Depression scale (HADS); Yale Physical Activity Questionnaire (YPAS). Ref: reference. The adjusted and unadjusted analyses separately by men and women are presented in the supplementary material (tables S1 to S4). In general, the association between respiratory symptoms and cumulative smoking consumption was stronger in men and that of depression and anxiety and symptoms was stronger in women. Age was only significantly associated with the presence of any symptom in women but not in men. Changes in the prevalence of respiratory symptoms over 20 years The prevalence of respiratory symptoms in the IBERPOC, EPISCAN and EPISCAN II studies was compared. The main characteristics of the population included in the three studies are presented in the supplementary material (table S5). The distribution of the populations by sex and smoking habits was very similar, but the mean age increased progressively from IBERPOC to EPISCAN and EPISCAN II due to the modified inclusion criteria. Nevertheless, the prevalence of symptoms was very similar among the surveys, with a slight but significant increase in dyspnoea, cough, sputum production and diagnosis of asthma and a decrease in wheezing, while the prevalence of chronic airflow obstruction ranged between 10.2% in EPISCAN and 11.8% in EPISCAN II and with an intermediate value in IBERPOC (10.6%) (figure 2 and supplementary table S5). Supplementary table S6 shows the comparison between IBERPOC and EPISCAN and the participants of the same age group in EPISCAN II. Prevalence of symptoms was very similar, with some differences reaching statistical significance due to the large sample size. Discussion The EPISCAN II study which included >9000 adult participants is the largest epidemiological study on COPD and respiratory symptoms conducted in Spain [5]. It has provided an accurate estimate of the prevalence of COPD [7] and has also collected important information about the prevalence of respiratory symptoms and their determinants in a representative sample of the global Spanish population. The results show that almost half of the Spanish adult population reports at least one respiratory symptom, wheezing being the most prevalent, followed by dyspnoea. The majority of symptoms were more frequent in women, and women also had worse CAT scores despite having a higher proportion of never-smokers than men. However, the prevalence of chronic bronchitis and airflow limitation was higher in men. All respiratory symptoms, except dyspnoea, were more frequent in smokers than in never-smokers; conversely, the prevalence of asthma was higher in never-smokers. We have also shown that this burden of symptoms on the Spanish population has changed little over the last 20 years. https://doi.org/10.1183/23120541.00067-2022 6 ERJ OPEN RESEARCH ORIGINAL RESEARCH ARTICLE | M. MIRAVITLLES ET AL. TABLE 4 Unadjusted and adjusted association between patients’ characteristics and chronic bronchitis and the presence of “any symptom” Variables Chronic bronchitis “Any symptom” Unadjusted analysis Adjusted analysis Unadjusted analysis Adjusted analysis OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) p-value Sex Male Ref Ref Ref Female 0.859 (0.703–1.051) 0.1391 1.171 (1.076–1.274) 0.0002 1.435 (1.302–1.582) <0.0001 Age years 1.006 (0.997–1.015) 0.1891 1.010 (1.006–1.014) <0.0001 BMI kg·m−2 1.029 (1.010–1.049) 0.0025 1.063 (1.054–1.073) <0.0001 1.051 (1.041–1.062) <0.0001 Smoking pack-years 0 Ref Ref Ref Ref 0–10 1.174 (0.784–1.757) 0.4360 1.258 (0.828–1.911) 0.2829 1.221 (1.073–1.389) 0.0025 1.415 (1.232–1.625) <0.0001 10–20 1.769 (1.222–2.582) 0.0031 1.803 (1.223–2.657) 0.0029 1.703 (1.484–1.955) <0.0001 1.916 (1.651–2.224) <0.0001 20–30 3.097 (2.216–4.327) <0.0001 3.069 (2.174–4.333) <0.0001 2.038 (1.762–2.356) <0.0001 2.192 (1.872–2.566) <0.0001 >30 5.726 (4.409–7.435) <0.0001 4.808 (3.655–6.324) <0.0001 3.377 (2.982–3.824) <0.0001 2.987 (2.605–3.426) <0.0001 FEV1 % 0.968 (0.963–0.973) <0.0001 0.977 (0.971–0.982) <0.0001 0.969 (0.966–0.971) <0.0001 0.975 (0.972–0.978) <0.0001 Charlson comorbidity index 0 Ref Ref Ref 1 1.629 (1.257–3.113) 0.0002 1.909 (1.690–2.156) <0.0001 1.457 (1.273–1.667) <0.0001 >1 2.184 (1.607–2.968) <0.0001 2.119 (1.797–2.498) <0.0001 1.537 (1.280–1.845) <0.0001 Depression 2.774 (2.177–3.535) <0.0001 1.388 (1.040–1.852) 0.0259 2.210 (1.923–2.541) <0.0001 1.240 (1.050–1.464) 0.0113 Anxiety 2.723 (2.222–3.337) <0.0001 2.457 (1.940–3.110) <0.0001 2.029 (1.841–2.236) <0.0001 1.825 (1.626–2.048) <0.0001 YPAS 0.992 (0.987–0.996) 0.0003 0.991 (0.989–0.993) <0.0001 0.996 (0.994–0.998) <0.0001 The analysis was adjusted for the following variables: body mass index (BMI); forced vital capacity (FVC); forced expiratory volume in 1 s (FEV1); Hospital Anxiety and Depression scale (HADS); Yale Physical Activity Questionnaire (YPAS). Ref: reference. Several studies have described the prevalence and characteristics of respiratory symptoms in patients with respiratory diseases, or in relation to environmental or professional activities, but only a few epidemiological surveys have provided estimates of the prevalence of respiratory symptoms and their determinants in the general adult population. Comparisons of prevalence of respiratory symptoms between studies must be made with caution, because of differences in age composition and smoking habits of the populations included, and especially due to the use of different symptoms questionnaires. Nevertheless, all 45 40 35 30 25 % 20 15 10 5 0 Dyspnoea Cough Wheezing CMH Chronic Asthma CAO (one floor) bronchitis IBERPOC (1999) EPISCAN (2009) EPISCAN II (2019) FIGURE 2 Prevalence of respiratory symptoms in three population-based epidemiological surveys conducted in Spain in 1999, 2009 and 2019. CMH: chronic mucus hypersecretion; CAO: chronic airflow obstruction. https://doi.org/10.1183/23120541.00067-2022 7 ERJ OPEN RESEARCH ORIGINAL RESEARCH ARTICLE | M. MIRAVITLLES ET AL. surveys agree on the high prevalence of respiratory symptoms in the general population. In a random sample of adults between 20 and 69 years in Nordic European countries, between 54% and 66% of participants in the participating countries presented at least one respiratory symptom [16], similar to the 50% observed among almost 20 000 subjects from Norway [17], the 49.7% of 786 subjects without COPD interviewed in Sweden [18], and also very close to the 47.5% obtained in our study. This high prevalence is very relevant because the presence of respiratory symptoms, even in subjects with normal lung function, has been associated with a significant impairment in quality of life [2]. Furthermore, our data have shown a significant association between respiratory symptoms in general and dyspnoea in particular, with a higher prevalence of depression and anxiety and reduced levels of physical activity. These results suggest that these factors may interact and constitute a vicious circle that requires a precise diagnosis and a multidisciplinary approach. The presence of respiratory symptoms also has important prognostic implications. Some prospective studies have demonstrated that adults with respiratory symptoms have an increased risk of being diagnosed in the future with a lung disease and an accelerated decline in lung function [19], more respiratory hospitalisations and even an increased risk of death [20, 21]. Nonetheless, the importance of respiratory symptoms may not be perceived by the individuals suffering from them. A large survey conducted in 2005 in +6500 subjects in Spain indicated that only 60% of respondents with respiratory symptoms had consulted a physician and, of these, only 45% had undergone spirometry [22]. 15 years later, the proportion of symptomatic subjects who consulted a physician remained at 59.3%, but the use of spirometry among these subjects improved to up to 66.2% [23]. Wheezing was the most prevalent symptom in our population (33.7%), followed by dyspnoea (26.8%). Similarly, ABRAHAMSEN et al. [24] found a prevalence of wheezing of 27% in a study in 16 000+ individuals between 16 and 50 years of age, and a prevalence of 23.4% of wheezing was observed among ever-smoking women between 40 and 69 years in a Korean population [25]. The prevalence of dyspnoea is more variable among surveys probably due to the different definitions and scales used. In the aforementioned Korean study, the prevalence of dyspnoea ranged from 23.8% in non-smoking men to 58.6% in smoking women [25]. In a study on 1500 individuals with a mean age of 49 years, VINNIKOV et al. [26] found a prevalence of dyspnoea mMRC >2 of 9%, which was higher than the 5% in our study. In a survey of 1000+ individuals older than 40 years in Brazil, the prevalence of dyspnoea ranged from 19% in subjects with normal weight to 36% in obese individuals [27]. The significant association of increased BMI with dyspnoea was also observed in our population, together with a higher prevalence of dyspnoea in women, despite a lower percentage of ever-smokers among women. All respiratory symptoms were significantly associated in a dose–response fashion with smoking. The impact of smoking on symptoms and respiratory health in general are well documented [18, 24, 25, 28], but other factors such as comorbidities may also be significantly associated with respiratory symptoms. In addition to a higher BMI, a higher Charlson comorbidity index and greater anxiety and depression were associated with wheezing and dyspnoea in our study. Conversely, chronic bronchitis was not significantly associated with BMI and the Charlson index indicating the clear respiratory origin of this symptom. The CAT questionnaire has been extensively used to evaluate symptoms in patients with COPD, and a CAT score >10 has been considered as a high level of symptoms [29, 30]. The mean CAT score in our population was 6.4, being higher in women than men (6.8 versus 5.8), but almost 20%, including 17.5% of never-smokers, presented a CAT score >10. There are few data about CAT scores in large samples of the general adult population, but our results are consistent with a study in 1500 adults in Kazakhstan in which 15% of the participants had a CAT score >10 [26]. Although CAT is considered a symptoms’ questionnaire and is used to modulate COPD pharmacologic treatment [30, 31], up to 38% of the variance in CAT scores may be due to non-respiratory factors such as depression [32], which may explain why up to one fifth of the adult population in our study had CAT scores >10. In fact, up to 54% of the individuals in our study with a CAT score >10 had some degree of depression. The EPISCAN II study is the third of a series of respiratory epidemiological surveys conducted in the general Spanish adult population over the course of 20 years. The three studies used a similar methodology and, in particular, they all used the European Community for Coal and Steel Questionnaire (ECSC) to investigate the prevalence of respiratory symptoms [3, 5, 22]. In a previous comparative study, SORIANO et al. [33] reported a slight reduction in the prevalence of COPD between the first two studies. In the current analysis, we observed that despite some differences in the characteristics of the populations included in the three studies, the prevalence of respiratory symptoms has remained quite stable over the course of 20 years. Only wheezing decreased slightly, while dyspnoea, cough, chronic mucus https://doi.org/10.1183/23120541.00067-2022 8 ERJ OPEN RESEARCH ORIGINAL RESEARCH ARTICLE | M. MIRAVITLLES ET AL. hypersecretion and asthma increased. The small increase in some of the respiratory symptoms may be explained at least in part by the older age of the population of EPISCAN II, which was 60.2 years compared with 56.6 years in EPISCAN [22] and 53.4 years in IBERPOC [3]. In fact, when comparisons were made between the prevalence of symptoms in the previous surveys and the corresponding age groups of EPISCAN II, the prevalence of symptoms were even more similar, with only small increases in cough and mucus hypersecretion in relation to IBERPOC and in cough and dyspnoea in relation to EPISCAN. A moderate increase in respiratory symptoms has also recently been reported in Sweden in a study that compared two different populations of individuals aged 16–75 years 8 years apart [34]. The main limitation of our study is derived from its cross-sectional design that does not allow establishing cause–effect relationships. It is very likely that increased depression and anxiety and reduced physical activity are a consequence of the presence of respiratory symptoms, but we cannot rule out the fact that anxiety and depression can make the subjects more sensitive to the sensation of shortness of breath, or that inactivity may generate deconditioning and therefore shortness of breath with activities of the daily life [35]. Other limitations derive from the definitions of symptoms used in the current study. We used the same questionnaire and same definitions as those in the previous surveys, but it has been demonstrated that some variability may exist, not only due to different diagnostic tools, but also due to language and geographical location [36, 37]. Conclusions Approximately half of the adult Spanish population has some respiratory symptoms, and the prevalence of respiratory symptoms has remained stable or slightly increased over the last 20 years. Smoking remains the main factor associated with respiratory symptoms, but chronic diseases, a high BMI, low FEV1 % pred and reduced physical activity are also significantly associated with respiratory symptoms. Female sex was strongly associated with a higher prevalence of dyspnoea. Provenance: Submitted article, peer reviewed. Acknowledgements: The collaboration of Monica Sarmiento and Neus Canal of IQVIA, and Carolina Peña and José Julio Jiménez from GSK is explicitly acknowledged. The following investigators have participated in EPISCAN II. Scientific Committee: Inmaculada Alfageme, Pilar de Lucas, Julio Ancochea, Marc Miravitlles, Juan José Soler-Cataluña, Francisco García-Río, Ciro Casanova, José Miguel Rodríguez González-Moro, Borja G. Cosio, Guadalupe Sánchez, and Joan B Soriano. Principal investigators (PIs), collaborators and participating centres: Madrid: H. La Princesa: Julio Ancochea Bermudez (PI), Elena García Castillo, Claudia Valenzuela and Joan B. Soriano. Castilla León: H.U. de Burgos: Ana Pueyo Bastida (PI), Lourdes Lázaro Asegurado, Luis Rodríguez Pascual and Maria José Mora. Aragón: H. Gral. San Jorge: Luis Borderias Clau (PI), Lourdes Arizón Mendoza and Sandra García. Extremadura: H. San Pedro de Alcántara: Juan Antonio Riesco Miranda (PI), Julián Grande Gutiérrez, Jesús Agustín Manzano and Manuel Agustín Sojo González. Castilla León: H. Clínico U. de Salamanca: Miguel Barrueco Ferrero (PI) and Milagros Rosales. Galicia: H. Álvaro Cunqueiro: José Alberto Fernández Villar (PI), Cristina Represas, Ana Priegue, Isabel Portela Ferreño, Cecilia Mouronte Roibás and Sara Fernández García. I. Baleares: H. Son Espases: Borja G. Cosío (PI), Rocío Cordova Díaz, Nuria Toledo Pons and Margalida Llabrés. Aragón: HU Miguel Servet: José María Marín Trigo (PI), Marta Forner, Begoña Gallego, Pablo Cubero and Elisabet Vera. C. Valenciana: H. Arnau de Vilanova, Valencia: Juan José Soler Cataluña (PI), Maria Begoña Picurelli Albero and Noelia González García. Andalucía: H. Virgen de la Macarena: Agustín Valido Morales (PI), Carolina Panadero, Cristina Benito Bernáldez, Laura Martín-Bejarano and Maria Velarde. Murcia: H. Gral. U. Santa Lucía, Cartagena: Antonio Santa Cruz Siminiani (PI), Carlos Castillo Quintanilla, Rocío Ibáñez Meléndez, José Javier Martínez Garcerán, Desirée Lozano Vicente, Pedro García Torres and Maria del Mar Valdivia. Navarra: Clínica Universidad de Navarra: Juan Pablo de Torres Tajes (PI), Montserrat Cizur Girones and Carmen Labiano Turrillas. La Rioja: H. de San Pedro, Logroño: Carlos Ruiz Martínez (PI), Elena Hernando, Elvira Alfaro, José Manuel García and Jorge Lázaro. País Vasco: H. Santiago Apóstol (H. Txagorritxu): David Bravo (PI), Laura Hidalgo, Silvia Francisco Terreros, Iñaki Zorrilla and Ainara Alonso Colmenero. Asturias: H. Central de Asturias: Cristina Martínez González (PI), Susana Margon, Rosirys Guzman Taveras, Ramón Fernández and Alicia Álvarez. Cantabria: H. de Valdecilla (Servicio de Neumología en el H. Santa Cruz de Liencres): José Ramón Agüero Balbín (PI) and Juan Agüero Calvo. Cataluña: HU Vall d’Hebron: Jaume Ferrer Sancho (PI), Esther Rodríguez González and Eduardo Loeb. Castilla la Mancha: HU de Guadalajara: José Luis Izquierdo Alonso (PI) and Maria Antonia Rodríguez García. I. Canarias: H.U. de Tenerife: Juan Abreu González (PI), Candelaria Martín García, Rebeca Muñoz and Haydée Martín García. Asturias: H.U. de San Agustín, Avilés: Miguel Angel Martínez Muñiz (PI), Andrés Avelino Sánchez Antuña, Jesús Allende González, Jose Antonio Gullón Blanco, Fernando José Alvarez Navascues, Manuel Angel Villanueva Montes, María Rodríguez Pericacho, Concepción Rodríguez García and Juan Diego Alvarez Mavárez. https://doi.org/10.1183/23120541.00067-2022 9 ERJ OPEN RESEARCH ORIGINAL RESEARCH ARTICLE | M. MIRAVITLLES ET AL. Availability of data and materials: Information on the GSK data sharing commitments and requesting access to anonymised individual participant data and associated documents can be found at www.clinicalstudydatarequest.com. Author contributions: The study concept and design: M. Miravitlles, J.J. Soler-Cataluña, J.B. Soriano, F. García-Río, P. de Lucas, I. Alfageme, C. Casanova, J.M.R. González-Moro, G. Sánchez, J. Ancochea and B.G. Cosío. Data acquisition: J.J. Soler-Cataluña, J. Ancochea and B.G. Cosío. Analysis and interpretation of the data: M. Miravitlles, J.J. Soler-Cataluña, J.B. Soriano and B.G. Cosío. Drafting of the manuscript: M. Miravitlles. Critical revision and approval for submission: M. Miravitlles, J.J. Soler-Cataluña, J.B. Soriano, F. García-Río, P. de Lucas, I. Alfageme, C. Casanova, J.M.R. González-Moro, G. Sánchez, J. Ancochea and B.G. Cosío. All authors have read and approved the final manuscript. Conflict of interest: M. Miravitlles has received speaker or consulting fees from AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Laboratorios Esteve, Gebro Pharma, Kamada, GlaxoSmithKline, Grifols, Menarini, Mereo Biopharma, Novartis, pH Pharma, Palobiofarma SL, Rovi, TEVA, Spin Therapeutics, Verona Pharma and Zambon, and research grants from Grifols. J.J. Soler-Cataluña has received speaker fees from AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, Esteve, Ferrer, GlaxoSmithKline, Menarini, Novartis and Teva, and consulting fees from AstraZeneca, Bial, Boehringer Ingelheim, GlaxoSmithKline, Ferrer and Novartis. F. García-Río has received speaker or consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini, Novartis, Pfizer and Rovi, and research grants from Chiesi, Esteve, Gebro Pharma, GlaxoSmithKline, Menarini and TEVA. J. Ancochea has received speaker or consulting fees from Actelion, Air Liquide, Almirall, AstraZeneca, Boehringer Ingelheim, Carburos Médica, Chiesi, Faes Farma, Ferrer, GlaxoSmithKline, InterMune, Linde Healthcare, Menarini, MSD, Mundipharma, Novartis, Pfizer, Roche, Rovi, Sandoz, Takeda and Teva. C. Casanova has received speaker or consulting fees from AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini and Novartis, and research grants from GlaxoSmithKline, Menarini and AstraZeneca. J.M.R. González-Moro has recieved research grants from GSK and Grifols, outside the submitted work; and speaker or consulting fees from AstraZeneca, Chiesi, GlaxoSmithKline, Meiji, and Orion pharma, outside the submitted work. G. Sanchez is a GlaxoSmithKline employee within the Medical Dept. B.G. 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