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Trends in asthma hospitalizations among adults in Spain: Analysis of hospital discharge data from 2011 to 2020

Open AccessPublished:October 11, 2022DOI:https://doi.org/10.1016/j.rmed.2022.107009

      Highlights

      • The incidence of hospitalizations for asthma exacerbations decreased from 2011 to 2019.
      • Hospitalizations for a diagnosis of asthma in any diagnostic position increased over time.
      • In-hospital mortality increased during the study period.
      • The trends analyzed in this study could help to plan use of healthcare resources.

      Abstract

      Aims

      To analyze trends in asthma hospitalizations in patients over 15 years of age in Spain. To identify possible changes in incidence, demographic characteristics, clinical conditions, and outcomes.

      Methods

      We conducted an observational retrospective epidemiological study using the Spanish National Hospital Discharge Database and included all patients hospitalized with a diagnosis of asthma from 2011 to 2020.

      Results

      A total of 1,102,923 patients were hospitalized with a code for asthma in any diagnostic position; of these, 153,749 (13.94%) had asthma coded as the primary diagnosis (asthma exacerbation). The number of patients with an asthma exacerbation decreased over time, from 15,356 in 2011 to 8804 in 2020. In-hospital mortality (IHM) remained low (around 1.5%) and stable in this subgroup of patients. When the diagnosis of asthma appeared in any diagnostic position, hospitalizations increased for all ages and sexes. In this case, a significant change was observed for IHM, which increased from 3.27% in 2011–12 to 4.36% in 2019–20 (p < 0.001). The main risk factors for IHM in both cases were age over 65 years, need for mechanical ventilation, and associated diagnoses of pneumonia, heart disease, or atrial fibrillation. In contrast, obesity was a predictor of lower mortality.

      Conclusion

      Our results suggest a decline in the incidence of hospitalizations for asthma exacerbations from 2011 to 2020. In contrast, the number of patients with asthma in any diagnostic position increased progressively, as did mortality, probably owing to an increase in comorbidities in a gradually ageing population.

      Keywords

      Abbreviations

      APC
      annual percent change
      COPD
      chronic obstructive pulmonary disease
      ICD
      International Classification of Diseases
      IHM
      in-hospital mortality
      IMV
      invasive mechanical ventilation
      LOHS
      length of hospital stay
      NIMV
      non-invasive mechanical ventilation
      OSA
      obstructive sleep apnea
      SNHDD
      Spanish National Hospital Discharge Database
      SMH
      Spanish Ministry of Health

      1. Introduction

      Asthma is a significant health problem in Spain and a recurrent cause of hospital admission and even death in all age groups. It is a heterogeneous chronic respiratory disease, characterized by chronic airway inflammation, bronchial hyperresponsiveness, and episodes of bronchial airflow obstruction [
      Global strategy for asthma management and prevention, global initiative for asthma (GINA).
      ,
      Guía Española para el manejo del asma (GEMA) Versión 5.2.
      ].
      The prevalence of asthma ranges from 1% to 18%, with wide variations between countries and regions [
      Global strategy for asthma management and prevention, global initiative for asthma (GINA).
      ]. The disease remains under-diagnosed globally, particularly in low- and middle-income countries. A large-scale study conducted in 2019 estimated that 262 million people worldwide had asthma and that the disease caused 455,000 deaths [
      • World Health Organization
      Asthma.
      ,
      • GBD 2019 Diseases and Injuries Collaborators
      Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.
      ]. In Spain, prevalence varies between regions and age groups, from 2.5% of adults of working age in Barcelona [
      • Vila-Rigat R.
      • Panadès Valls R.
      • Hernandez Huet E.
      • Sivecas Maristany J.
      • Blanché Prat X.
      • Muñoz-Ortiz L.
      • et al.
      Prevalence of work-related asthma and its impact in primary health care.
      ] to 13.4% of adolescents in rural areas of Navarra [
      • Elizalde-Beiras I.
      • Guillén-Grima F.
      • Aguinaga-Ontoso I.
      Factores asociados al asma en los niños y adolescentes de la zona rural de Navarra (España).
      ] and 6.3% in Madrid for all age groups [
      • López P.
      • Gandarilla A.M.
      • Díez L.
      • Ordobás M.
      Evolución de la prevalencia de asma y factores demográficos y de salud asociados en población de 18-64 años de la Comunidad de Madrid (1996-2013).
      ].
      In more than 90% of asthma patients, disease can be controlled with specific conventional therapeutic management, including inhaled corticosteroids combined with long-acting β2-agonists or oral corticosteroids. However, 3–4% of the asthmatic population is diagnosed with severe uncontrolled disease, which requires a complex, often multidisciplinary diagnostic and therapeutic approach [
      Global strategy for asthma management and prevention, global initiative for asthma (GINA).
      ,
      • Hekking P.-P.W.
      • Wener R.R.
      • Amelink M.
      • Zwinderman A.H.
      • Bouvy M.L.
      • Bel E.H.
      The prevalence of severe refractory asthma.
      ].
      Asthma has a high social impact owing to its effect on quality of life, work absenteeism, use of healthcare resources, and mortality. In addition, it is estimated that 70% of the healthcare costs of asthma are due to poor control of the disease [
      • Martínez-Moragón E.
      • Serra-Batllés J.
      • De Diego A.
      • Palop M.
      • Casan P.
      • Rubio-Terrés C.
      • et al.
      Economic cost of treating the patient with asthma in Spain: the AsmaCost study.
      ].
      Hospitalizations due to asthma exacerbations are a consequence of uncontrolled disease. Exacerbations generate morbidity and mortality, healthcare costs, and loss of lung function [
      Guía Española para el manejo del asma (GEMA) Versión 5.2.
      ]. External factors such as non-adherence to bronchodilator therapy or poor inhalation technique are also causes of hospital admission and poor disease control [
      • Hekking P.-P.W.
      • Wener R.R.
      • Amelink M.
      • Zwinderman A.H.
      • Bouvy M.L.
      • Bel E.H.
      The prevalence of severe refractory asthma.
      ,
      • Gamble J.
      • Stevenson M.
      • Heaney L.G.
      A study of a multi-level intervention to improve non-adherence in difficult to control asthma.
      ]. Other factors include comorbidities, aggravating factors and triggers such as smoking, exposure to allergens, indoor and outdoor air pollution, occupational agents, molds, and harmful chemicals [
      • Hekking P.-P.
      • Amelink M.
      • Wener R.R.
      • Bouvy M.L.
      • Bel E.H.
      Comorbidities in difficult-to-control asthma.
      ,
      • Cisneros Serrano C.
      • Melero Moreno C.
      • Almonacid Sánchez C.
      • Perpiñá Tordera M.
      • Picado Valles C.
      • Martínez Moragón E.
      • et al.
      Guidelines for severe uncontrolled asthma.
      ].
      Data on hospital admissions for asthma are one of the best sources of information on control of the disease in a specific region but are not available in many countries [
      • Gonzalez-Barcala F.J.
      • Aboal J.
      • Valdes L.
      • Carreira J.M.
      • Alvarez-Dobaño J.M.
      • Puga A.
      • et al.
      Trends in adult asthma hospitalization: gender-age effect.
      ]. A key source of information in this regard in Spain is the Spanish National Hospital Discharge Database (SNHDD), which provides information on multiple variables and indicators for the analysis of hospitalizations for asthma at the national level [
      • de Miguel Díez J.
      • López de Andrés A.
      • Jiménez García R.
      The minimum basic data set (MBDS), our big data for the epidemiological investigation of respiratory diseases.
      ].
      This study aimed to analyze trends in hospitalizations with asthma among patients aged ≥16 years in Spain from the year 2011–2020 and to identify possible changes in incidence, demographic characteristics, clinical conditions, and hospital outcomes such as length of hospital stay (LOHS) and in-hospital mortality (IHM). We also analyzed the time trend and the factors associated with IHM among adults admitted to Spanish hospitals with asthma. The analysis was conducted for asthma coded in the primary diagnostic position (asthma exacerbation) and with asthma coded in any other diagnostic position of the discharge report.

      2. Material and methods

      We conducted an observational retrospective epidemiological study using information collected from the SNHDD. This nationwide database is managed by the Spanish Ministry of Health (SMH) and providing data to this registry is mandatory for all private and public hospitals.
      The SNHDD includes patient variables (age, sex), date of admission and discharge, and discharge destination, with four options: home, died in hospital, transfer to other healthcare or social institution, and voluntary discharge. Clinical conditions and diagnostic and therapeutic procedures performed during the admission are coded using the International Classification of Diseases (ICD). The Ninth Revision (ICD-9) was used from implementation of the SNHDD in 1992 to the year 2015. In 2016, ICD-9 was replaced by the Tenth Revision (ICD-10) [
      • Ministerio de Sanidad
      Servicios Sociales e Igualdad
      Real Decreto 69/2015, de 6 de febrero, por el que se regula el Registro de Actividad de Atención Sanitaria Especializada (Spanish National Hospital Discharge Database).
      ,
      • Gonzalo Marco Cuenca G.
      • Salvador Olivan J.A.
      From MBDS to big data: a hospital information system for the 21st century- Scire.
      ].
      For each hospital admission, the SNHDD used 14 diagnostic codes until the year 2015 and 20 from 2016 onward.
      Throughout the study period, and according to the SNHDD methodology, for each patient, a maximum of 20 diagnostic or therapeutic procedures performed during the hospital admission can be coded using the ICD procedure codes [
      • Ministerio de Sanidad
      Servicios Sociales e Igualdad
      Real Decreto 69/2015, de 6 de febrero, por el que se regula el Registro de Actividad de Atención Sanitaria Especializada (Spanish National Hospital Discharge Database).
      ,
      • Gonzalo Marco Cuenca G.
      • Salvador Olivan J.A.
      From MBDS to big data: a hospital information system for the 21st century- Scire.
      ].

      2.1 Study population and variables

      We selected all admissions of persons aged over 15 years with an asthma code in any diagnostic position. Supplementary Table 1 shows the ICD-9 and ICD-10 codes used to define the study variables.
      The study population was analyzed using asthma in the primary diagnostic position and with asthma in any diagnostic position. According to the SNHDD methodology, the primary diagnosis is the clinical condition that is considered by the physician responsible for the discharge report to have been the main reason for the patient being admitted to hospital [
      • Ministerio de Sanidad
      Servicios Sociales e Igualdad
      Real Decreto 69/2015, de 6 de febrero, por el que se regula el Registro de Actividad de Atención Sanitaria Especializada (Spanish National Hospital Discharge Database).
      ,
      • Gonzalo Marco Cuenca G.
      • Salvador Olivan J.A.
      From MBDS to big data: a hospital information system for the 21st century- Scire.
      ]. In previous investigations, when “asthma” was coded in this position, the admission was defined as an “asthma exacerbation” [
      Guía Española para el manejo del asma (GEMA) Versión 5.2.
      ,
      • de Miguel-Díez J.
      • Jiménez-García R.
      • Hernández-Barrera V.
      • López de Andrés A.
      • Villa-Asensi J.R.
      • Plaza V.
      • et al.
      National trends in hospital admissions for asthma exacerbations among pediatric and young adult population in Spain (2002-2010).
      ,
      • Ministerio de Sanidad
      Serie histórica CMBD-RAE - Hospitales de Agudos. Manual de definiciones y glosario de términos. Año.
      ]. We also analyzed patients with a code for asthma in “any diagnostic position” to assess possible changes in the way of coding the disease in the SNHDD over time. Coding of asthma in a diagnostic position other than the primary position means that the main reason the patient was admitted to hospital was not asthma, although this condition could have affected treatment or clinical course and, therefore, hospital outcome (LOHS, IHM, costs).
      For the purposes of this study, we excluded cases in which data on age, sex, LOHS, and discharge destination were missing, with no imputation of missing data.
      Our main study variables were the incidence of hospitalizations for asthma and IHM. The incidence for each year from 2011 to 2020 was estimated by sex and for three age groups (16–44 years, 45–64 years, and 65 years or over). Yearly populations for incidence calculations were obtained from the Spanish National Statistics Institute [
      • Instituto Nacional de Estadística
      Población por edad (año a año), Españoles/Extranjeros, Sexo y Año.
      ]. The IHM is defined as the proportion of patients who died during admission for each year studied.
      Study covariates included the presence of pneumonia, influenza, COVID-19 (only for the year 2020), chronic obstructive pulmonary disease (COPD), diabetes type 1 and 2, heart failure or ischemic heart disease, obesity, atrial fibrillation, hypertension, obstructive sleep apnea (OSA), smoking, and bronchiectasis. We also described the use of invasive mechanical ventilation (IMV) and non-invasive mechanical ventilation (NIMV). If both procedures were used, the patient was included in the IMV group. The ICD codes for these conditions and procedures are defined in Supplementary Table 1.

      2.2 Statistical analysis

      The incidence rates were expressed in terms of 100,000 inhabitants. Joinpoint log linear regression was applied to identify the years in which changes in trends occurred in the rates for hospital admissions for asthma as either the primary diagnosis or in any diagnostic position. Results were reported by sex. Joinpoint regression provides the annual percent change (APC) in each of the periods delimited by the points of change and tests whether or not an apparent change in trend is statistically significant [
      • Kim H.-J.
      • Fay M.P.
      • Feuer E.J.
      • Midthune D.N.
      Permutation tests for joinpoint regression with applications to cancer rates.
      ].
      The study variables were expressed as means with standard deviations and total numbers with relative frequencies (expressed as percentages) for continuous and categorical variables, respectively. To assess the time trend from 2011 to 2020 for categorical variables, we conducted a Cochran-Mantel-Haenszel test (age group) or Cochran-Armitage test (binary variables); for LOHS, we used the Jonckheere-Terpstra test.
      Finally, we constructed a multivariable logistic regression model to identify which study variables were independently associated with IHM when asthma was coded in the primary diagnostic position and in any diagnostic position. The model was constructed according to the methods described by Hosmer et al. [
      • Hosmer D.W.
      • Lemeshow S.
      • Sturdivant R.X.
      Applied Logistic Regression.
      ].
      Joinpoint Regression Program, version 4.0.4 [
      Joinpoint Regression Program, Version 4.9.0
      Statistical Methodology and Applications Branch, Surveillance Research Program.
      ] and Stata version 14 (Stata, College Station, Texas, USA) were used for data analysis. Significance was set at p < 0.05 (two-sided).

      2.3 Ethical aspects

      The SMH evaluated the protocol of our investigation prior to providing us with the SNHDD database. All data were anonymized.
      For the previous reasons and according to the Spanish legislation, ethical approval was not necessary. Any investigator can request the SNHDD from the SMH by completing an application form [
      • Ministerio de Sanidad
      • Consumo y Bienestar Social
      Solicitud de Extracción de Datos—extraction request (Spanish national hospital discharge database).
      ].

      3. Results

      From 2011 to 2020, a total of 1,102,923 patients aged 16 years or over were hospitalized in Spain with a code for asthma in any diagnostic position. Over the 10-year period assessed, 153,749 patients (13.94%) had asthma coded as the primary diagnosis and could therefore be considered as having had an asthma exacerbation. The proportion of adults with a primary diagnosis of asthma decreased significantly from 16.40% and 17.11% in the years 2011 and 2012 to 11.53% and 7.49% in the years 2019 and 2020 (p < 0.001) (Table 1).
      Table 1Adults hospitalized with asthma in the primary diagnosis position and in any diagnosis position in Spain from 2011 to 2020 according to sex and age group.
      Diagnosis positionSexAge2011201220132014201520162017201820192020
      PrimaryMena16–44 years, n (%)1039(30.97)1105(29.21)1191(31.15)1149(28.02)1144(26.75)1042(34.93)1157(36.08)1105(32.7)1002(31.77)779(34.45)
      45–64 years, n (%)834(24.86)912(24.11)900(23.54)1081(26.37)1051(24.58)758(25.41)873(27.22)976(28.88)945(29.96)772(34.14)
      65+ years, n (%)1482(44.17)1766(46.68)1732(45.3)1870(45.61)2081(48.67)1183(39.66)1177(36.7)1298(38.41)1207(38.27)710(31.4)
      ≥16 years, n (%)3355(100)3783(100)3823(100)4100(100)4276(100)2983(100)3207(100)3379(100)3154(100)2261(100)
      Womena16–44 years, n (%)1856(15.47)1950(15.08)2068(16.04)2066(15.69)2003(13.94)1960(17.04)1983(16.52)2094(16.99)1909(16.33)1299(19.85)
      45–64 years, n (%)2628(21.9)2769(21.41)2778(21.54)2984(22.66)3008(20.94)2466(21.44)2613(21.77)2861(23.22)2680(22.92)1611(24.62)
      65+ years, n (%)7517(62.64)8214(63.51)8050(62.42)8118(61.65)9356(65.12)7077(61.52)7407(61.71)7368(59.79)7102(60.75)3633(55.52)
      ≥16 years, n (%)12001(100)12933(100)12896(100)13168(100)14367(100)11503(100)12003(100)12323(100)11691(100)6543(100)
      Both sexesa16–44 years, n (%)2895(18.85)3055(18.28)3259(19.49)3215(18.62)3147(16.88)3002(20.72)3140(20.64)3199(20.37)2911(19.61)2078(23.6)
      45–64 years, n (%)3462(22.54)3681(22.02)3678(22)4065(23.54)4059(21.77)3224(22.26)3486(22.92)3837(24.44)3625(24.42)2383(27.07)
      65+ years, n (%)8999(58.6)9980(59.7)9782(58.51)9988(57.84)11437(61.35)8260(57.02)8584(56.44)8666(55.19)8309(55.97)4343(49.33)
      ≥16 years, n (%)15356(100)16716(100)16719(100)17268(100)18643(100)14486(100)15210(100)15702(100)14845(100)8804(100)
      Any positionMena16–44 years, n (%)7969(31.41)7748(29.37)8299(28.83)8502(28.18)8516(26.65)7229(26.59)8054(25.19)8432(23.54)8833(23.57)8154(22.13)
      45–64 years, n (%)6436(25.37)6821(25.85)7376(25.62)7885(26.13)8321(26.04)7218(26.55)8608(26.93)9941(27.75)10658(28.45)11485(31.17)
      65+ years, n (%)10962(43.21)11814(44.78)13114(45.55)13788(45.69)15113(47.3)12740(46.86)15306(47.88)17451(48.71)17977(47.98)17212(46.71)
      ≥16 years, n (%)25367(100)26383(100)28789(100)30175(100)31950(100)27187(100)31968(100)35824(100)37468(100)36851(100)
      Womena16–44 years, n (%)16757(24.54)16910(23.71)18002(23.98)18507(23.28)18120(21.95)15079(21.01)16839(20.59)18197(20.51)18540(20.32)17417(21.58)
      45–64 years, n (%)13257(19.41)13713(19.23)14682(19.56)15975(20.09)15864(19.22)14119(19.68)16124(19.71)17994(20.28)18697(20.49)17393(21.55)
      65+ years, n (%)38275(56.05)40691(57.06)42379(56.46)45023(56.63)48564(58.83)42560(59.31)48826(59.7)52535(59.21)54015(59.19)45907(56.87)
      ≥16 years, n (%)68289(100)71314(100)75063(100)79505(100)82548(100)71758(100)81789(100)88726(100)91252(100)80717(100)
      Both sexesa16–44 years, n (%)24726(26.4)24658(25.24)26301(25.33)27009(24.63)26636(23.26)22308(22.55)24893(21.88)26629(21.38)27373(21.27)25571(21.75)
      45–64 years, n (%)19693(21.03)20534(21.02)22058(21.24)23860(21.75)24185(21.12)21337(21.56)24732(21.74)27935(22.43)29355(22.81)28878(24.56)
      65+ years, n (%)49237(52.57)52505(53.74)55493(53.43)58811(53.62)63677(55.61)55300(55.89)64132(56.38)69986(56.19)71992(55.93)63119(53.69)
      ≥16 years, n (%)93656(100)97697(100)103852(100)109680(100)114498(100)98945(100)113757(100)124550(100)128720(100)117568(100)
      Primary diagnosis%16.4017.1116.1015.7416.2814.6413.3712.6111.537.49
      a Significant change (p < 0.001) in the distribution by age groups from 2011 to 2020 (Cochran-Mantel-Haenszel statistic).
      b Significant change (p < 0.001) in the proportion of patients with asthma as the primary diagnosis from 2011 to 2020 (Cochran-Armitage tests for trend).

      3.1 Time trends in the incidence and characteristics of adults hospitalized with an asthma exacerbation

      Table 1 reflects the total number of adults hospitalized with an asthma exacerbation and with asthma in any diagnostic position according to age group and sex. The number of adults with an asthma exacerbation decreased from 15,356 in the year 2011 to 8804 in 2020. The highest proportion of hospitalizations for both sexes was observed in patients aged ≥65 years. However, a significant increase in the younger age groups was observed over time. From 2011 to 2020, the percentage of adults aged 16–44 years rose from 18.85% to 23.6%; that of patients aged 45–64 years increased from 22.54% to 27.07% (p < 0.001).
      Women outnumbered men throughout the study period (119,428 [77.68%] vs. 34,321 [22.32%]) for all the age groups.
      Fig. 1 shows the incidence of hospitalizations for asthma exacerbations over time according to the joinpoint analysis for both sexes (Fig. 1A), men (Fig. 1B), and women (Fig. 1C).
      Fig. 1
      Fig. 1Time trends in the incidence of hospitalizations for asthma exacerbations, according to joinpoint analysis for both sexes (A), men (B) and women (C).
      As can be seen in Fig. 1A, the incidence of hospitalizations declined, with a non-significant APC of −3.08% from 2011 to 2020. The trend for men (APC –3.39%; p > 0.05) and women (APC –3.03%; p > 0.05) is almost identical (Fig. 1B and C), showing a constant non-significant reduction over time.
      Table 2 shows the prevalence of clinical conditions, use of mechanical ventilation, LOHS, and IHM among adults hospitalized with asthma exacerbations in Spain from 2011 to 2020. Significant increases were observed for concomitant pneumonia (1.67% in 2011–12 vs. 4.49% in 2019–20; p < 0.001) and influenza (0.38% in 2011–12 vs. 2.59% in 2019–20; p < 0.001). In the year 2020, a total of 264 adults were hospitalized in Spain with a primary diagnosis of asthma and COVID-19.
      Table 2Comorbidities, use of mechanical ventilation and in-hospital outcomes among adults hospitalized with asthma exacerbations (primary diagnosis position) and in any diagnosis position in Spain from 2011 to 2020 according to sex.
      Diagnosis positionVariable2011–22013–42015–62017–182019–20p
      Primary (Asthma exacerbation)Pneumonia, n(%)535(1.67)526(1.55)734(2.22)1034(3.34)1061(4.49)<0.001
      Influenza, n(%)122(0.38)146(0.43)288(0.87)704(2.28)613(2.59)<0.001
      COVID 19, n(%)NANANANA264(1.12)<0.001
      COPD, n(%)338(1.05)377(1.11)513(1.55)823(2.66)668(2.82)<0.001
      Diabetes, n(%)6576(20.5)7196(21.17)6682(20.17)6049(19.57)4567(19.31)<0.001
      Heart disease, n(%)4865(15.17)5417(15.94)5396(16.29)5026(16.36)3889(16.44)<0.001
      Obesity, n(%)5289(16.49)6047(17.79)5878(17.74)5767(18.66)4804(20.31)<0.001
      Atrial fibrillation, n(%)4001(12.48)4329(12.74)4146(12.51)3904(12.63)2977(12.59)0.867
      Hypertension, n(%)11976(37.34)12742(37.49)12044(36.35)10595(34.27)7290(30.83)<0.001
      OSA, n(%)1123(3.5)1576(4.64)1879(5.67)2345(7.59)2064(8.73)<0.001
      Tobacco use, n(%)7333(22.86)8694(25.58)6655(20.09)4472(14.47)3713(15.7)<0.001
      Bronchiectasis, n(%)1528(4.76)1744(5.13)1750(5.28)1421(4.6)1199(5.07)<0.001
      IMV, n (%)374(1.17)367(1.08)342(1.03)381(1.23)346(1.46)<0.001
      NIMV, n (%)910(2.84)1136(3.34)840(2.54)613(1.98)581(2.46)<0.001
      LOHS, mean (SD)7.01(6.34)6.83(5.95)6.89(6.52)6.65(5.88)6.48(5.83)<0.001
      IHM, n (%)510(1.59)539(1.59)528(1.59)485(1.57)393(1.66)0.935
      Any positionPneumonia, n(%)12168(6.36)13039(6.11)14806(6.94)16974(7.12)26861(10.91)<0.001
      Influenza, n(%)601(0.31)1181(0.55)2047(0.96)4472(1.88)4406(1.79)<0.001
      COVID 19, n(%)NANANANA13428(5.45)NA
      COPD, n(%)10333(5.4)12068(5.65)13227(6.2)18229(7.65)17866(7.25)<0.001
      Diabetes35190(18.39)40084(18.77)41653(19.51)47908(20.1)50026(20.31)<0.001
      Heart disease33053(17.27)37625(17.62)37854(17.73)42650(17.89)44156(17.93)<0.001
      Obesity23389(12.22)27903(13.07)29220(13.69)34738(14.58)37802(15.35)<0.001
      Atrial fibrillation24915(13.02)27989(13.11)30518(14.3)36905(15.49)37864(15.37)<0.001
      Hypertension66922(34.97)75995(35.59)77483(36.3)83624(35.09)79108(32.12)<0.001
      OSA5460(2.85)7951(3.72)10122(4.74)14742(6.19)17811(7.23)<0.001
      Tobacco use29580(15.46)36596(17.14)30099(14.1)25399(10.66)26823(10.89)<0.001
      Bronchiectasis5305(2.77)6740(3.16)7146(3.35)8326(3.49)8120(3.3)<0.001
      IMV, n (%)2001(1.05)2115(0.99)2097(0.98)2462(1.03)3310(1.34)<0.001
      NIMV, n (%)3733(1.95)4605(2.16)3723(1.74)2896(1.22)3576(1.45)<0.001
      LOHS, mean (SD)7.10(9.12)7.09(8.06)7.07(11.48)7.09(12.76)7.11(13.71)0.068
      IHM, n (%)6266(3.27)6901(3.23)7574(3.55)8940(3.75)10743(4.36)<0.001
      COPD: Chronic Obstructive Pulmonary Disease. NA, not available. OSA; Obstructive sleep apnea: IMV: Invasive mechanical ventilation: NIMV; Non-invasive mechanical ventilation: LOHS: length of hospital stay; IHM: in-hospital mortality.
      Significant increases were found in the prevalence of COPD, heart disease, obesity, OSA, and bronchiectasis among adults admitted with an asthma exacerbation. On the other hand, significantly lower percentages were recorded for diabetes, hypertension, and smoking.
      Regarding procedures, we observed an increase in the use of IMV, and a significant reduction in the use of NIMV from 2011–12 to 2019–20.
      In our study, the mean LOHS decreased over time from 7.01 days in 2011–12 to 6.48 days in 2019–20 (p < 0.001). IHM remained low (around 1.5%), with no significant changes detected over the study period.

      3.2 Time trends in the incidence and characteristics of adults hospitalized with asthma in any diagnostic position

      From 2011 to 2020, over 1.1 million adults in Spain were hospitalized with asthma in any diagnostic position (1,102,923). The highest figure corresponds to the year 2019, with 128,720, and the lowest to the year 2011, with only 93,656 (Table 1). In contrast, for asthma in the primary diagnostic position, the number of hospitalizations increased for all age groups and both sexes. The proportion of men and women in the ≥65-year group increased over time as the youngest age group became proportionally smaller. Women accounted for 71.71% (790,961) and men for 28.29% (311,963) of the study population.
      Fig. 2 shows the trends in incidence analyzed using joinpoint regression. For the adult population (Fig. 2A), incidence increased significantly over time, with an APC of 2.69% from 2011 to 2020 (p < 0.05). Trends also increased constantly in both sexes from 2011 to 2020, with a similar pattern (Fig. 2B and C). However, the APC was higher among men (4.37%) than among women (2.37%).
      Fig. 2
      Fig. 2Time trends in the incidence of hospitalizations for asthma in any diagnosis position according to joinpoint analysis for both sexes (A), men (B) and women (C).
      Table 2 shows the prevalence of comorbid diseases, use of ventilatory support, and hospital outcomes among adults with asthma in any diagnostic position.
      The diagnosis of pneumonia appeared much more frequently when asthma was present in any diagnostic position than when only the primary position was analyzed. The prevalence of pneumonia ranged from 6.36% in 2011–12 to 10.91% in 2019–20, with a significant increase over time (p < 0.001).
      Influenza was coded more frequently in recent years, with 1.79% presenting this diagnosis in 2019–20 compared with 0.31% in 2011–12 (p < 0.001). In the year 2020, the discharge reports of 13,428 Spanish adults contained codes for asthma and COVID-19. The overall prevalence of COVID-19 in the year 2020 was 11.42%.
      The prevalence of all the clinical conditions analyzed rose significantly over the study period, except for hypertension and smoking, whose prevalence decreased significantly.
      As for patients with asthma exacerbations, the use of IMV increased slightly and the use of NIMV decreased slightly from 2011 to 2020, with both procedures being required by a small proportion of patients. The LOHS remained stable over time at around 7 days. A significant increase was observed for the IHM, from 3.27% in 2011–12 to 4.36% in 2019–20.

      3.3 Variables associated with IHM among adults hospitalized with asthma exacerbations and with asthma in any diagnostic position

      Table 3 shows the results of the multivariable logistic regression model to identify which study variables were independently associated with IHM according to the diagnostic position of asthma in the discharge report.
      Table 3Logistic regression model to identify factors associated with in hospital mortality among adults hospitalized with asthma according to the diagnosis position.
      VariablePrimary diagnosis (Asthma exacerbation)Any diagnosis position
      OR (95%CI)OR (95%CI)
      Women1.08(1.06–1.11)
      16–44 yearsReferencereference
      45–64 years2.04(1.56–2.68)4.5(4.17–4.85)
      65+ years8.99(7.09–11.4)16.31(15.21–17.49)
      Pneumonia,2.68(2.29–3.14)1.67(1.62–1.72)
      Influenza0.75(0.68–0.83)
      COPD1.18(1.14–1.23)
      Diabetes1.07(1.05–1.1)
      Heart disease2.23(2–2.48)1.59(1.54–1.63)
      Obesity0.75(0.67–0.85)0.73(0.71–0.75)
      Atrial fibrillation1.79(1.64–1.97)1.58(1.54–1.61)
      IMV13.56(11.48–16.03)10.14(9.66–10.63)
      NIMV2.89(2.47–3.4)2.56(2.43–2.69)
      2011/2012referencereference
      2013/20140.99(0.96–1.03)
      2015/20161.12(1.08–1.16)
      2017/20181.28(1.23–1.32)
      2019/20201.37(1.33–1.42)
      Asthma as primary diagnosis0.41(0.39–0.42)
      OR; Odds ratio: IC; Confidence interval: Only significant OR are shown in the table. COPD: Chronic Obstructive Pulmonary Disease. IMV: Invasive mechanical ventilation: NIMV; Non-invasive mechanical ventilation: LOHS: length of hospital stays; IHM: in-hospital mortality.
      Among patients hospitalized with an asthma exacerbation, compared with the reference age group (16–44 years), the risk of dying in hospital was 2.04-fold higher (95%CI 1.56–2.68) in those aged 45–64 years and 8.99-fold higher (95%CI 7.09–11.4) in those aged ≥65 years. The risk factors for IHM also included pneumonia, heart disease, atrial fibrillation, and the use of IMV or NIMV. However, obesity was a protective factor (OR 0.75; 95%CI 0.67–0.85). Multivariable adjustment revealed no significant change in IHM over time.
      The variables associated with higher IHM when asthma was coded in any diagnostic position included those found for asthma in the primary position and also for COPD and diabetes. However, obesity (OR 0.73; 95%CI 0.71–0.75) and influenza (OR 0.75; 95%CI 0.68–0.83) were protective factors. Furthermore, patients with asthma in the first diagnostic position had a lower IHM than those with asthma coded in a secondary position (OR 0.41; 95%CI 0.39–0.42). COVID-19 was not significantly associated with IHM in any of the multivariable models among patients with asthma.
      Finally, if asthma was coded in any diagnostic position, the probability of dying in hospital increased progressively from 2011–12 to 2019–20 (OR 1.37; 95%CI 1.33–1.42).

      4. Discussion

      Our study revealed changes in asthma hospitalizations from 2011 to 2020, namely, admissions for asthma exacerbation as the primary diagnosis decreased progressively over time. This trend has been observed in other countries, such as the USA (1994–2016), and may be due to changes in coding [
      American Lung Association
      Asthma trends and burden.
      ] or the fact that asthma is leading to fewer and fewer hospitalizations as the primary diagnosis, giving way to other, more relevant comorbidities.
      Previous studies have shown a decreasing trend in hospital admissions for asthma in most developed countries [
      • Lourido Cebreiro T.
      • Valdés Cuadrado L.
      • González-Barcala F.J.
      Hospitalizaciones por asma.
      ], with wider availability of asthma medication as a potential protective factor [
      • Gupta R.
      • Anderson H.R.
      • Strachan D.P.
      • Maier W.
      • Watson L.
      International trends in admissions and drug sales for asthma.
      ,
      • Anderson H.R.
      • Gupta R.
      • Strachan D.P.
      • Limb E.S.
      50 years of asthma: UK trends from 1955 to 2004.
      ]. Furthermore, the emergence of biological therapies for the treatment of this disease has led to major changes in the management of patients with severe asthma, ie, those with the highest number of exacerbations and hospitalizations. Since the approval of omalizumab in 2005 by the European Medicines Agency, multiple biological therapies have been developed [
      • Porsbjerg C.M.
      • Menzies-Gow A.N.
      • Tran T.N.
      • Murray R.B.
      • Unni B.
      • Audrey Ang S.L.
      • et al.
      Global variability in administrative approval prescription criteria for biologic therapy in severe asthma.
      ]. Given their key role in improving asthma control and decreasing the frequency of hospitalization, part of the decrease in hospital admissions found in this study is likely due to the use of these treatments. Our results may not be reproducible in other countries because of the high cost of biologics [
      • Hardtstock F.
      • Krieger J.
      • Wilke T.
      • Lukas M.
      • Ultsch B.
      • Welte R.
      • et al.
      Use of biologic therapies in the treatment of asthma - a comparative real world data analysis on healthcare resource utilization and costs before and after therapy initiation.
      ]. Furthermore, international and national clinical practice guidelines, which optimize asthma management and are frequently updated with available evidence, probably go a long way toward preventing hospitalizations [
      Global strategy for asthma management and prevention, global initiative for asthma (GINA).
      ,
      Guía Española para el manejo del asma (GEMA) Versión 5.2.
      ].
      The rate of hospital admissions for asthma varies significantly between geographical areas. In 2012, the highest hospitalization rates in Spain were in the north and the lowest in the south; therefore, climate and geography may affect this finding [
      • Lourido Cebreiro T.
      • Valdés Cuadrado L.
      • González-Barcala F.J.
      Hospitalizaciones por asma.
      ]. A recent large-scale study showed that meteorological factors were related to the risk of asthma exacerbation [
      • Romaszko-Wojtowicz A.
      • Cymes I.
      • Dragańska E.
      • Doboszyńska A.
      • Romaszko J.
      • Glińska-Lewczuk K.
      Relationship between biometeorological factors and the number of hospitalizations due to asthma.
      ], and outdoor environmental factors are thought to affect the asthmatic population differently according to age group [
      • Lee S.W.
      • Yon D.K.
      • James C.C.
      • Lee S.
      • Koh H.Y.
      • Sheen Y.H.
      • et al.
      Short-term effects of multiple outdoor environmental factors on risk of asthma exacerbations: age-stratified time-series analysis.
      ].
      In our study, the highest number of admissions for asthma as the primary diagnosis was recorded for patients aged ≥65 years. In other studies performed outside Spain, older patients also constituted the largest group of patients hospitalized for asthma exacerbation [
      • Bloom C.I.
      • Nissen F.
      • Douglas I.J.
      • Smeeth L.
      • Cullinan P.
      • Quint J.K.
      Exacerbation risk and characterisation of the UK's asthma population from infants to old age.
      ,
      • Baptist A.P.
      • Busse P.J.
      Asthma over the age of 65: all's well that ends well.
      ]. We also detected a significant progressive increase for patients aged 16–44 years and 45–64 years. These results could be explained by increased awareness of allergy and the atopic involvement in the asthmatic syndrome.
      Asthma is increasingly coded as a comorbidity, with the result that the number of hospitalizations of asthma patients in any diagnostic position has increased in all age groups and for both sexes. The proportion of patients aged over 65 years increased during the study period, whereas that of younger patients did not, in contrast with the findings recorded when the admission was for asthma as the primary diagnosis. This observation could indicate that the overall prevalence of asthma is rising owing to ageing of the Spanish population. However, asthma is becoming more a secondary condition for hospital admission than the main reason.
      Whether asthma was coded as a primary or secondary diagnosis, women outnumbered men, representing 77.68% of patients when asthma was the primary diagnosis and 71.71% when it was coded in any diagnostic position; this trend was observed for all years and age groups. The marked difference between the sexes has been widely studied. During childhood, the risk of hospitalization for asthma is twice as high in boys as in girls [
      • Kynyk J.A.
      • Mastronarde J.G.
      • McCallister J.W.
      Asthma, the sex difference.
      ]; in adulthood, the trend is reversed, and women are three times more likely than men to be hospitalized for an asthma-related event. This difference has been linked to the regulatory activity of sex hormones in the pathophysiology of asthma, although the mechanism has not yet been clearly established [
      • Fuseini H.
      • Newcomb D.C.
      Mechanisms driving gender differences in asthma.
      ].
      Diagnoses of pneumonia or influenza increased significantly from 2011–12 to 2019–2020. Specifically, the frequency of pneumonia peaked at 10.91% when asthma was listed in any diagnostic position in 2019–20, falling to 4.49% if asthma was the primary diagnosis. The highest incidence of influenza was recorded when asthma was the primary diagnosis, at 2.59% in 2019–2020. Although small, this percentage is consistent with those reported in studies showing the influenza virus to be a likely trigger of asthma exacerbations [
      • Wark P.A.B.
      Why are people with asthma more susceptible to influenza?.
      ].
      The prevalence of other diagnoses also increased significantly during the study period. These included COPD, heart disease, obesity, OSA, and bronchiectasis, findings that are consistent with an ageing population. Only smoking and hypertension were recorded as diagnoses in a decreasing number of patients during the study period, regardless of the diagnostic position of asthma. The decrease in smoking correlates with the decreasing number of daily smokers in recent years in the general population [
      • Instituto Nacional de Estadística
      Encuesta Europea de Salud en España (EESE). Año.
      ].
      Regarding procedures, we observed an increase in IMV and a decrease in NIMV over time. However, we found low absolute numbers for these procedures in the population studied, with them being more frequent when asthma was the primary diagnosis in all the years studied. Peak values were recorded for IMV (1.46% of admissions) in 2019–20 and for NIMV (3.34%) in 2013–14, the latter decreasing in 2019–2020 (2.46%). Multiple studies support use of NIMV in COPD exacerbations but not in asthma. The evidence of its benefit in asthma remains insufficient, although some studies support it, thus explaining the changes observed over time [
      • Althoff M.D.
      • Holguin F.
      • Yang F.
      • Grunwald G.K.
      • Moss M.
      • Vandivier R.W.
      • et al.
      Noninvasive ventilation use in critically ill patients with acute asthma exacerbations.
      ].
      LOHS remained stable, at around 7 days, with a slightly significant reduction to 6.48 days in 2019–2020, when asthma was the primary diagnosis. The broad interest of the scientific community in optimizing the management of this disease may account for the better management of exacerbations and partly explain the decrease in LOHS [
      Global strategy for asthma management and prevention, global initiative for asthma (GINA).
      ,
      Guía Española para el manejo del asma (GEMA) Versión 5.2.
      ,
      • Ramsahai J.M.
      • Hansbro P.M.
      • Wark P.A.B.
      Mechanisms and management of asthma exacerbations.
      ].
      The COVID-19 pandemic may have been the cause of the decrease in admissions for asthma exacerbation observed in 2020 compared with 2019. A decline in admissions with asthma as a secondary diagnosis was also observed, although this was more modest. COVID-19 was more frequently reported as a diagnosis during 2020 if asthma appeared as a secondary diagnosis rather than as the primary diagnosis. This observation is consistent with the suspicion that there was no increased risk of asthma exacerbations triggered by SARS-CoV-2 compared with other respiratory viruses such as influenza [
      • Adir Y.
      • Saliba W.
      • Beurnier A.
      • Humbert M.
      Asthma and COVID-19: an update.
      ]. In the year 2020, COVID-19 tended to be coded as the primary diagnosis when it did appear, with the result that a diagnosis of asthma was moved to a secondary position. Therefore, the real prevalence of asthma exacerbations that year may have been falsely reduced. As concluded in a recent meta-analysis [
      • Sunjaya A.P.
      • Allida S.M.
      • Di Tanna G.L.
      • Jenkins C.
      Asthma and risk of infection, hospitalization, ICU admission and mortality from COVID-19: systematic review and meta-analysis.
      ], we found that asthma was not related with IHM. However, further data from more years with COVID-19 will be necessary to confirm these results.
      A decline in asthma exacerbations was observed in many countries in 2020. While the reasons for this finding are not clear, it is thought that factors such as hand washing, use of masks, and social distancing may have reduced exposure to triggers, such as respiratory infections and exposure to allergens [
      • Adir Y.
      • Saliba W.
      • Beurnier A.
      • Humbert M.
      Asthma and COVID-19: an update.
      ,
      • Sunjaya A.P.
      • Allida S.M.
      • Di Tanna G.L.
      • Jenkins C.
      Asthma and risk of infection, hospitalization, ICU admission and mortality from COVID-19: systematic review and meta-analysis.
      ,
      • Abe K.
      • Miyawaki A.
      • Nakamura M.
      • Ninomiya H.
      • Kobayashi Y.
      Trends in hospitalizations for asthma during the COVID-19 outbreak in Japan.
      ,
      • Davies G.A.
      • Alsallakh M.A.
      • Sivakumaran S.
      • Vasileiou E.
      • Lyons R.A.
      • Robertson C.
      • et al.
      Impact of COVID-19 lockdown on emergency asthma admissions and deaths: national interrupted time series analyses for Scotland and Wales.
      ]. Furthermore, inhaled corticosteroids are thought to confer some degree of protection against SARS-CoV-2 infection and the development of severe disease [
      • Adir Y.
      • Saliba W.
      • Beurnier A.
      • Humbert M.
      Asthma and COVID-19: an update.
      ].
      In this study, mortality remained stable at around 1.5% when asthma was the primary diagnosis, a figure consistent with that obtained in other countries, although it is difficult to draw comparisons owing to population variability, years analyzed, coding systems, and differences in health outcomes [
      • Lourido Cebreiro T.
      • Valdés Cuadrado L.
      • González-Barcala F.J.
      Hospitalizaciones por asma.
      ,
      • Chang Y.-L.
      • Ko H.-K.
      • Lu M.-S.
      • Chou C.-L.
      • Su K.-C.
      • Hsu C.-C.
      • et al.
      Independent risk factors for death in patients admitted for asthma exacerbation in Taiwan.
      ,
      • Para O.
      • Montagnani A.
      • Guidi S.
      • Bertù L.
      • Manfellotto D.
      • Campanini M.
      • et al.
      Hospitalization and mortality for acute exacerbation of asthma: an Italian population-based study.
      ]. On the other hand, mortality increased significantly when asthma was coded in any diagnostic position, reaching 4.36% in 2019–2020, suggesting causes other than asthma itself, such as increasingly frequent comorbidities in the population and ageing.
      Risk factors for IHM in our study were as expected, with age being the most important. The population aged 65 years and older had a 16.31-fold higher risk of mortality than the reference group aged 16–44 years when asthma was coded in any diagnostic position and an 8.99-fold higher risk if it was coded as the primary diagnosis. Pneumonia, heart disease, atrial fibrillation, and the need for mechanical ventilation (mainly invasive) were the other factors favoring IHM. Influenza, in contrast to pneumonia, was a predictor of lower mortality.
      Obesity was a protective factor for IHM, with an OR of about 0.7, both for asthma as the primary diagnosis and asthma in any diagnostic position. This finding is surprising and requires further investigation, since, in obese patients, asthma is commonly severe, poorly controlled, and less responsive to therapy [
      • Bianco A.
      • Nigro E.
      • Monaco M.L.
      • Matera M.G.
      • Scudiero O.
      • Mazzarella G.
      • et al.
      The burden of obesity in asthma and COPD: role of adiponectin.
      ,
      • Dixon A.E.
      • Que L.G.
      Obesity and asthma.
      ]. However, the obesity paradox reported in other conditions, such as COPD, chronic kidney disease, and myocardial infarction, shows that mortality is lower in some diseases when patients are obese or overweight. Similarly, a diagnosis of diabetes was also a protective factor, although only when asthma was the primary diagnosis [
      • Gravina G.
      • Ferrari F.
      • Nebbiai G.
      The obesity paradox and diabetes.
      ,
      • Yano C.
      • Kawayama T.
      • Kinoshita T.
      • Tokunaga Y.
      • Sasaki J.
      • Sakazaki Y.
      • et al.
      Overweight improves long-term survival in Japanese patients with asthma.
      ].
      Our study has several strengths and limitations. The main strength is its large sample size and the consistency of the analysis methodology over the ten years reviewed. In fact, few scientific publications are based on a similar magnitude of data, both nationally and internationally. The total number of hospitals (private and public) in Spain over the study period ranged between 760 and 780. The SNHDD collects information from all these hospitals, thus covering more than 95% of all hospital discharges at the national level [
      • de Miguel Díez J.
      • López de Andrés A.
      • Jiménez García R.
      The minimum basic data set (MBDS), our big data for the epidemiological investigation of respiratory diseases.
      ,
      • Ministerio de Sanidad
      Serie histórica CMBD-RAE - Hospitales de Agudos. Manual de definiciones y glosario de términos. Año.
      ].
      Spain is a large country, with more than 47 million inhabitants. Its health system provides almost universal health coverage (greater than 99%) [
      • Bernal-Delgado E.
      • Garcia-Armesto S.
      • Oliva J.
      • Sanchez Martinez F.I.
      • Repullo J.R.
      • Pena-Longobardo L.M.
      • et al.
      Spain: health system review.
      ], thus improving the external validity of our results.
      A potential source of bias may be the change in the coding version of the ICD from ICD-9 to ICD-10 in the year 2016 [
      • Gogorcena M.A.
      • Equipo de Trabajo Rae-Cmbd-Cie10
      [The adoption of the ICD-10-ES codification rules or how to make of necessity a virtue].
      ]. Another limitation was the impossibility of obtaining more data on the patients analyzed than those completed in the discharge report and collected in the SNHDD, such as disease severity and pre-admission treatment. Furthermore, as we used ICD codes, it was not possible to differentiate between allergic asthma and other types of asthma, as the codes 493 (ICD-9) and J45 (ICD-10) include all subtypes. Future investigations based in hospital cohorts should include the type of asthma due to its importance. The lack of information on hospital readmissions is also a limiting factor caused by using an anonymous database. This parameter would be a potential indicator of the quality of healthcare provided and an objective of effectiveness and efficiency [
      • Ashton C.M.
      • Kuykendall D.H.
      • Johnson M.L.
      • Wray N.P.
      • Wu L.
      The association between the quality of inpatient care and early readmission.
      ,
      • Obaidat B.
      • Alkhatib A.
      • Garcia M.
      • Tabba M.
      Trends of asthma exacerbation readmission rates: a review of a national database.
      ].

      5. Conclusions

      In conclusion, the data obtained in this study indicate a decrease in the incidence of hospitalizations for asthma exacerbation as the primary diagnosis from 2011 to 2019, with a more marked decrease in 2020, probably secondary to the epidemiological changes caused by the COVID-19 pandemic. The patients were predominantly women. LOHS decreased slightly to 6.48 days, as did mortality, which remained constant when asthma was the primary diagnosis. In contrast, the data on patients hospitalized with a diagnosis of asthma in any diagnostic position diverge significantly. The number of these hospitalizations increased progressively during the period analyzed, as did mortality, probably owing to an increase in comorbidities in a progressively ageing population.
      The data and trends analyzed in this study could help to improve our understanding of the disease and to plan use of healthcare resources.

      Funding

      This study is a part of the research funded by: Convenio V-PRICIT de la Comunidad de Madrid y la Universidad Complutense de Madrid (“ Programa de Excelencia para el Profesorado Universitario ” INV.AY.20.2021.1E126 ). And by: Universidad Complutense de Madrid . Grupo de Investigación en Epidemiología de las Enfermedades Crónicas de Alta Prevalencia en España ( 970970 ).

      CRediT authorship contribution statement

      Francisco J. Caballero-Segura: Conceptualization, Validation, Writing – original draft, Writing – review & editing. Ana Lopez-de-Andres: Conceptualization, Validation, Writing – original draft, Writing – review & editing. Rodrigo Jimenez-Garcia: Data curation, Writing – original draft, Writing – review & editing. Jose M. de Miguel-Yanes: Writing – original draft, Writing – review & editing. Valentin Hernández-Barrera: Data curation, Writing – review & editing. David Carabantes-Alarcon: Validation, Writing – review & editing. Jose J. Zamorano-Leon: Software, Writing – review & editing. Javier de Miguel-Díez: Conceptualization, Validation, Writing – original draft, Writing – review & editing.

      Declaration of competing interest

      All authors declare that they have none Conflict of Interest.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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