Comorbidome, Pattern, and Impact of Asthma-COPD Overlap Syndrome in Real Life

Comorbidome, Pattern, and Impact of Asthma-COPD Overlap Syndrome in Real Life Job F. M. van Boven, PharmD, PhD; Miguel Román-Rodríguez, MD; Josep F. Palmer, MD; Núria Toledo-Pons, MD; Borja G. Cosío, MD, PhD; and Joan B. Soriano, MD, PhD CHEST 26; 149(4):11-1020 26 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.16/j.chest.25.12.002

e-appendix 1. 1. Institituto de Investigacíón Sanitaria de Palma (IdISPa), Hospital Universitario Son Espases, Carretera de Valldemossa 79, 07102 Palma de Mallorca, Spain 2. Unit of PharmacoEpidemiology & PharmacoEconomics, Department of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands 3. Department of Primary Care, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands 4. Primary Care Health Service, Servei de Salut de les Illes Balears. c/ Reina Esclaramunda 9, 07003 Palma de Mallorca, Spain 5. Department of Respiratory Medicine, Hospital Universitario Son Espases, Carretera de Valldemossa 79, 07102 Palma de Mallorca, Spain 6. Ciber de enfermedades respiratorias (Ciberes), Instituto de Salud Carlos III, Calle Sinesio Delgado s/n, 285 Madrid, Spain 7. Instituto de Investigación Hospital Universitario de la Princesa (IISP), Universidad Autónoma de Madrid, Cátedra UAM-Linde, Calle de Diego Leon, 62, 28030 Madrid, Spain

e-figure 1: Flow diagram showing patient selection for main analysis (physician diagnosis) and subanalyses (stringent diagnostic criteria). Footnote: Of all patients in the MAJORICA-database (68,578), 6,411 patients had a physician-confirmed COPD diagnosis and FEV1/FVC<0.7 documented. 87 were younger than 40 and were excluded, leaving 6,324. Of those, 6,113 had a documented smoking status of which 1,244 were never smokers and therefore excluded, leaving 4,869. Of those, 3,667 (75.3%) were using respiratory medication in 22. The final sub-population comprised 709 ACOS patients (19.3%) and 2,958 COPD-only patients (80.7%) of whom characteristics are presented in e-table 1.

100% 90% 80% COPD and ACOS (%) 70% 60% 50% 40% 30% 20% 10% 0% 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ COPD female COPD male ACOS female ACOS male Age group e-figure 2: Relative ACOS prevalence (%) compared with total physician-diagnosed COPD population, by age and gender

CKD: chronic kidney disease; GERD: gastroesophageal reflux disease; HIV: human immunodeficiency virus; OR: odds ratio e-figure 3: Relationship between occurrence of comorbidities in ACOS (%) and their relative rate in ACOS versus COPD-only (coloured text indicates significant positive [red] or negative [blue] difference) using stringent diagnostic criteria.

e-table 1: Comorbidities in ACOS patients (N=5,093) and hospitalization risk: 2-year-logistic regression analysis (main analysis using physician diagnoses) 2-year all-cause hospitalization risk (23-24) Comorbidity Prevalence OR 95%CI p (%) Hypertension 49.0 1.07 0.93-1.25 0.32 Anxiety 37.7 1.13 0.98-1.30 0.10 Diabetes 21.8 1.41* 1.20-1.65 <0.0 Osteoporosis 18.8 1.18 0.99-1.41 0.06 Allergic rhinitis 15.5 0.73* 0.60-0.88 0.0 Atrial fibrillation 14.3 1.47* 1.21-1.79 <0.0 Heart failure 11.2 2.10* 1.68-2.61 <0.0 Ischemic heart 1.44* 1.17-1.78 0.0 disease 10.5 GERD 9.3 1.31* 1.05-1.63 0.02 Cerebrovascular 1.36* 1.06-1.75 0.02 disease 7.2 Sleep apnoea 7.2 1.27 0.99-1.64 0.06 Chronic kidney 1.07 0.60-1.52 0.71 disease 3.5 Depression 2.6 1.32 0.88-1.99 0.18 Cor pulmonale 1.2 2.30* 1.25-4.24 0.008 Lung cancer 0.6 2.11 0.92-4.86 0.08 HIV 0.2 2.33 0.57-9.61 0.24 *significantly (p<0.05) associated with hospitalization; GERD: gastroesophageal reflux disease; HIV: human immunodeficiency virus; OR: odds ratio; 95%CI: 95% confidence interval Footnote: In 24, a total of 1,993 all-cause hospitalizations occurred in 1,135 unique patients (22.3% with at least one hospitalization). Of those, 799 (40.1%) had a respiratory cause. The average length of stay was 8.2 days (SD: 7.8). Most cardiovascular diseases (except hypertension) and GERD were significantly positively associated with hospitalization risk. Allergic rhinitis was negatively associated. Notably, lung cancer was not significantly associated with hospitalization anymore. In addition, current smoking status (OR: 1 52, 95%CI: 1 26-1 83) and hospitalization in 22 (OR: 2 87, 95%CI: 2 45-3 36) were significantly associated with all-cause hospitalization in 23-24.

e-table 2: Comorbidities in ACOS patients (N=709) and hospitalization risk: logistic regression analysis (sub-analysis using stringent diagnostic criteria) 1-year hospitalization risk (23) 2-year hospitalization risk (23-24) Comorbidity Prevalence OR 95%CI p OR 95%CI p (%) Hypertension 47.1 1.09 0.72-1.64 0.68 1.08 0.75-1.54 0.69 Anxiety 34.8 1.18 0.78-1.79 0.44 1.50* 1.04-2.15 0.03 Diabetes 22.7 1.46 0.92-2.31 0.11 1.23 0.81-1.88 0.33 Allergic rhinitis 13.7 0.67 0.37-1.23 0.20 0.88 0.54-1.45 0.62 Osteoporosis 13.0 1.96* 1.16-3.33 0. 1.52 0.92-2.52 0.10 Atrial fibrillation 2.48* 1.45-4.24 0.00 2.04* 1.20-3.45 0.00 12.6 1 8 Ischemic heart 0.98 0.54-1.79 0.95 1.21 0.70-2.11 0.49 disease 10.6 GERD 8.3 1.65 0.87-3.11 0.12 1.77 0.99-3.16 0.05 Heart failure 2.55* 1.33-4.90 0.00 2.65* 1.34-5.23 0.00 8.0 5 5 Sleep apnoea 7.2 1.07 0.51-2.25 0.85 1.11 0.57-2.14 0.76 Cerebrovascular 1.17 0.57-2.40 0.66 1.03 0.51-2.06 0.94 disease 6.5 Chronic kidney 1.63 0.59-4.49 0.35 0.98 0.37-2.64 0.97 disease 3.0 Lung cancer 2.3 1.90 0.61-5.92 0.27 1.18 0.39-3.53 0.77 Depression 1.1 3.42 0.74-15.88 0.12 5.23 0.95-28.84 0.05 Cor pulmonale 0.8 2.44 0.42-14.13 0.32 1.16 0.18-7.32 0.87 HIV 0.1 NA NA NA NA NA NA *significantly (p<0.05) associated with hospitalization; GERD: gastroesophageal reflux disease; HIV: human immunodeficiency virus; OR: odds ratio; 95%CI: 95% confidence interval Footnote: In the sub-analysis with stringent diagnostic criteria (N=709), 171 ACOS patients had at least one allcause hospitalization in 23 (24.1%). In 24, there occurred 329 hospitalizations in 182 unique patients (25.7%). Comorbidities significantly associated with 1-year hospitalization were atrial fibrillation, heart failure and osteoporosis. Again, hospitalization in 22 was strongly associated (OR: 2 85; 95%CI: 1 88-4 33) with hospitalization in 23. Smoking status, age and gender were not significantly associated with hospitalization. For the 2-year hospitalization risk, similar patterns were found, except that osteoporosis lost its significance and here also current smoking (OR: 1 50; 95%CI: 1 03-2 17) was associated with hospitalization.

e-figure 4: Comorbidomes of ACOS (left) and COPD-only (right) patients (sub-analysis using stringent diagnostic criteria). Diameter of the coloured circles represents the prevalence of each comorbidity. Proximity to the black centre of the circle represents stronger positive association with 1-year all-cause hospitalization. Comorbidities (bold) within the inner circle are significantly associated with increased risk. Comorbidities within the outer circle are non-significantly associated with risk. Comorbidities outside the outer circle are negatively associated with hospitalization.

e-table 3: Comorbidities in COPD-only patients (N=22,778) and hospitalization risk: logistic regression analysis (main analysis using physician diagnoses) 1-year hospitalization risk (23) 2-year hospitalization risk (23-24) Comorbidity Prevalence OR 95%CI p OR 95%CI p (%) Hypertension 49.9 1.03 0.95-1.11 0.51 1.07 0.99-1.14 0.06 Anxiety 1.30* 1.17-1.38 <0.0 1.20* 1.12-1.29 <0.0 28.9 Diabetes 1.30* 1.20-1.41 <0.0 1.32* 1.22-1.42 <0.0 24.2 Atrial fibrillation 1.51* 1.37-1.67 <0.0 1.63* 1.49-1.78 <0.0 14.7 Ischemic heart 1.29* 1.17-1.43 <0.0 1.38* 1.26-1.51 <0.0 disease 13.8 Osteoporosis 12.0 1.08 0.96-1.21 0.23 1.09 0.99-1.21 0.09 Heart failure 1.73* 1.55-1.93 <0.0 2.10* 1.89-2.33 <0.0 10.8 Cerebrovascular 1.38* 1.23-1.56 <0.0 1.44* 1.29-1.61 <0.0 disease 8.1 Sleep apnoea 1.30* 1.15-1.48 <0.0 1.41* 1.26-1.59 <0.0 7.6 Allergic rhinitis 7.4 0.93 0.81-1.08 0.35 0.91 0.80-1.03 0.12 GERD 6.9 1.09 0.95-1.26 0.23 1.13 1.00-1.28 0.05 Chronic kidney 1.26* 1.08-1.46 0.003 1.27* 1.10-1.47 0.0 disease 4.6 Depression 1.43* 1.14-1.80 0.002 1.67* 1.37-2.05 <0.0 2.2 Lung cancer 1.84* 1.37-2.48 <0.0 3.23* 2.42-4.29 <0.0 1.1 Cor pulmonale 2.05* 1.50-2.81 <0.0 2.48* 1.79-3.42 <0.0 1.0 HIV 0.3 2.03* 1.04-3.96 0.04 1.51 0.81-2.82 0.19 *significantly (p<0.05) associated with hospitalization; GERD: gastroesophageal reflux disease; HIV: human immunodeficiency virus; OR: odds ratio; 95%CI: 95% confidence interval Footnote: In this analysis on physician-diagnosed COPD-only patients (N=22,778), 4,373 COPD-only patients had at least one all-cause hospitalization in 23 (19.2%), summing up to a total of 7,164 all-cause hospitalizations. Of those, 2,302 (32.1%) had a respiratory cause. The average length of stay was 7.9 days (SD: 13.2). In 24, there occurred 8,657 hospitalizations in 4,891 unique patients (21.5%). Comorbidities significantly associated with 1-year hospitalization were mainly in the cardiovascular spectrum. Hospitalization in 22 was strongly associated (OR: 2 80; 95%CI: 2 57-3 05) with hospitalization in 23.In addition to comorbidities, higher age (P<0.0), male gender (P=0.004), patient being current or ex-smoker (P<0.0) and previous hospitalization (P<0.0) were associated with all-cause hospitalization. For the 2-year hospitalization risk, similar patterns were found, except that HIV lost its significance.

e-table 4: Comorbidities in COPD-only patients (N=2,958) and hospitalization risk: logistic regression analysis (sub-analysis using stringent diagnostic criteria) 1-year hospitalization risk (23) 2-year hospitalization risk (23-24) Comorbidity Prevalence OR 95%CI p OR 95%CI p (%) Hypertension 55.8 0.97 0.80-1.18 0.77 0.99 0.84-1.18 0.99 Diabetes 27.7 1.26* 1.03-1.53 0.03 1.30* 1.08-1.56 0.005 Anxiety 24.9 1.23 0.99-1.52 0.05 1.22* 1.-1.47 0.04 Atrial fibrillation 16.3 1.41* 1.11-1.78 0.004 1.47* 1.18-1.84 0.0 Ischemic heart 1.34* 1.06-1.70 0.02 1.72* 1.37-2.15 <0.0 disease 15.0 Heart failure 11.7 1.65* 1.27-2.14 <0.0 1.87* 1.44-2.43 <0.0 Osteoporosis 10.4 1.15 0.85-1.54 0.36 1.05 0.81-1.38 0.70 Sleep apnoea 9.5 1.36* 1.-1.81 0.04 1.58* 1.20-2.07 0.0 Cerebrovascular 1.66* 1.25-2.21 0.0 1.66* 1.26-2.19 <0.0 disease 8.9 Allergic rhinitis 6.9 0.97 0.67-1.39 0.85 0.88 0.64-1.21 0.42 GERD 6.8 0.99 0.69-1.40 0.94 1.39* 1.02-1.90 0.04 Chronic kidney 0.93 0.63-1.36 0.70 1.19 0.83-1.72 0.35 disease 5.1 Depression 2.1 1. 0.55-1.86 0.98 1.33 0.77-2.29 0.31 Lung cancer 1.6 1.43 0.74-2.78 0.29 2.32* 1.24-4.35 0.008 Cor pulmonale 1.3 1.94 0.96-3.91 0.07 2.55* 1.23-5.28 0. HIV 0.1 2.35 0.20-27.16 0.50 4.35 0.38-50.20 0.24 *significantly (p<0.05) associated with hospitalization; GERD: gastroesophageal reflux disease; HIV: human immunodeficiency virus; OR: odds ratio; 95%CI: 95% confidence interval Footnote: In this sub-analysis with stringent diagnostic criteria for COPD (N=2,958), 705 COPD-only patients had at least one all-cause hospitalization in 23 (23.8%), summing up to a total of 1,249 all-cause hospitalizations. Of those, 513 (41.1%) had a respiratory cause. The average length of stay was 9.1 days (SD: 18.2). In 24, there occurred 1,591 hospitalizations in 819 unique patients (27.7%). Comorbidities significantly associated with 1-year hospitalization were most cardiovascular diseases, diabetes and sleep apnea. Hospitalization in 22 was strongly associated (OR: 2 96; 95%CI: 2 44-3 58) with hospitalization in 23. Gender and smoking status were not significantly associated with hospitalization, while age was (P=0.0). For the 2-year hospitalization risk, similar patterns were found, except that lung cancer, anxiety and GERD were also significantly associated with hospitalization.

STROBE Statement checklist of items that should be included in reports of observational studies Item No Recommendation Title and abstract 1 (a) Indicate the study s design with a commonly used term in the title or the abstract: In abstract (Methods) (b) Provide in the abstract an informative and balanced summary of what was done and what was found: In abstract (Methods and Results) Introduction Background/ rationale 2 Explain the scientific background and rationale for the investigation being reported: Introduction Objectives 3 State specific objectives, including any prespecified hypotheses: Introduction (last sentence) Methods Study design 4 Present key elements of study design early in the paper: Methods (study design) Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection: Methods (Setting, Data source and Population) Participants 6 (a) Cohort study Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up. Methods (Data source and population, including Flow diagram in appendix) (b) Cohort study For matched studies, give matching criteria and number of exposed and unexposed: Not a matched study Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable: see Methods (Outcomes and statistics) Data sources/ measurement 8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group: see Methods (Outcomes and statistics) Bias 9 Describe any efforts to address potential sources of bias: Methods: No selection bias present as complete population, diagnostic bias addressed by sub-analysis Study size 10 Explain how the study size was arrived at: see Methods (Study size) Quantitative variables Statistical methods Continued on next page 11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why: see Methods (Variables) 12 (a) Describe all statistical methods, including those used to control for confounding: see Methods (Outcomes and statistics) (b) Describe any methods used to examine subgroups and interactions: see Methods (Outcomes and statistics) (c) Explain how missing data were addressed: No missing data, only in sub-analysis, see flow diagram in appendix (d) Cohort study If applicable, explain how loss to follow-up was addressed. Not applicable as MAJORICA cohort included 2 years follow up for all patients. (e) Describe any sensitivity analyses: see Methods (Population and Outcomes)

Results Participants 13* (a) Report numbers of individuals at each stage of study eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed: see flow diagram in Appendix (b) Give reasons for non-participation at each stage: Not applicable (c) Consider use of a flow diagram: see Appendix Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders: Results (Table 1) (b) Indicate number of participants with missing data for each variable of interest Results (Table 1) (c) Cohort study Summarise follow-up time (eg, average and total amount) 2 years maximum Outcome data 15* Cohort study Report numbers of outcome events or summary measures over time: See Figure 1 & 2 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included: Results (Patterns of comorbidities and table 2) (b) Report category boundaries when continuous variables were categorized: Not applicable (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period: Not applicable Other analyses 17 Report other analyses done eg analyses of subgroups and interactions, and sensitivity analyses: Sub-analyses in Appendix Discussion Key results 18 Summarise key results with reference to study objectives: Discussion (first section) Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias: Discussion (mid section) Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence Discussion (mid section) Generalisability 21 Discuss the generalisability (external validity) of the study results Discussion (mid section) Other information Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based. Following conclusions *Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies. Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org 152317