ORIGINAL ARTICLE The importance of symptoms in the longitudinal variability of clusters in COPD patients: A validation study JUAN P. de TORRES, 1 JOSE M. MARIN, 2,3 CRISTINA MARTINEZ-GONZALEZ, 4 PILAR de LUCAS-RAMOS, 5 BORJA COSIO, 3,6 CIRO CASANOVA 7 for the COPD History Assessment In SpaiN (CHAIN) cohort * 1 Pulmonary Department, University Clinic of Navarra, Pamplona; 2 Pulmonary Department, University Hospital Miguel Servet, Zaragoza; 3 CIBER of Respiratory Diseases (CIBERES), Health Institute Carlos III, Madrid; 4 Pulmonary Department, Central Hospital of Asturias, Oviedo; 5 Pulmonary Department I, Gregorio Marañon Hospital, Madrid; 6 Pulmonary Department, Son Espases Hospital, Palma de Mallorca; 7 Pulmonary Department, Ntra Sra de Candelaria Hospital, Tenerife, Spain ABSTRACT Background and objective: Cluster analysis has been utilized to explore phenotypic heterogeneity in chronic obstructive pulmonary disease (COPD). To date, little is known about the longitudinal variability of clusters in COPD patients. We aimed to evaluate the 2-year cluster variability in stable COPD patients. Methods: We evaluated the following variables in COPD patients at baseline and 2 years later: age, gender, pack- year history, body mass index (BMI), modified Medical Research Council (MMRC) scale, 6-min walking dis- tance (6MWD), spirometry and COPD Assessment Test (CAT). Patient classification was performed using clus- ter analysis at baseline and 2 years later. Each patient’s cluster variability after 2 years and its parameters asso- ciated with cluster change were explored. Results: A total of 521 smokers with COPD were evalu- ated at baseline and 2 years later. Three different clus- ters were consistently identified at both evaluation times: cluster A (of younger age, mild airway limitation, few symptoms), cluster B (intermediate) and cluster C (of older age, severe airway limitation and highly symp- tomatic). Two years later, 70% of patients were unchanged, whereas 30% changed from one cluster to another: 20% from A to B; 15% from B to A; 15% from B to C; 42% from C to B and 8% from C to A. 6MWD, forced expiratory volume in 1 s (FEV 1 ) % and CAT were the principal parameters responsible for this change. Conclusion: After 2 years of follow-up, most of the COPD patients maintained their cluster assignment. Exercise tolerance, lung function and quality of life were the main driving parameters in those who change their cluster assignment. Clinical trial registration: NCT01122758 at ClinicalTrials.gov Key words: chronic obstructive pulmonary disease, clinical factor clusters, longitudinal changes. Abbreviations: ACOS, asthma–COPD overlap syndrome; ATS, American Thoracic Society; CAT, COPD Assessment Test; CHAIN, COPD History Assessment In SpaiN; GOLD, Global Initiative for Chronic Obstructive Lung Disease; FEV 1 , forced expiratory volume in 1 s; HTA, hypertension; MMRC, modified Medical Research Council; OSA, obstructive sleep apnoea. INTRODUCTION Chronic obstructive pulmonary disease (COPD) is an important health problem and is ranked as the third disease burden worldwide since 2010. 1 COPD is char- acterized by a persistent airflow limitation that is usually progressive and is associated with an enhanced chronic inflammatory response in the air- ways and lungs to noxious particles or gases, primar- ily cigarette smoke. 2 COPD is a complex disease with a heterogeneous clinical presentation. 3 Several efforts have been conducted to classify COPD patients into subgroups or clinical phenotypes to allow their easy identification regarding prognostic and therapeutic purposes. 4–9 Cluster analysis, whose aim is to organize informa- tion so that heterogeneous groups of variables can be classified into relatively homogeneous groups, 10 has been proposed for the examination of clinical pheno- typic heterogeneity in COPD patients. Several studies have investigated different databases, identifying Correspondence: Juan P. de-Torres, Pulmonary Department, Clínica Universidad de Navarra, Av Pio XII, 36, Pamplona 31200, Spain. Email: jupa65@hotmail.com *Members of the COPD History Assessment In SpaiN (CHAIN) cohort are listed in Appendix S1 (Supplementary Information). Received 3 May 2017; invited to revise 30 June and 17 August 2017; revised 6 July and 28 August 2017; accepted 7 September 2017 (Associate Editor: Robert Young; Senior Editor: Paul KIng). SUMMARY AT A GLANCE This longitudinal analysis of a large chronic obstruc- tive pulmonary disease (COPD) study explored the identification of clusters and their behaviour over 2 years. We validated previous data on the topic but in a multicentre study and with 2 years of follow-up (previously only 1 year). We also identified factors associated with cluster changes. © 2017 Asian Pacific Society of Respirology Respirology (2018) 23, 485–491 doi: 10.1111/resp.13194