The most recent update of the Global Strategy for Obstructive Lung Disease (GOLD) recommends reassessing chronic obstructive pulmonary disease (COPD) patients after initial treatment based on symptoms and exacerbations1; however, there is no clear guidance as to how or how often this reassessment should be conducted. The development and validation of a control tool that easily identifies patients who may require a step up/down in treatment and a closer follow-up has been successfully achieved in the management of asthma,2 but the concept of control has been elusive in COPD.3 The main reason for this is the identification of the concept of control with normality in fact, controlled asthma is associated with normal lung function and absence of symptoms.2 While it is obvious that these objectives are not attainable in COPD, it is also true that thanks to smoking cessation, vaccinations and appropriate pharmacological and non-pharmacological treatments many COPD patients may achieve a low level of symptoms and remain stable, without exacerbations and without significant worsening in lung function over prolonged periods of time.4 This status of low level of symptoms (or low impact) and stability is what has been defined as control in COPD.5,6

A recent study demonstrated that the evaluation of control in COPD is more sensitive to clinical changes than changes in GOLD stage, in risk level or in phenotype.7 Moreover, a change in control status over 3 months is followed by significant changes in COPD assessment test (CAT) scores, thereby, making evaluation of COPD control a potential tool to reassess patients at each clinical visit.7

However, the risk of poor outcomes (i.e. exacerbations of different severity) in the short term in association with the uncontrolled status or with the change in status from controlled to uncontrolled has not been previously reported. This is critical to understand the clinical value of the evaluation of control. If uncontrolled status or change to uncontrolled status is associated with increased risk of exacerbations during the next months, this would justify investigating the cause of the lack of control and an intervention to restore the control status and prevent undesirable outcomes.

The current study is the first prospective, international, multicenter study designed with the objective to investigate the concept of control of COPD. In a previous publication we described control status as a marker of increased risk of poor outcomes during follow-up.8 Here, we describe the changes in control status in patients over long-term follow-up, the short-term risk associated with uncontrolled patient visits and the main characteristics of patients that remained either controlled or uncontrolled during the study.

According to the previously defined control criteria, more than half of the population of our study was classified as controlled at baseline; however, the control status changed frequently during the 18-month follow-up. Only 30% of patients remained controlled and 16% persistently uncontrolled throughout the observation period, while the control status changed in 54% of patients during follow-up.

Patients who remained controlled over the course of the study were more frequently men, with a normal (not increased) BMI and with a more preserved FEV1(%). Uncontrolled status had a great predictive value for adverse outcomes with 3-fold higher risk of an emergency room visit for an exacerbation, a 3.4-fold increased risk of an ambulatory exacerbation and a 4-fold increased risk of hospitalization during the next 6 months. These results suggest that lack of control is a useful warning sign that should prompt investigation of the causes and intervention in order to minimize the short-term risk of exacerbations.

Control is a term frequently used to describe a status in which the disease has a minimal impact on the health status of the patient and the prognosis is the best possible. Intuitively, when a chronic disease is uncontrolled it should require more careful evaluation and action taking to improve the symptoms and/or prognosis.17,18 This concept has been very well established in asthma2 but has been elusive in COPD for a variety of reasons, mainly because of a lack of control standard. Since COPD is defined as a chronic, progressive, and non fully reversible airflow limitation, control cannot be defined as the normalization of lung function and disappearance of symptoms and exacerbations. Instead, we need to define a tool that includes some easy to obtain clinical characteristics with meaningful thresholds adjusted for severity, that allow the identification of “uncontrolled” patients and which has prognostic value for relevant outcomes. Control in COPD was initially defined as including two dimensions: impact and stability,5 and the criteria were refined and validated in subsequent prospective studies.6,8,19,20

The criteria selected are easy to obtain at each clinical visit and basically consist in variables that patients should be questioned about, such as the level of dyspnea, sputum production and characteristics, the level of physical activity and the use of rescue medication, in addition to the history of previous moderate or severe exacerbations.21 Using the thresholds derived from previous studies,19 it has been demonstrated that control status is a good predictor of long-term outcomes,8,19,20 and that control evaluation based on clinical data is a better predictor than the definition of control based on CAT scores.19,20 Therefore, we used these clinical criteria in the current analysis.

The last revision of the GOLD strategic document separated, for the first time, the recommendations for initial treatment of COPD and changes in treatment based on a reassessment of the patients in subsequent visits.1 In this context, the control evaluation can be a useful tool to reassess the clinical status of the patients and their future risks. A previous study using the same criteria of control demonstrated that the control tool is more sensitive to changes in the clinical status of the patient than changes in phenotype, the level of risk according to the Spanish COPD guidelines,22 or the GOLD A-D classification frequently used to guide therapy.7 In addition, changes in control status were clinically relevant because they resulted in changes in health status over a period of only 3 months.7 However, the importance of the evaluation of control status at each clinical visit was not demonstrated. In this study, we observed that the control status of the patients frequently changes in subsequent clinical visits separated by 6 months, and more importantly, after an uncontrolled patient visit, the risk of having a moderate or severe exacerbation in the following 6 months is increased by 3–4-fold according to the type of episode. This increased risk justifies the use of control evaluation as a warning sign to foster more careful evaluation of the patients and the adoption of therapeutic measures according to the results of these investigations. In contrast, if the patient fulfills the criteria of control during a clinical visit, we may be quite confident that the risk of an adverse outcome during the next months is low. Therefore, the control status could be used to reduce or extend the time period between routine follow-up visits, with uncontrolled patients probably requiring more frequent appointments compared to controlled patients.

Regarding the limitations of the present study, it is important to consider that control status does not provide any specific diagnosis; a patient may be uncontrolled for a variety of reasons. The uncontrolled status is only an alert to take action but does not tell us what action to take. However, the control tool can be an excellent reminder to the clinician about the questions that COPD patients must be asked at each clinical visit and provide a simple prognostic tool. Only one quarter of the population were women, so extrapolation of the results to women must be made with caution.

The results of the current study are in agreement with those of previous studies demonstrating the predictive value of control status. The results obtained in our study highlight the significantly increased risk of moderate or severe exacerbations during the following 6 months in patients classified as uncontrolled. If these results are confirmed in other cohorts, control criteria should be incorporated into clinical practice as a simple to use tool to help reassess COPD patients at each follow-up visit.

Conceptualization: MM, VC, AK, DBP. Data curation: MM, CE, AK. Data acquisition: MM, PS, CKR, RWC, VC, JHYT, TSL, BA, CG, JLG-R, AT, MR-R. Formal analysis: MM, CE, AK. Funding acquisition: MM, DBP. Investigation: MM, PS, CKR, RWC, VC, JHYT, TSL, BA, CG, JLG-R, AT, MR-R, JJS-C, DBP. Project administration: MM, AK, DBP. Writing-original draft: MM. Writing-review and editing: PS, CKR, RWC, VC, JHYT, TSL, BA, CG, JLG-R, AT, MR-R, JJS-C, DBP.

The study was funded by an unrestricted grant from Novartis AG.

MM has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Sandoz, Zambon, CSL Behring, Grifols and Novartis, consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, Kamada, CSL Behring, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, TEVA, pH Pharma, Novartis, Sanofi and Grifols and research grants from GlaxoSmithKline and Grifols. PS has received speaker fees from Boehringer Ingelheim, AstraZeneca, Chiesi, GlaxoSmithKline, Grifols, Novartis, Roche and Teva, and consulting fees from Boehringer Ingelheim, GlaxoSmithKline, Chiesi, Grifols, Novartis and Roche.

CK Rhee received consulting/lecture fees from MSD, AstraZeneca, Novartis, GSK, Takeda, Mundipharma, Sandoz, Boehringer-Ingelheim, and Teva-Handok.

RWC has board membership with GSK, Aerogen, Novartis, and Teva Pharmaceuticals; consultancy agreements with, Aerogen, GlaxoSmithKline, Novartis, Teva Pharmaceuticals, and Vitalograph as well as grants and unrestricted funding for investigator-initiated studies from Vitalograph, Aerogen and GlaxoSmithKline.

TL has received speaker and consulting fees from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca and Novartis.

BA reports grants and personal fees from GSK, grants, personal fees and non-financial support from Novartis AG, personal fees and non-financial support from Boehringer Ingelheim and Chiesi, grants, personal fees and non-financial support from Laboratorios Menarini, personal fees from Gebro, Astra- Zeneca, Laboratorios Rovi and Laboratorios Ferrer, outside the submitted work.

JJSC has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Esteve, Ferrer, GSK, Menarini, Novartis, and Pfizer, and consulting fees from AirLiquide, Boehringer Ingelheim, Chiesi, GSK, AstraZeneca, Ferrer and Novartis.

DBP has board membership with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals, Thermofisher; consultancy agreements with Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Novartis, Pfizer, Teva Pharmaceuticals, Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Mylan, Mundipharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Teva Pharmaceuticals, Theravance, UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma, Novartis; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartism, Thermofisher; funding for patient enrolment or completion of research from Novartis; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); and is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation programme, and Health Technology Assessment.

AT has participated as a member of the local COPD advisory board for Astra Zeneca, GlaxoSmithKline, Bayer, Takeda and Novartis and has received meeting/conference travel grants from Boehringer Ingelheim, Novartis, Astra Zeneca and GlaxoSmithKline.

JGR has received speaker fees from Novartis, GSK, Boehringer-Ingelheim, AstraZeneca, Chiesi, ALK, Teva, Menarini, Rovi, Esteve and Pfizer; and consulting fees from Novartis, GSK, Astra-Zeneca, Teva, Boehringer-Ingelheim, ALK and Esteve.

MRR has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Gebro Pharma, GlaxoSmithKline, Menarini, Mundipharma, Novartis, Pfizer and Teva, and consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Novartis.