Longitudinal comparison of outcomes in patients with smoking-related asthma-COPD overlap and in non-smoking asthmatics with incomplete reversibility of airway obstruction

Introduction

Asthma may be associated with an incomplete reversibility of airway obstruction (IRAO). When patients demonstrate features of both asthma and COPD, they are often considered to have asthma-COPD overlap (ACO).^1,2 We previously showed that patients with ACO, defined as asthmatic patients with an IRAO and a significant smoking history, had a different phenotype compared to non-smoking asthmatic patients with IRAO.³

The clinical course of patients with smoking-related ACO remains, however, to be compared to that of non-smokers with IRAO (NS-IRAO), and these observations may have important implications for the clinical management of these patients. The present analysis is a 12-month longitudinal follow-up of patients with ACO or NS-IRAO who were the subject of an extensive cross-sectional phenotypic characterization.³ The present investigation was intended to specifically focus on the clinical outcomes of these two groups of asthmatics with emphasis on the frequency of exacerbations and symptom control.

Materials and methods

Subjects

Two groups of asthmatic subjects with an IRAO were recruited from the asthma outpatient clinic of the Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval (IUCPQ-UL), a tertiary care center in Quebec city: 1) one composed of current smokers or ex-smokers (≥20 pack-years history of cigarette smoking), ACO and 2) one involving never-smokers or ex-smokers with a non-significant smoking history of less than five pack-years who had quitted smoking more than 12 months before study inclusion, NS-IRAO. Inclusion criteria and baseline evaluation have been reported previously.³ Briefly, we included patients aged 40 years and over, with a previous diagnosis of asthma based on the Canadian Thoracic Society criteria,⁴ who required inhaled corticosteroids with or without additional asthma medication, and who showed IRAO, as defined by persistence of a post-bronchodilator FEV₁/FVC ratio <0.7 in addition to a FEV₁ less than 80% of predicted value on at least two occasions while on a treatment considered as optimal by a respirologist.⁴ Patients with any other respiratory conditions than asthma (including previous diagnosis of COPD without a confirmed diagnosis of asthma), an unstable respiratory or non-respiratory condition, previous bronchial thermoplasty, who experienced a respiratory infection in the 4 weeks preceding study entry, or who changed respiratory medication in the 4 weeks before baseline visit were excluded. This study was conducted in accordance with the Declaration of Helsinki. All subjects signed an informed consent form and the study was approved by the Ethics committee of the IUCPQ-UL (CER21047).

Study design

This was a 12-month longitudinal study. Following baseline assessment, telephone calls were made by the study coordinators (JM and JL) at 3-month intervals to gather information related to exacerbations and asthma control. The study was registered on Clinical Trials (NCT03817333).

Outcomes

Patients were asked about events related to asthma exacerbations including: 1) unscheduled medical visits, 2) emergency department visits (<24 hours in the emergency room), 3) hospitalizations (>24 hours in the emergency room or formal hospitalization), 4) increase in maintenance dose of inhaled corticosteroids (ICSs) for at least 3 consecutive days, 5) oral corticosteroids use, including new therapy or increased maintenance dose for at least 2 consecutive days as a consequence of exacerbation,⁵ and 6) antibiotic treatments for bronchitis or pneumonia. In addition, study coordinators administered the validated French version of the asthma control questionnaire-6 (ACQ-6 [0–6], a lower score indicating better asthma control and scores >1.5 suggesting uncontrolled asthma)^6,7 and the clinical subsection of the asthma control scoring system (ACSS [20–100], a higher score indicating better asthma control).^8,9 Lastly, patients answered questions about changes in maintenance medication, allergen exposure, and smoking habit at each phone call.

Statistical analyses

Results are presented as mean ± SD. The outcomes were analyzed using a generalized linear mixed model. Statistical thresholds were set at P-values<0.05 for number of exacerbations (primary end point) and P<0.01 for control scores (secondary end points). All analyses were conducted using the statistical package SAS, version 9.4 (SAS Institute Inc, Cary, NC, USA) and R (R Core Team [2016], Foundation for Statistical Computing, Vienna, Austria).

Results

From the initial cohort of 75 patients with ACO and 40 patients with NS-IRAO who were the subject of the cross-sectional study,³ 71 patients with ACO and all patients with NS-IRAO completed this 12-month follow-up study. The main characteristics are available in Table S1 of the online supplement while detailed phenotypic assessment of these patients have been published elsewhere.³

Very few exacerbation events were reported in this population over the 12-month follow-up. No significant differences in the number of asthma exacerbations per patient at 12 months were observed between ACO and NS-IRAO: 1) total events per year: 2.0 vs 2.3, respectively, 2) number of unscheduled medical visits per year: 0.33 vs 0.30, respectively, 3) number of emergency department visits per year: 0.11 vs 0.25, respectively, 4) number of hospitalizations per year: 0.06 vs 0, respectively, 5) number of increases in maintenance dose of ICS for at least 3 consecutive days per year: 0.92 vs 1.2, respectively, 6) number of oral corticosteroid uses per year: 0.42 vs 0.38, respectively, and 7) number of antibiotic treatments for bronchitis or pneumonia per year: 0.15 vs 0.18, respectively.

Consistent with better asthma control in patients with NS-IRAO, there was strong tendency for ACQ-6 scores to be lower in the NS-IRAO as compared to the ACO group (P=0.016), while ACSS clinical scores were significantly higher (P=0.004) in the NS-IRAO as compared to the ACO group (Figure 1) throughout the study. However, the time course of symptom scores followed a similar pattern in both groups of asthmatics. No significant change in life habits or environment was reported in either group.

Figure 1 Comparison of symptom control at baseline and over the follow-up period of 12 months between ACO and NS-IRAO. Notes: (A) ACQ-6 scores were higher in ACO as compared to NS-IRAO at baseline and throughout the follow-up period (P=0.016) with no significant variations between time points. (B) ACSS clinical scores were significantly lower in ACO as compared to NS-IRAO at baseline and throughout the follow-up period (P=0.004) with no significant variations between time points. Abbreviations: ACO, asthma-COPD overlap; NS-IRAO, non-smokers with incomplete reversibility of airway obstruction; ACQ-6, asthma control questionnaire-6; ACSS, asthma control scoring system.

Discussion

In this study, patients with ACO and NS-IRAO experienced a similar low number of exacerbation events over 12 months. Despite this, symptom control was poorer in ACO as compared to NS-IRAO throughout the 12-month follow-up, although the time course of asthma control showed a similar pattern between the two groups.

Our results are at variance with several studies reporting a higher frequency of exacerbations^10–12 and increased health care use^13–16 in patients with ACO compared to those with asthma or patients with COPD, although this is not a universal finding.^17–19 Several factors may explain the low exacerbation event rates in the present cohort of patients with ACO. First, patients with ACO who were involved in this study were former smokers, while current but not past smoking has been associated with a greater risk of hospitalization and hospital-based care for asthma,²⁰ more unscheduled health care visits,²¹ and more rescue courses of oral steroids as compared to ex-smokers.²¹ Second, as our patients were followed in a tertiary care practice, they may have benefited from optimal management, with better access to asthma/COPD education and optimal therapy. Indeed, although this was not part of the study, all study patients were seen and followed by a qualified asthma educator to assess inhalator technique and review self-management strategies, including asthma control, smoking cessation, use of an action plan, and environmental control which may also have contributed to lowering the exacerbation event rates in the present study. Hence, clinicians should insist not only on optimal pharmacotherapy but also on the accessibility to self-management strategies for their patients.

Our findings suggest that there could be a dissociation between asthma control scores which indicated better asthma control in patients with NS-IRAO and the exacerbation rates which was similar between the two groups. The clinical implication of this observation is that the exacerbation rates should not be used as a surrogate for asthma control. Also, lower asthma control in ACO than in NS-IRAO was likely driven by worse symptoms that were unrelated to exacerbations. This indicates the importance of focusing on improving symptoms such as dyspnea and functional limitation and not solely on reducing exacerbation rates when treating patients with IRAO. From a mechanistic point of view, the lower asthma control scores in patients with ACO were possibly related to the persistence of smoking-induced chronic changes in the airways (as in COPD), contributing to symptom generation. For example, glandular hyperplasia, increased/different airway remodeling, or factors associated with lung air trapping (loss of elastic recoil) could all be worse in ACO compared to NS-IRAO group, although this needs to be further studied.

Conclusion

Our results suggest that although symptom control is poorer in patients with ACO as compared to NS-IRAO, the few exacerbations observed in each group do not suggest a higher risk of such events in patients with ACO when appropriately managed. Finally, focusing on symptom control seems equally important than reducing the exacerbation rate in this population.

Acknowledgments

The authors thank Serge Simard for performing all statistical analyses and Justine Veilleux for data entry. We also thank the patients who participated to the study. This study received a non-restrictive investigator-initiated grant from AstraZeneca Canada Inc.

Disclosure

The authors report no conflicts of interest in this work.

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Supplementary material

Table S1 Baseline characteristics of subjects Notes: Results are presented as mean ± SD for continuous variables or as number [%] of patients for categorical variables unless stated otherwise. Bold values represent statistically significant P-values. *Patients not having a SABA as rescue medication were using their combined ICS-LABA as rescue medication. **Sputum samples were obtained for 47 ACO and 23 NS-IRAO. Abbreviations: ACO, asthma-COPD overlap; ACSS, asthma control scoring system; BD, bronchodilator; BMI, body mass index; ICS, inhaled corticosteroid; DLCO, single-breath diffusing capacity for carbon monoxide; FRC, functional residual capacity; KCO, diffusing capacity for carbon monoxide corrected for alveolar volume; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist; NS-IRAO, non-smokers with incomplete reversibility of airway obstruction; RV, residual volume; SABA, short-acting beta-agonist; SAMA, short-acting muscarinic antagonist; TLC, total lung capacity.