COPD 2017: A Year in Review

ABSTRACT

In this review, we focused on original manuscripts published in the 2017 that provided additional information on the clinical and therapeutic features of the chronic obstructive pulmonary disease (COPD).

We have chosen eight of these studies, collected in four topics concerning the pharmacological treatment (tiotropium) of mild-moderate patients, the pharmacological (fluticasone furoate/vilanterol/umeclidinium) and non-pharmacological treatment (non-invasive mechanical ventilation) of severe patients, the etiology of acute exacerbation of COPD involving seasonal airway pathogens and the role of eosinophils with particular interest to the monoclonal antibody directed against interleukin-5 (mepolizumab).

For each topic, we report a brief description of studies, take-home messages, and brief comments.

KEYWORDS:

• chronic obstructive pulmonary disease
• pharmacological treatment
• non-invasive mechanical ventilation
• acute exacerbation of COPD
• eosinophils

Introduction

In 2017, several original manuscripts were published on chronic obstructive pulmonary disease (COPD) that provided additional information on the clinical and therapeutic features of this disease. We have chosen eight of these studies, covering phase III and IV clinical trials, observational studies and randomized controlled studies, which we think might stimulate debate and provide new take-home messages. We will discuss these studies in four topics:

a)	Characteristics and pharmacological treatment of mild-moderate COPD patients;
b)	The once-daily triple therapy and domiciliary use of non-invasive mechanical ventilation (NIMV) in severe COPD patients;
c)	Etiology of acute exacerbation of COPD (AECOPD) involving seasonal airway pathogens;
d)	The role of eosinophils in COPD patients and the role of specific treatments in these patients.

(a) Characteristics and pharmacological treatment of mild-moderate COPD patients

Brief description of studies

According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), COPD patients are divided into four categories (1). Traditionally, patients in stage B present moderate COPD, with a high burden of symptoms and low exacerbation risk. Lawrence et al. (2). explored and described the characteristics and natural history of these moderate COPD patients. In an observational multicenter study conducted on 370 COPD patients (29% were moderate patients), a subgroup of patients who progressed to GOLD stage D (severe COPD patients with a high exacerbation risk and high burden of symptoms) were identified and defined as unstable patients. During follow-up at 1 year, the percentage of unstable patients in stage B was 25%. These patients presented a lower post-bronchodilator forced expiratory volume at the first second (FEV₁) % predicted (mean 62% vs. 70%; p = 0.016), a worse health status (St George's Respiratory Questionnaire (SGRQ-C) total median score of 50 vs. 40; p = 0.019) and a worse impact of disease (COPD assessment test (CAT) median score of 21 vs. 14; p = 0.006) at baseline compared to stable patients (who remained in stage B). At the 2-year follow-up, 67% of unstable patients remained in stage D, representing patients with a definite progression of disease.

Regarding treatment, the Chinese study by Zhou and colleagues (3) hypothesized that the long-term use of tiotropium would reduce the lung function decline in mild or moderate COPD patients. In a phase IV, multicenter, randomized, double-blind, placebo-controlled trial, the authors treated 841 mild to moderate COPD patients with a once-daily inhaled dose of tiotropium (18 µg) or placebo, administered by an inhaler (HandiHaler) at a 1:1 ratio over a 2-year period. The change in FEV₁ from baseline to 2 years (primary end point) was greater in patients receiving tiotropium than in those on placebo, with a between-group difference of 157 ml (95% confidence interval (CI): 123–192; p < 0.001; ranges of mean differences at each visit were 127–169 ml and 71–133 ml in the FEV₁ for before and after bronchodilator use, respectively; p < 0.001 for all comparisons). The annual decline in the FEV₁ after bronchodilator treatment was less in patients on tiotropium than in those on placebo (29 ml per year vs. 51 ml per year, respectively; p = 0.006). Furthermore, the total number of exacerbation per patient per year (0.27 vs. 0.50; p < 0.001), the severity of the exacerbations (0.20 vs. 0.38; p < 0.001), the number of hospitalization per patient per year (0.03 vs. 0.07; p = 0.009) and the number of days of hospitalization per patient per year (0.27 vs. 0.65; p = 0.03) were lower in the tiotropium group than in the placebo group. The incidence of adverse events was similar in the two groups.

Take-home messages

Moderate but symptomatic COPD patients show rapid disease progression. Tiotropium may be useful in improving lung function and decline.

Brief comments

It is well known that symptoms have a significant effect on COPD patients (1). The 2017 GOLD document emphasized symptoms and/or disease burden as pharmacological targets because these predict disease progression (4) and mortality (5). In this context, a symptomatic GOLD B patient will rapidly progress to GOLD D (very severe COPD patient) (2) and will need to be followed carefully over repeated visits. Tiotropium for mild-moderate patients may be useful in the long term, even if the effect on lung decline needs to be clarified. In the study by Zhou et al. (3), the effect of tiotropium on patients with relevant airflow obstruction was compared to that of placebo (mean [standard deviation] FEV₁, 73.4 [17.9]; FEV₁/forced vital capacity (FVC), 58.5 ± 8.3). The results on the effect of tiotropium on lung decline were probably affected by missing data, especially those relating to the first 6 months of the study (29% of patients in the placebo group and 16% of those in the tiotropium group withdrew before 6 months) (6). The UPLIFT study found improvements in lung function, quality of life and exacerbations in COPD patients on tiotropium during a 4-year period; however, there were no improvements in the FEV₁ decline (7). In the study by Zhou et al. (3) investigating the effect of tiotropium on the exacerbation rate at the 2-year follow-up, the authors should have indicated whether the patients presented frequent exacerbations or not (8) by providing data on the number of previous exacerbations.

(b) The once-daily triple therapy and domiciliary use of non-invasive mechanical ventilation (NIMV) in severe COPD patients

Brief description of studies

Severe COPD patients are commonly treated with three inhaled drugs (1). The once-daily triple therapy (using the ELLIPTA inhaler) with an inhaled corticosteroid (ICS) (100 µg of fluticasone furoate), a long-acting β₂-agonist (LABA) (25 µg of vilanterol) and a long-acting muscarinic antagonist (LAMA) (62.5 µg of umeclidinium) has more clinical benefits on lung function and health-related quality of life than the twice-daily ICS/LABA (400 µg budesonide/12 µg formoterol administered by the Turbuhaler inhaler) therapy. To compare these treatment strategies, the Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy (FULFIL) trial was undertaken by Lipson et al. (9) as a phase III, randomized, double-blind, double-dummy, multicenter study performed over a 6-month period in 1,810 patients with advanced COPD. In the intent-to-treat analysis, the triple therapy produced a mean change of 142 ml (95% CI: 126–158) in the FEV₁ from baseline (primary endpoint), while the ICS/LABA therapy generated a mean change of -29 ml (95% CI: −46 to −13) (p < 0.001). The mean changes from baseline in the SGRQ scores (co-primary endpoint) were −6.6 units (95% CI: −7.4 to −5.7) and −4.3 units (95% CI: −5.2 to −3.4) for the triple therapy and ICS/LABA therapy, respectively (p < 0.001). The mean rate of moderate/severe exacerbations in the triple therapy group vs. the ICS/LABA group was 0.22 vs. 0.34, giving a ratio of 0.65 (95% CI: 0.49–0.86; p = 0.002). Thus, the triple therapy produced a reduction of 35% (95% CI: 14–51%) compared to the ICS/LABA therapy. Moreover, the triple therapy decreased the rate of all types of exacerbations (mild, moderate and severe). The blinded trial was continued for 52 weeks in a subgroup of patients (n = 430), which provided further data on the primary endpoint and exacerbation rates (moderate/severe exacerbations and all types of exacerbations), demonstrating the greater clinical efficacy of the triple therapy compared to the ICS/LABA treatment. The safety profile of the triple therapy reflected the known profiles of the individual components.

Readmission for AECOPD is associated with a subsequent progressive increase in the mortality risk for COPD patients (10,11). Although predictors are known (12,13), few treatments are used to reduce hospital readmission. In severe COPD patients experiencing an AECOPD and requiring intra-hospital NIMV, the efficacy of domiciliary NIMV in preventing another acute event after discharge is unclear. Previous studies show no advantages in this regard (e.g., the Respiratory Support in COPD after Acute Exacerbation (RESCUE) trial) (14). The phase III, open-label, multicenter, randomized trial with a 1:1 allocation performed by Murphy et al. (15) in the UK aimed to evaluate the effect of domiciliary NIMV plus oxygen therapy (57 patients) versus oxygen therapy alone (59 patients) in COPD patients with persistent hypercapnia after hospital admission for an AECOPD. The main outcome is the time to readmission or death within 12 months adjusted for the number of previous COPD admissions, previous use of long-term oxygen, age, and body mass index. The median time to readmission or death was higher in the group receiving NIMV plus oxygen than in the group receiving oxygen only (4.3 months vs. 1.4 months, adjusted hazard ratio of 0.49 (95% CI: 0.31–0.77); p = 0.002). The risk for readmission or death was 63.4% in the group receiving domiciliary NIMV plus oxygen vs. 80.4% in the group receiving oxygen alone, with an absolute risk reduction of 17.0%.

Take-home messages

In severe COPD patients, once-daily triple therapy induces more clinical benefits than twice-daily ICS/LABA treatment. In patients with hypercapnia after an AECOPD, domiciliary NIMV in combination with oxygen therapy reduces readmission and mortality rates.

Brief comments

In patients with advanced disease, the GOLD document suggests using three drugs (1). In general, the observation by the FULFIL trial (9) that once daily is better than twice daily might be speculative because the study compared different active substances delivered by different devices instead of making head-to-head comparisons of the same drugs and devices (16). In the study by Murphy et al. (15), domiciliary NIMV in combination with oxygen, which reduces the partial arterial carbon dioxide pressure (PaCO₂), appeared to be effective in the follow-ups at 6 weeks and 3 months, but not in the subsequent follow-ups. The slopes of admission-free survival were different in the first three months of treatment, but similar afterwards (15), which might be a residual effect of an AECOPD sometimes causing early readmission (10–13). In this context, a follow-up visit soon after discharge from hospital might be useful in monitoring patients requiring frequent hospital admission by measuring PaCO₂ levels. In the study of Murphy and colleagues (15), the rate of readmission was high and associated with the severity of COPD, with 53% of the enrolled patients undergoing ≥ three COPD-related readmissions within the past year.

(c) Etiology of acute exacerbation of COPD (AECOPD) involving seasonal airway pathogens

Brief description of study

Wilkinson and colleagues (17) conducted a study in England to evaluate the relationship between the seasonality of AECOPD and chronic airway bacterial infection and viral exposure. The Acute Exacerbation and Respiratory InfectionS in COPD (AERIS) study was a prospective, long-term (1 year), observational cohort study assessing 127 COPD patients who underwent sputum sampling every month and at each AECOPD event to detect pathogens. The seasons were divided into high season (October-March) and low season (April–September). The most common bacterial species detected during an AECOPD were non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis, while the most common virus was rhinovirus. M. catarrhalis and rhinovirus were associated with an increased risk of AECOPD regardless of season (odds ratio (OR), 5.09; 95% CI: 2.76–9.41; p < 0.001 and OR, 10.26; 95% CI: 5.82–18.10; p < 0.001, respectively). The increased risk of exacerbation associated with NTHi was greater in high season (OR, 3.04; 95% CI: 1.80–5.13; p < 0.001) than low season (OR, 1.22; 95% CI: 0.68–2.22; p = 0.506). Similar data were obtained for chronic NTHi infections. Bacterial and viral coinfection was more frequent at exacerbation (24.9%) than in stable state (8.6%). The increased risk for AECOPD associated with NTHi was greater in the presence of rhinovirus than in the absence of this virus (OR, 5.18; 95% CI: 1.92–13.99; p = 0.001 and OR, 1.69; 95% CI: 1.10–2.59; p = 0.016, respectively). In conclusion, the study demonstrated a close relationship between the occurrence of AECOPD and season.

Take-home messages

The presence of non-typeable H. influenzae is associated with the occurrence of AECOPD, especially during autumn–winter. The interaction between bacterial infection and seasonal exposure to viruses plays a determinant role in the risk for AECOPD.

Brief comments

COPD exacerbations and hospitalizations are more frequent in winter (18), with ambient temperature affecting the number of hospitalizations for AECOPD (19). Wilkinson and colleagues (17) indicated a possible relationship between pathogens and season on the risk for AECOPD, with a relevant role for H. influenzae (especially in the presence of rhinovirus). However, oral vaccination against non-typeable H. influenzae to prevent acute exacerbations of chronic bronchitis and COPD has been reported not to significantly reduce the number and severity of exacerbations (20).

(d) The role of eosinophils in COPD patients and the role of specific treatments in these patients.

Brief description of studies

Couillard et al. (21) investigated the role of eosinophils in COPD, assessing clinical outcomes of 1-year COPD-related readmission to hospital, all-cause readmission, length of stay and time to COPD-related readmission. This observational study (although data on hospitalizations for severe COPD exacerbations were collected retrospectively) followed 167 COPD patients, of whom 55 had blood eosinophilia, which was defined as eosinophil levels on admission of ≥ 200 cells/µL and/or ≥ 2% of the total white blood cell count. The authors observed that the percentage of patients with COPD-related and all-cause readmissions at 1 year was higher in COPD patients with blood eosinophilia than in those without eosinophilia (47% vs. 25%; adjusted OR, 3.59; 95% CI: 1.65-7.82; p = 0.001 and 67% vs. 54%; adjusted OR, 2.32; 95% CI: 1.10-4.92; p = 0.027, respectively). Moreover, eosinophilic COPD patients underwent early COPD-related readmission (hazard ratio (HR), 2.74; 95% CI: 1.56-4.83; p < 0.001). In conclusion, blood eosinophil levels can be used as a biomarker in severe COPD exacerbations to predict higher readmission rates.

Roche and colleagues (22) studied whether the presence of blood eosinophils in COPD patients acted as a predictive biomarker for ICS efficacy by analyzing data from the Effect of Indacaterol Glycopyronium vs. Fluticasone Salmeterol on COPD Exacerbations (FLAME) trial (23). This trial was a 52-week, multicenter, double-blind study comparing once-daily LABA/LAMA (110 µg indacaterol/50 µg glycopyrronium) with twice-daily LABA/ICS (50 µg salmeterol/500 µg fluticasone) treatment. The authors compared the responsiveness to ICS by measuring the blood eosinophil percentage (2%, 3% and 5%) and absolute blood eosinophil counts (< 150 cells/µL, 150 to 300 cells/µL and ≥ 300 cells/µL). The indacaterol/glycopyrronium treatment was more effective than the salmeterol/fluticasone therapy in preventing AECOPD (all types of AECOPD and moderate/severe AECOPD) in the < 2%, ≥ 2%, < 3%, < 5% and < 150 cells/µL subgroups. There were no subgroups in which salmeterol/fluticasone was more effective than indacaterol/glycopyrronium. Moreover, AECOPD rates did not increase with the level of blood eosinophils.

In the triple therapy of COPD patients with a history of moderate/severe AECOPD, the use of a monoclonal antibody directed against interleukin-5 (mepolizumab) has been tested in two studies (24). Pavord et al. (24) reported data from two phase III, 52-week, multicenter, randomized, placebo-controlled, double-blind trials that compared mepolizumab with placebo. In the first study (METREX), COPD patients were stratified according to their blood eosinophil count (≥ 150/mm³ at screening visit or ≥ 300/mm³ during the previous year) and treated with 100 mg of mepolizumab. In the second study (METREO), all COPD patients with a blood eosinophil count of at least 150/mm³ at screening or at least 300/mm³ during the previous year were included, with mepolizumab doses of 100 and 300 mg tested. The annual rate of moderate/severe AECOPD was the primary outcome. Pavord et al. (24) found that the mean annual rate of moderate/severe AECOPD in the METREX study (462 patients) was 1.40 vs. 1.71 in the mepolizumab vs. placebo groups, respectively (rate ratio, 0.82; 95% CI: 0.68–0.98; p = 0.04). In the METREO study, the mean annual rate of moderate/severe AECOPD was 1.19, 1.27 and 1.49 for the mepolizumab (100 mg), mepolizumab (300 mg) and placebo groups, respectively. The rate ratios for AECOPD in the mepolizumab groups (100 mg and 300 mg) and the placebo group were 0.80 (95% CI: 0.65–0.98; adjusted p = 0.07) and 0.86 (95% CI: 0.70–1.05; adjusted p = 0.14), respectively. Mepolizumab had a greater effect on the annual rate of AECOPD among patients with higher blood eosinophil counts at screening. In conclusion, 100 mg of mepolizumab reduced the annual rate of moderate/severe AECOPD among COPD patients with an eosinophilic phenotype.

Take-home messages

Eosinophilic airway inflammation contributes to AECOPD. This COPD phenotype might play a role in COPD-related readmission and appears to be susceptible to mepolizumab, but not ICS.

Brief comments

Up to 40% of COPD patients have an eosinophilic phenotype (25). In recent years, several papers have been published on the role of blood eosinophils in COPD, especially as a response to ICS treatment (26–29). The methodology of data collection may plays a crucial role on findings (22,23,26–29); recent data from the FLAME study (22,23). did not confirm blood eosinophils as a potential biomarker for ICS response. A prospective study on the use of a monoclonal antibody in COPD produced interesting results. In patients treated with the triple therapy containing ICS, mepolizumab (24). could make a difference and act as a marker for treatment response. However, choosing the interleukin target of the monoclonal antibody might influence the clinical response (30).

Conclusion

In 2017, several interesting studies have provided further information on new aspects of COPD, especially regarding the early and very severe forms of the disease. Moreover, new data on the possible role of eosinophils in COPD have generated a lot of interest. However, further research is required to examine their function in COPD.

Conflict of interest statements

The authors report no conflicts of interest

Author contributions

Drafting the work or revising it critically for important intellectual content: EC, AT. Final approval of the version submitted for publication: AT.