Characterizing COPD phenotypes [
56] may identify patients who will respond better to a specific type of treatment and thereby individualize therapy [
57,
58]. Unfortunately, clinical trial inclusion criteria do not always match the phenotypes of patients used by guidelines. For example, exacerbation frequency may not be specified as an inclusion criterion, or if exacerbation criteria are specified, the frequency (≥1) may be different than those specified by guidelines (≥2). The following pharmacologic therapies employed in the management of COPD are reviewed with a specific focus on their effect on the risk of exacerbations (Tables
2,
3 and
4), and evidence for use in specific COPD phenotypes.
Table 2
Effect of bronchodilators on the risk of COPD exacerbation
LAMA |
| 0.54 | Placebo | 0.80 | 34 % | Secondary (moderate or severe) | NA | ≥30– < 80 % (post-BD) |
| 0.43 | Placebo | 0.59 | NS | Secondary (moderate or severe) | NA | ≥30– < 80 % (post-BD) |
| 0.61 | Indacaterol | 0.79 | 29 % | Secondary (all) | ≥1 | ≥30– < 50 % (post-BD) |
| 0.64 | Salmeterol | 0.72 | 11 % | Primary (moderate or severe) | ≥1 | <70 % (post-BD) |
| 0.69 | Placebo | 0.87 | 21 % | Secondary (any) | NS | ≤60 % (pre-BD) |
| 0.73 | Placebo | 0.85 | 14 % | Secondary (moderate) | NA | <70 % (post-BD) |
| 1.17 | Placebo | 2.46 | 52 % | Secondary (any) | NA | <80 % |
| 1.57 | Placebo | 2.41 | 35 % | Secondary (any) | ≥1 | 30–65 % (pre-BD) |
| 0.85 | Placebo | 1.05 | 20 % | Secondary (any) | NA | ≤60 % |
| 1.07 | Placebo Salmeterol | 1.49 1.23 | 28 % NS | Secondary (any) | NA | ≤65 % |
| 0.73 | Placebo | 0.96 | 24 % | Secondary (any) | NA | ≤65 % |
| 0.76 | Placebo | 0.95 | 20 % | Secondary (any) | NA | ≤65 % |
LABA |
| 0.97 | Placebo | 1.13 | 15 % | Secondary (moderate or severe) | NA | <60 % (pre-BD) |
| 1.04 | Placebo | 1.30 | 20 % | Secondary (any) | ≥1 | 25–70 % (pre-BD) |
LAMA/LABA |
| 0.42 | Placebo | 0.29 | 29 % (pooled data) | Moderate or severe | NA | ≥30– < 80 % (post-BD) |
| 0.84 | Glycopyrronium | 0.95 | 12 % | Primary (moderate or severe) | ≥1 | <50 % (post-BD) |
Tiotropium + salmeterol [ 64] | 1.75 | Tiotropium | 1.61 | NS | Secondary (any) | ≥1 | <65 % (post-BD) |
| NR | Tiotropium | NR | NS | Secondary endpoint | NA | ≤70 % (post-BD) |
Table 3
Effect of ICS based therapies on the risk of COPD exacerbation
ICS |
| 0.93 | Placebo | 0.73 | NS | Primary | NA | <90 % (post-BD) |
| 0.93 | Placebo | 1.13 | 18 % | Secondary (moderate or severe) | NA | <60 % (pre-BD) |
| 1.05 | Placebo | 1.30 | 19 % | Secondary (any) | ≥1 | 25–70 % (pre-BD) |
| 0.99 | Placebo | 1.32 | 25 % | Secondary (any) | NA | <85 % (post-BD) |
LABA/ICS |
| 0.44 | Salmeterol | 0.48 | NS | Primary (severe) | ≥1 (last 14 days) | <70 % (pre-BD) |
| 1.10 | Salmeterol | 1.59 | 30.4 % | Primary (moderate or severe) | ≥1 | <50 % |
| 0.85 | Placebo Salmeterol FP | 1.13 0.97 0.93 | 25 % 12 % 9 % | Secondary (moderate or severe) | NA | <60 % (pre-BD) |
| 0.97 | Placebo | 1.30 | 25 % | Secondary (moderate) | ≥1 | 25–70 % (pre-BD) |
| 1.06 | Salmeterol | 1.53 | 30.5 % | Primary | ≥1 | <50 % |
| 1.28 | Tiotropium | 1.32 | NS | Primary (moderate or severe) | NA | <50 % (post-BD) |
| 0.92 | Salmeterol | 1.4 | 35 % | Primary (moderate or severe) | ≥2 | <50 % (post-BD) |
| 1.38 | Placebo Formeterol Budesonide | 1.80 1.85 1.60 | 23.6 % NS NS | Primary (all) | ≥1 | <50 % (pre-BD) |
| 1.42 | Placebo Formoterol Budesonide | 1.87 1.84 1.59 | 24 % 23 % NS | Primary (severe) | ≥1 | <50 % |
| 0.70 (320/9 μg) 0.79 (160/9 μg) | Formoterol | 1.07 | 34.6 % 25.9 % | Primary (moderate or severe) | ≥1 | ≤50 % (pre-BD) |
| NR | Formoterol | NR | 36 % | Secondary (any) | ≥1 | ≤50 % (pre-BD) |
| 0.81 | Vilanterol | 1.11 | 30 %(Pooled data) | Primary (moderate or severe) | ≥1 | <70 % (post-BD) |
| 0.80 | Formoterol | 1.12 | 28 % | Primary (moderate or severe) | ≥1 | <50 % |
| 0.41 | Bud/Form Formoterol | 0.42 0.43 | NS | Primary | ≥1 | 30–50 % (post-BD) |
Triple therapy |
Tiotropium + salmeterol + FP [ 64] | 1.37 | Tiotropium | 1.61 | NS | Secondary (any) | ≥1 | <65 % (post-BD) |
Table 4
Effect of other therapies on the risk of COPD exacerbation
Macrolide antibiotics |
| 1.94 | Placebo | 3.22 | 42 % | Primary (any) | ≥3 | NA |
| 1.48 | Placebo | 1.83 | 27 % | Primary (moderate or severe) | ≥1 severe | <70 % (post-BD) |
| 2.8 | Baseline | 6.8 | 59 % | Moderate or severe | ≥4 | <50 % (post-BD) |
| 1 | Placebo | 2 | 35 % | Primary (moderate or severe) | NA | 30–70 % |
Mucolytics |
| 1.01 | Placebo | 1.35 | 25 % | Primary (any) | ≥2 in 2 years | 25–79 % |
N-acetylcysteine (high dose) [ 113] | 1.16 | Placebo | 1.49 | 22 % | Primary (any) | NA | 30–70 % |
| 0.96 | Placebo | 1.71 | 43.9 % | Secondary | ≥1 | Not stated |
| 1.00 | Placebo | 0.73 | NS | Primary | NA | <90 % (post-BD) |
| 1.25 | Placebo | 1.29 | NS | Primary | ≥2 (previous 2 years) | 40–70 % (post-BD) |
PDE-4 inhibitor |
| 0.81 | Placebo | 0.93 | NS | Primary (moderate or severe) | ≥2 (and chronic cough/sputum) | <50 % (post-BD) |
| 1.14 | Placebo | 1.37 | 16.9 % | Primary (moderate or severe) | ≥1 | ≤50 % (post-BD) |
| 1.14 | Placebo | 1.37 | 17 % (2 studies pooled) | Primary (moderate or severe) | ≥1 (and chronic cough/sputum) | <50 % (post-BD) |
| 0.86 | Placebo | 0.92 | NS | Primary (moderate or severe) | NA | <50 % (post-BD) |
Long-acting bronchodilators
Bronchodilation with long-acting muscarinic antagonists (LAMAs) and long-acting β
2-agonists (LABAs), alone or in combination, is a recommended treatment option for most patients with COPD [
9,
34,
35,
59]. Long-acting bronchodilators reduce exacerbation risk by improving expiratory airflow when patients are stable, thereby decreasing air trapping that develops during an exacerbation [
11].
Several studies have demonstrated the efficacy of long-acting bronchodilators in reducing exacerbation risk in populations of patients with or without a history of exacerbations (Table
2). Some of these studies have specifically recruited patients with a history of ≥1 exacerbation in the previous year, in order to “enrich” the population with patients more likely to exacerbate during the study period [
60‐
64]. Table
2 shows that long-acting bronchodilators reduce exacerbation rates compared with placebo both in these “enriched” populations and in studies where there were no specific inclusion criteria regarding exacerbation history. This demonstrates the broad ability of long-acting bronchodilators to prevent future exacerbations irrespective of previous exacerbation history.
LABA monotherapy with salmeterol has been shown to reduce the annual rate of moderate or severe exacerbations by 15 % compared with placebo (
p < 0.001) in a population of patients that may or may not have a history of exacerbations [
13] and by 20 % compared with placebo (
p = 0.003) in patients with more than one exacerbation in the prior year [
65] (Table
2). Other LABAs seem to be effective at reducing exacerbations, and in a
post-hoc pooled analysis of 6-month data from three large Phase III trials of indacaterol 150 and 300 μg once daily versus placebo in 2716 patients with moderate-to-severe COPD, exacerbation rates were significantly reduced by about 30 % with both doses of indacaterol (rate ratios: 0.69; 95 % confidence interval [CI] 0.55, 0.87 and 0.71; 95 % CI 0.57, 0.88, respectively; both
p = 0.002) [
66].
The Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial in patients with stable COPD demonstrated a 14 % reduction in exacerbations with tiotropium 18 μg once daily versus usual treatment at 4 years’ follow-up (
p < 0.001) [
15]. In a recent systematic review of 22 studies and >23,000 patients with stable COPD, which included UPLIFT, tiotropium was associated with a 22 % reduction in exacerbations versus placebo (OR 0.78; 95 % CI 0.70, 0.87) [
67]. Other LAMAs have also demonstrated efficacy on exacerbations. In the GLOW 1 and 2 studies, where ~95 % of patients had an exacerbation history of 0 or 1 at baseline, glycopyrronium significantly reduced the risk of first moderate or severe exacerbation (by 31 %,
p < 0.05) and the rate of moderate or severe COPD exacerbations (by 34 %,
p = 0.001) versus placebo [
68,
69]. Data on exacerbations with aclidinium are mixed, with one study showing fewer patients experiencing a moderate or severe exacerbation (hazard ratio [HR] 0.7; 95 % CI 0.55, 0.90;
p = 0.0046) compared with placebo, and another study showing no effect [
70], although the overall exacerbation rate was low, which can reduce the ability to detect an effect of treatment. Studies specifically in patients with prior exacerbations suggest that LAMAs may be more effective than LABAs at reducing the risk of exacerbations [
60,
63]. For example, in the Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) study, which included patients having had at least one exacerbation requiring treatment or hospitalization in the previous year, tiotropium significantly reduced the risk of exacerbations by 17 % versus salmeterol (
p < 0.001) [
60]. Genotyping of a subgroup of patients in this study highlighted that polymorphisms of the β
2-adrenoceptor can affect exacerbation outcomes in response to salmeterol but not tiotropium [
71], and this may have contributed to the difference between treatments in exacerbations.
Data are emerging on the benefits of LABA/LAMA combination therapies in reducing the risk of exacerbations versus various comparators. In a pooled analysis of two 6-month randomized trials, aclidinium/formoterol (LABA/LAMA fixed combination) reduced the rate of moderate or severe exacerbations by 29 % compared with placebo (
p < 0.05) [
72]. In the SPARK study of 2224 patients with GOLD stages 3–4 COPD and ≥1 moderate COPD exacerbation in the past year, indacaterol/glycopyrronium (IND/GLY) significantly reduced the rate of moderate-to-severe exacerbations by 12 % (
p = 0.038) and all exacerbations by 15 % (
p = 0.0012) compared with glycopyrronium monotherapy. In addition, IND/GLY reduced the risk of all exacerbations vs tiotropium monotherapy (14 %;
p = 0.0017) and had a trend to a reduction in the risk of moderate-to-severe exacerbations (10 %;
p = 0.096) [
62]. Recently, the LANTERN study of 744 patients with moderate-to-severe COPD and one or no exacerbations in the previous year reported a significant 31 % reduction in the rate of moderate or severe exacerbations (an exploratory endpoint) with IND/GLY compared with salmeterol/fluticasone propionate (SFC) (
p < 0.05) [
73]. The FLAME study has investigated the effect of IND/GLY compared with SFC on exacerbations as the primary outcome in a population of 3362 patients with a history of exacerbations [
74], and demonstrated that IND/GLY was more effective than SFC for reducing the rate of all exacerbations by 11 % (
p = 0.0003) and moderate or severe exacerbations by 17 % (
p < 0.001) [
74]. Moreover, although the annual rate of severe exacerbations did not reach statistical significance between the two treatment arms due to the low number of events, the time to first severe exacerbation was significantly longer with IND/GLY compared with SFC (19 % lower risk,
p = 0.046).
Much data are available demonstrating the effectiveness of long-acting bronchodilators in terms of exacerbation reduction in patients with COPD, with studies showing rate reductions compared with placebo of up to 20–30 % with LABAs and 34–35 % with LAMAs (Table
2). Interestingly, combining a LABA and LAMA results in a reduction of risk compared with a LAMA alone and, more importantly, a significant reduction of exacerbation risk compared with a LABA/ICS [
62,
73,
74].
Inhaled corticosteroids and long-acting bronchodilators
Inhaled corticosteroids (ICS) are generally licensed in COPD for use in combination with a LABA for patients with a history of exacerbations in the past year [
9]. GOLD recommends that patients with ≥2 exacerbations (or one hospitalization) should be considered for ICS/LABA treatment [
9], and this is also echoed in other guidelines [
34‐
37]. The Spanish, the Finnish and Czech guidelines recommend ICS for patients classified as frequent exacerbators or of the ACOS phenotype [
33‐
35].
Although ICS alone have been shown to produce modest reductions in the occurrence of exacerbations [
75], their efficacy is enhanced when combined with a LABA, as demonstrated in a Cochrane review and in a Bayesian network meta-analysis [
76,
77]. In the Towards a Revolution in COPD Health (TORCH) study
1, SFC was associated with a 25 % reduction in exacerbation rate versus placebo (
p < 0.001), a 12 % reduction versus salmeterol (
p = 0.002) and a 9 % reduction versus fluticasone propionate (
p = 0.02) [
13] (Table
3). Although SFC was more effective than salmeterol monotherapy for reducing the risk of moderate-to-severe exacerbations, there was no significant difference in the risk of severe exacerbations (requiring hospitalization) [
13]. Similarly, in a study
2 of 797 patients with COPD (FEV
1 < 50 % predicted and at least one exacerbation in the year prior to the study), SFC significantly reduced the annual rate of moderate/severe exacerbations (30.4 %,
p < 0.001) versus salmeterol [
78]. An analysis of pooled data from two studies
2 in which participants were given fluticasone furoate/vilanterol also noted significantly fewer moderate or severe exacerbations compared with vilanterol alone (rate ratio 0.7; 95 % CI 0.6, 0.8;
p < 0.0001) [
79]. In patients with severe airflow limitation (GOLD stage III or IV) and ≥1 exacerbation in the previous year
1, a combination of budesonide/formoterol significantly reduced the risk of exacerbations by 28.5, 22.7 and 29.5 % vs placebo, budesonide and formoterol respectively (
p < 0.05 for all) [
80]. In a similar population
1, budesonide/formoterol has been reported to reduce severe exacerbations by 24 % vs placebo [
81].
The use of ICS in COPD is still controversial [
82]. Long-term use of ICS in patients with COPD is associated with an increased risk of pneumonia [
83], fractures [
84] and diabetes [
85], among other potential side effects. With questions concerning the long-term safety of ICS and also data showing similar exacerbation rates with ICS/LABA compared with some long-acting bronchodilators [
61], there is emerging consensus that withdrawal of corticosteroids may be appropriate in some patient populations. The WISDOM trial, a 12-month, double-blind, active-controlled study of 2485 patients with severe/very severe COPD and a history of exacerbations, showed no increase in the risk of moderate or severe exacerbations in patients who withdrew from ICS therapy but remained on LABA/LAMA compared with those who remained on ICS with LABA/LAMA [
86], although there was an initial drop in FEV
1 of approximately 40 mL. Corticosteroid withdrawal without long-acting bronchodilation in severe COPD patients may produce a different pattern of results. This observation supports a systematic review of other trials of ICS withdrawal in which there was no conclusive evidence that withdrawal of ICS increased exacerbations [
87]. Moreover, switching to LABA from LABA/ICS has been shown to occur without loss of efficacy or increase in exacerbations in patients with a low risk of exacerbations in the INSTEAD (Indacaterol: Switching Non-exacerbating Patients with Moderate COPD From Salmeterol/Fluticasone to Indacaterol) and OPTIMO (Real-Life study On the aPpropriaTeness of treatment In MOderate COPD patients) studies [
88,
89].
Patients with ACOS may be particularly likely to benefit from ICS therapy because of the predominance of eosinophilic bronchial inflammation associated with this COPD phenotype [
90‐
92]. In fact, it has been demonstrated that a high Th2 signature in COPD correlates with increased airway wall and blood eosinophil counts, and greater response of hyperinflation to ICS in COPD patients with Th2 type of inflammation [
92].
The response to ICS in patients with respiratory disease can be predicted by sputum eosinophil counts [
93,
94]. A randomized crossover trial in patients with COPD in the absence of clinical diagnosis of asthma demonstrated an improvement in post-bronchodilator FEV
1 with ICS treatment (mometasone furoate) compared with placebo in those patients with the greatest degree of sputum eosinophilia [
93]. More recently, two post-hoc analyses have shown that blood eosinophil counts may predict the effects of ICS/LABA combination treatment on exacerbation rates [
95,
96]. Thus, the identification of patients with eosinophilic inflammation in COPD, even in the absence of asthma, may be a useful phenotype to target those most likely to benefit from ICS therapy, although this approach should be validated in prospective studies first.
There is little doubt from the studies reviewed that an ICS combined with a LABA is an effective intervention for patients with a history of exacerbations. As shown, such treatment is associated with reductions in exacerbations averaging 25 % compared with placebo and between 23–36 % (12 % if we include the TORCH study) compared with LABA monotherapy (Table
3). However, there is growing evidence indicating that not all patients with COPD respond to ICS treatment. Given the potential for pneumonia and other important side effects with ICS in COPD populations, emerging data reveal that it may be possible to withdraw the ICS component in certain patient groups provided that adequate bronchodilation is in place [
86‐
89].
Phosphodiesterase-4 inhibitors
PDE-4 inhibitors represent an anti-inflammatory approach that is recognized as a treatment option for patients with COPD who are at high risk of exacerbations and have a chronic bronchitis phenotype [
9]. In a pooled analysis of two 1-year, placebo-controlled, double-blind, multicenter studies, roflumilast (a PDE-4 inhibitor) was associated with a 17 % reduction in the rate of moderate-to-severe exacerbations compared with placebo in patients with severe COPD, chronic bronchitis and a history of previous exacerbation (
p < 0.0003) (Table
4) [
97]. A subsequent systematic review of 29 trials with PDE-4 inhibitors (15 roflumilast studies, 14 cilomilast studies) has confirmed these observations [
98]. More recently, roflumilast was noted to reduce the rate of moderate or severe exacerbations by 13.2 % vs placebo in high-risk patients (severe COPD, symptoms of chronic bronchitis and ≥2 exacerbations in the previous year) receiving LABA/ICS (of which ~70 % were on triple therapy) in the REACT (Roflumilast and Exacerbations in patients receiving Appropriate Combination Therapy) study [
99]. Overall, roflumilast is well tolerated with a safety profile consistent with that expected for the PDE-4 inhibitor class [
100]. The most common adverse events with roflumilast are gastrointestinal in nature, specifically diarrhea, nausea and weight loss [
101]. Psychiatric events (insomnia, anxiety, depression/suicidal behavior) are also more common with roflumilast in clinical trials [
102]. However, studies have demonstrated beneficial effects of roflumilast in terms of glycemic parameters [
103] and risk of major adverse cardiovascular events [
104].
Overall, current clinical trial data indicate that the PDE-4 inhibitor roflumilast is associated with a reduction in the rate of moderate/severe exacerbations of 13–17 % when compared with placebo in a subset of patients that exhibit symptoms of chronic bronchitis and are at a high risk of exacerbations despite optimal inhaled therapy. However, tolerance of roflumilast may be a hurdle for more extensive use in severe COPD.
Macrolide antibiotics
Bacterial infections can trigger COPD exacerbations and, consequently, long-term antibiotic use has been considered as a strategy for the prevention of exacerbations. A meta-analysis of six randomized controlled trials on the use of prophylactic macrolide antibiotics has reported a 37 % risk reduction for exacerbations compared with placebo [
105]. A systematic review of seven trials covering more than 3000 patients identified a significant effect of continuous antibiotics for reducing the number of patients experiencing an exacerbation (OR 0.55; 95 % CI 0.30, 0.77) [
106]. Since these analyses, a small study (
n = 92) confirmed a 42 % decrease in exacerbation rate with maintenance azithromycin treatment compared with placebo (OR 0.58; 95 % CI 0.42, 0.79;
p = 0.001) in patients that suffered at least three exacerbations the previous year while on maximal respiratory medications (Table
4) [
107]. The continuous use of antibiotics may raise a concern about bacterial resistance, and an increase in respiratory pathogens resistant to macrolides has been identified with this approach in patients with COPD [
108]. Long-term use of macrolides has also been linked to hearing loss and gastrointestinal events [
106]. Thus, this approach may be best for patients who experience frequent bacterial exacerbations despite optimal treatment with bronchodilators and anti-inflammatory agents [
109] and it may be prudent to limit their use to reference centers with adequate follow-up [
59]. A post-hoc analysis of patients treated with continuous azithromycin reported that ex-smokers and patients who are older and have milder COPD may have a better treatment response [
110].
Based on the evidence reviewed here, macrolide antibiotic therapy may be a beneficial strategy for patients who suffer frequent bacterial exacerbations while on maximal bronchodilator therapy, as demonstrated in clinical trials that show reductions in exacerbations ranging from 27 to 42 % compared with placebo (Table
4). Nevertheless, given the potential for development of bacterial resistance alongside long-term safety concerns, such treatment needs to be targeted to the most appropriate patient and include careful supervision [
111].
Mucolytics
Mucolytic therapies, such as carbocysteine or N-acetylcysteine, may represent an attractive treatment strategy for frequent exacerbators with chronic bronchitis, and particularly those who may be unable to receive ICS (Table
4). A systematic review of 30 trials has reported an increased likelihood of being exacerbation free with mucolytic therapy compared with patients without mucolytic therapy (OR 1.84; 95 % CI 1.63, 2.07) [
112]. However, it should be noted that there are considerable differences in the patient populations and definitions of exacerbations used in these studies; for example, some of these studies were performed in patients with chronic bronchitis, without the requirement for COPD to be diagnosed. More recently, a study in 1006 patients with moderate-to-severe COPD in China reported that long-term use of high-dose N-acetylcysteine (600 mg b.i.d.) was associated with a significant decrease in exacerbations compared with placebo (risk ratio 0.78; 95 % CI 0.67, 0.90;
p = 0.0011) [
113]. A smaller study in China has also confirmed a benefit of high-dose N-acetylcysteine (600 mg b.i.d.) for reducing exacerbations in high-risk patients [
114]. Treatment with mucolytics appears to be well tolerated, with similar frequencies of adverse events compared with placebo [
112,
113]. Erdosteine, a mucolytic agent with anti-inflammatory, antioxidant and bacterial anti-adhesive properties, has recently been reported to reduce the rate (17 %) and duration (44 %) of exacerbations compared with placebo in patients with COPD GOLD stage II-III and at least two exacerbations requiring medical intervention in the previous year [
115].
In summary, while data indicate that the risk of exacerbation is reduced with mucolytic therapies compared with placebo in patients with COPD, as demonstrated in an updated systematic review, much heterogeneity exists meaning that current data should be interpreted cautiously [
112].
Future therapeutic strategies
A multiple treatment comparison meta-analysis of 26 studies has compared the effects of various combinations of treatments and noted that, although combination therapies differ in their effects for reducing the risk of COPD exacerbations, they reduce risks more than monotherapy [
116]. Further studies are required to confirm the optimal combinations for reducing exacerbations. However, randomized controlled studies to evaluate the effects of treatments on exacerbation risk are ongoing or have recently completed, such as the FLAME study comparing IND/GLY with SFC [
74], and a comparison of umeclidinium/vilanterol/fluticasone furoate with fixed-dose dual combinations of fluticasone furoate/vilanterol and umeclidinium/vilanterol [NCT02164513] [
117]. Various other combination therapies are being developed for the prevention of exacerbations, including triple therapies of ICS/LABA/LAMA [
11]. In addition, combined PDE-3 and PDE-4 inhibitors (RPL554), monoclonal antibodies and p38 mitogen activated protein kinase inhibitors are in development for the prevention of exacerbations [
11]. Benralizumab, an anti-interleukin-5 (IL-5) receptor alpha monoclonal antibody, has been investigated in Phase II studies in patients with sputum eosinophilia and COPD [
118]. Although no significant benefit was noted with benralizumab on the rate of exacerbations in the overall study population, a non-significant numerical improvement was seen in subgroups of patients with elevated blood eosinophils [
118]. Further studies with anti-IL-5 therapies are warranted.