American Journal of Respiratory and Critical Care Medicine

Clinical phenotyping is currently used to guide pharmacological treatment decisions in chronic obstructive pulmonary disease (COPD), a personalized approach to care. Precision medicine integrates biological (endotype) and clinical (phenotype) information for a more individualized approach to pharmacotherapy, to maximize the benefit versus risk ratio. Biomarkers can be used to identify endotypes. To evolve toward precision medicine in COPD, the most appropriate biomarkers and clinical characteristics that reliably predict treatment responses need to be identified. FEV1 is a marker of COPD severity and has historically been used to guide pharmacotherapy choices. However, we now understand that the trajectory of FEV1 change, as an indicator of disease activity, is more important than a single FEV1 measurement. There is a need to develop biomarkers of disease activity to enable a more targeted and individualized approach to pharmacotherapy. Recent clinical trials testing commonly used COPD treatments have provided new information that is likely to influence pharmacological treatment decisions both at initial presentation and at follow up. In this Perspective, we consider the impact of recent clinical trials on current COPD treatment recommendations. We also focus on the movement toward precision medicine and propose how this field needs to evolve in terms of using clinical characteristics and biomarkers to identify the most appropriate patients for a given pharmacological treatment.

Chronic obstructive pulmonary disease (COPD) is a complex condition, encompassing many elements that contribute to its clinical presentation. COPD is also heterogeneous, as these different elements vary in both presence and severity between patients (1). These characteristics may be dynamic, varying over time within the same patient (2). The variability between patients with COPD means that an individualized approach is required for pharmacological treatment (2, 3).

Clinical phenotypes are subgroups of patients defined by clinical characteristics and sharing common clinical outcomes (e.g., exacerbations, response to treatment) (4). In 2011, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) proposed a combined assessment of FEV1, symptoms, and exacerbation history, resulting in four groups representing clinical phenotypes (A/B/C/D) (5). Pharmacological treatments were proposed for each phenotype, targeting the short- and long-term relief of symptoms and the long-term risk reduction of future events such as exacerbations (or death). Potential criticisms of this approach are that these clinical phenotypes require prospective validation regarding their links with future outcomes and treatment responses and that some pharmacological treatment propositions were not supported by firm clinical evidence (3). Nevertheless, many national respiratory societies have embraced the GOLD principles to construct COPD guidelines, although with several variations (6).

Each clinical feature of COPD is likely caused by more than one biological mechanism. Consequently, pharmacological targeting of clinical characteristics does not specifically match the drug to underlying biological mechanisms and may result in limited efficacy. An endotype is a subtype of a (clinical) condition defined by a distinct pathophysiological mechanism (3). An endotype gives rise to one or more clinical characteristics, and clinical phenotypes can be the result of multiple endotypes. The “precision medicine” strategy uses both biological (endotype) and clinical (phenotype) information to identify the most appropriate individuals for a given pharmacological treatment, to maximize the benefit-versus-risk ratio (7). COPD pharmacotherapy faces a challenge to incorporate precision medicine, as easily accessible biomarkers that identify clinically relevant endotypes need to be developed.

Recent studies have raised issues about the clinical characteristics and biomarkers that can reliably predict treatment responses and whether the existing evidence supports current pharmacological treatment recommendations. This article focuses on current controversies in COPD pharmacological management and considers the future evolution of COPD pharmacotherapy toward precision medicine.

At a population level, there is a loose association in COPD cross-sectional studies between FEV1 and symptoms; consequently, FEV1 poorly predicts the symptom burden on an individual level (1) and is a suboptimal measurement to guide symptom-based treatment decisions. However, the change in FEV1 in COPD randomized clinical trials (RCTs) is still a useful measurement, as improvements in FEV1 associate with improvements in symptoms, health status, and exacerbation rates (8, 9).

Inhaled corticosteroid/long-acting β-agonist (ICS/LABA) combinations reduce exacerbation rates and improve lung function and health status (1013). RCTs of ICS/LABA combinations commonly enrich the population to include individuals more likely to exacerbate, to maximize treatment efficacy (1214). The ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) and COPDgene longitudinal cohort studies demonstrated that the past exacerbation history is a better predictor of future exacerbations than FEV1 (15, 16). Furthermore, a notable proportion (22%) of patients with FEV1 50 to 80% predicted in ECLIPSE had two or more exacerbations (defined as frequent exacerbators) each year for 3 years (15). Therefore, relying on FEV1 to identify patients at risk of exacerbations (e.g., using 50% predicted as a threshold) may prevent some patients from receiving appropriate pharmacotherapy. Indeed, recent evidence shows that ICS/LABA combinations reduce exacerbations in patients with an exacerbation history and FEV1 up to 70% predicted (14).

Long-acting bronchodilators improve lung function, thereby improving symptoms and exercise performance, and prevent exacerbations (11, 17, 18). These agents show similar efficacy in patients with moderate (GOLD II) compared with more severe (GOLD III/IV) COPD (19, 20), indicating that FEV1 does not predict bronchodilator treatment response. Furthermore, short-acting bronchodilator reversibility does not predict response to long-acting bronchodilators or ICS/LABA combinations (21, 22), as bronchodilator reversibility can change between visits (23), and patients with a negative reversibility test can still obtain clinical benefit from a long-acting bronchodilator.

An “FEV1-free” approach to pharmacotherapy in COPD has been proposed (24), where the use of long-acting bronchodilators would be directed by symptoms and the presence of exacerbations. The use of antiinflammatory treatments would be recommended if the patient continues to suffer exacerbations despite appropriate bronchodilator treatment (Figure 1). The current GOLD C and D categories comprise three different patient subgroups: low FEV1 alone, exacerbation history alone, or both. This causes confusion in clinical practice regarding pharmacological treatments. The FEV1-free approach makes the definition of GOLD C and D more homogeneous, including only frequent exacerbators. The FEV1-free approach applies to pharmacotherapy only, as spirometry is required for COPD diagnosis, and FEV1 remains a prognostic risk marker for mortality (25) and is required when considering interventional care for COPD (i.e., lung volume reduction or lung transplantation).

The different components of COPD can be categorized into severity, activity, and impact groupings (26). Severity refers to functional impairment, including airflow limitation, hyperinflation, arterial hypoxemia, and reduced exercise capacity (27). Disease activity refers to features associated with disease progression, such as exacerbations, FEV1 decline, and weight loss (26). Impact refers to the individual patient’s perception of disease severity and activity (26). Bronchodilators improve severity (lung function), which consequently reduces the impact level. However, as already discussed, the level of impact rather than severity should guide individual treatment decisions regarding bronchodilator use; this is illustrated in Figure 2, which also shows that pharmacological treatments can target disease activity, such as preventing exacerbations. RCTs have used inclusion criteria to select individuals with more active disease on the basis of exacerbation history (13, 14, 28, 29). We now consider alternative means of assessing disease activity, through longitudinal assessments and biomarkers.

Longitudinal Data

The speed of lung function loss with age is the paradigmatic marker of disease activity. However, years of follow up are needed to be confident of the rate of change. FEV1 does not decline precipitously in all treated patients with COPD, remaining stable or even improving in a significant proportion (30). Furthermore, a recent analysis of three independent cohorts showed that COPD can be the result of different trajectories of lung function decline, depending on underlying mechanisms, including failure to reach maximal lung growth (31). The mean rate of lung function decline was 27 ml/yr compared with 53 ml/yr in individuals with low and normal FEV1 in early adult life, respectively, suggesting greater disease activity in the latter group. A single FEV1 measurement is a severity marker but may be misleading regarding disease activity.

COPD RCTs have not proved, as a primary endpoint, that pharmacotherapy reduces the rate of lung function decline. However, post hoc analysis of a 3-year RCT showed a reduced rate of FEV1 decline with ICS/LABA treatment and the monocomponents (32), whereas a prespecified subgroup analysis showed similar results for long-acting muscarinic antagonist (LAMA) treatment in GOLD II patients (19). The SUMMIT (Study to Understand Mortality and Morbidity in COPD) study showed that ICS/LABA treatment, but not LABA monotherapy, reduced the rate of FEV1 decline in patients with COPD with FEV1 50 to 70% predicted, but a definitive conclusion from this secondary outcome could not be made, as the primary outcome (mortality) was negative, and a hierarchical testing approach was used (33). These studies have shown attenuation of FEV1 decline by pharmacotherapies ranging from 6 to 16 ml/yr. These effect sizes may be greater in patient subgroups with more rapid FEV1 decline; risk factors for rapid decline include current smoking, exacerbations, and emphysema (15, 34). Smoking cessation reduces the rate of lung function decline (35), and the evidence reviewed here suggests an effect of long-acting bronchodilators and ICS through exacerbation prevention, thereby reducing disease activity. There is a need for RCTs that specifically address pharmacological approaches to prevent emphysema progression.


Fibrinogen is a biomarker of cardiovascular risk and predicts exacerbation risk and mortality in patients with COPD (36). Plasma fibrinogen measurements have been accepted by the U.S. Food and Drug Administration as a biomarker for enriching RCTs with patients more likely to suffer with these outcomes, when used in conjunction with clinical information such as the past history of exacerbations. Importantly, fibrinogen cannot yet be used at an individual level in clinical practice; it is a biomarker that can be used at a group level to identify patients with greater disease activity. There are currently no disease activity biomarkers validated for use at an individual level.

Biomarkers that have been investigated include club cell protein 16 (CC16) and soluble, circulating form of the receptor for advanced glycation end products (sRAGE). CC16 is a protective immunosuppressant secreted by club cells; low CC16 levels are associated with lung function decline (37, 38). sRAGE may be associated with emphysema severity and progression (39). Most of the evidence for these biomarkers comes from cohort studies or small clinical trials. Their potential usefulness to enrich the population studied, and/or to measure treatment effects, should be prospectively evaluated in large RCTs. The validation and harmonization of the laboratory measurement methods also needs to be established.

A panel of several biomarkers may provide more reliable information than a single one; for example, patients with persistent systemic inflammation assessed by blood leukocytes and serum IL-6, C-reactive protein, and fibrinogen had significantly higher all-cause mortality (13 vs. 2%) and exacerbation frequency (1.5 vs. 0.9/yr) (40). In addition, a biomarker panel increased the ability of clinical variables to predict future exacerbations and mortality (41, 42). Biomarkers of disease activity are likely to be most useful when used with clinical measurements.

Combination inhalers containing a LABA and LAMA cause improvements in FEV1 compared with placebo that are usually approximately 250 to 300 ml at peak and 150 to 200 ml at trough (4345). These combination inhaler effects on FEV1 are greater than long-acting bronchodilator monotherapies, with treatment differences of approximately 150 ml at peak and 50 to 90 ml at trough (4345). The important clinical question is the degree of symptom improvement associated with these lung function changes. Initial studies used lung function as a primary endpoint for regulatory purposes and were not specifically powered or designed for patient-reported outcome (PRO) measurements (4446). These studies showed that the mean PRO improvements with LABA/LAMA combinations versus placebo exceeded the minimal clinically important difference (MCID) thresholds for breathlessness scores (>1-point change in the transition dyspnea index focal score) and health-related quality of life (>4-point reduction in the St. George’s Respiratory Questionnaire total score) (47), whereas monotherapies often failed to meet these MCID thresholds versus placebo. Individual responder analysis also showed that significantly more patients reached the MCID thresholds with dual therapy versus monotherapy. However, the mean differences between dual bronchodilators versus monotherapy were often small in magnitude or not statistically significant. Subsequent studies specifically designed with PROs as the primary endpoint (48, 49), and pooled analysis with greater statistical power (50), have shown statistically significant differences of 0.5 for transition dyspnea index and 2 for St. George’s Respiratory Questionnaire for this treatment comparison. These are lower than the MCID thresholds, but the associated reductions in reliever medication use suggest clinical relevance (43, 47).

The daily variation in lung function is reduced with two short-acting bronchodilators compared with one, suggesting greater stabilization of airway tone (23). LABA/LAMA combinations may also provide increased airway stabilization. RCTs usually focus on improvements in FEV1 and symptoms with bronchodilators, but the prevention of short-term clinical deterioration, which may progress to exacerbation, is also of importance.

Long-acting bronchodilator monotherapies reduce exacerbation rates (11, 18). There is also a greater effect on exacerbations with LABA/LAMAs compared with LAMA monotherapy in patients at risk of exacerbations; indacaterol/glycopyrronium reduced exacerbations requiring oral corticosteroids and/or antibiotics by 12% compared with glycopyrronium (29). There was also a reduction in mild exacerbations requiring increased bronchodilator treatment, which may be due to better airway stabilization with LABA/LAMA treatment.

Exacerbations may be associated with increased airway inflammation (51), but there is no consistent evidence from clinical trials that bronchodilators have antiinflammatory effects. Long-acting bronchodilators improve airflow obstruction, air trapping, and hyperinflation, thus reducing dyspnea and improving exercise performance (17). These improvements in lung mechanics and clinical status probably allow patients to cope better with the pathophysiological impact of factors that may trigger exacerbations, such as infections (52).

Patients with COPD at high risk of cardiovascular events are often excluded from RCTs. The SUMMIT study in patients at increased risk of cardiovascular disease showed no increase in adverse cardiac events with LABA treatment (33). More studies in high-risk patients with COPD, and real-world observational studies, would provide further reassurance about long-acting bronchodilator safety.

Many RCTs have shown a reduction in exacerbations of approximately 25 to 30% for various ICS/LABAs versus LABAs, suggesting a “class effect” for ICSs (1214). ICSs may have side effects; RCTs, metaanalyses, and observational studies concur in finding an increased rate of nonfatal pneumonia in patients receiving ICSs (11, 13, 14, 53). Risk factors include past exacerbations, low body mass index, or low FEV1 (54); this may explain the lack of increase in pneumonia events in the SUMMIT study, which enrolled patients with moderate COPD, without a requirement for past exacerbations. This effect may relate more to the dose than to the properties of individual molecules. Observational studies suggest increased risk of mycobacterial infection (55, 56), diabetes occurrence or aggravation (57), bone fractures (58), and cataract (59) with ICSs, but residual confounders could influence the results. RCT evidence exists only for skin bruises (60) and loss of bone mineral density (58), indicating that ICSs can cause clinically relevant systemic effects. Other ICS systemic side effects are difficult to firmly demonstrate in RCTs due to the long duration of follow up and large sample size required.

Patients with COPD with greater sputum eosinophil counts have a better response to corticosteroid treatment (61, 62). Sputum sampling is only performed in specialist centers. Blood eosinophil counts are more accessible and show a degree of correlation to sputum eosinophils (63). Post hoc analyses of RCTs investigating ICS/LABA combinations versus LABA monotherapy have reported greater effects of ICS/LABA on exacerbation prevention in patients with higher blood eosinophil counts (6466). Post hoc analysis of the INSPIRE (Investigating New Standards for Prophylaxis in Reduction of Exacerbations) study reported that an ICS/LABA had a significantly greater effect on exacerbations than a LAMA in patients with blood eosinophils greater than 2% (rate ratio, 0.75), but there was no difference with blood eosinophils less than 2% (65). Similarly, ICS withdrawal in the WISDOM (Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management) study increased the exacerbation rate only in patients with blood eosinophils greater than 2% (67). Although a threshold of 2% has been commonly used in these analyses, the effects of ICS appear to become greater when using higher thresholds (64, 66, 67), and it is not clear whether percentage or absolute eosinophil counts should be used. It has also been reported that blood eosinophils greater than 2% predict a reduced rate of FEV1 decline with ICSs compared with placebo (difference, 33.9 ml/yr) (68). Prospective RCTs are needed to validate the use of blood eosinophil counts to predict ICS response and to identify the appropriate cut-off level. The mechanism(s) for the differential effects of ICSs according to eosinophil counts remain unclear. Higher blood eosinophil counts in some (but not all) analyses predict higher exacerbation rates (63, 69), suggesting more active disease, with eosinophils greater than or equal to 340 cells/μl predicting an increased exacerbation risk in patients with COPD in the Copenhagen general population study (69).

GOLD makes propositions for initial pharmacotherapy, with different options for groups A through D (5). Pharmacotherapy for groups A and B is dominated by short- and long-acting bronchodilator treatments. The majority of patients with COPD on long-acting bronchodilator monotherapy remain significantly breathless (70). There is no evidence to suggest which patients should initially receive an LABA/LAMA combination. This could be investigated in patients who have not received long-acting bronchodilator treatments previously, unlike the majority of patients in published studies. ICS/LABAs should not be used for groups A and B, and RCTs have shown superiority for LABA/LAMAs over ICS/LABAs in these patients for lung function and symptoms (71, 72).

Groups C and D include patients with frequent exacerbations defined by a history of two or more moderate to severe exacerbations or one hospitalization in the last year. Clinical outcomes, including future exacerbation risk, health-related quality of life, FEV1 decline, and mortality are significantly impaired in patients with two or more exacerbations per year (15). Many exacerbation events are unreported (73, 74), and a threshold of two events using patient recall may underestimate the true event rate. Exacerbation frequency may change (15), and using a lower threshold (a single exacerbation event in a year) may identify patients with no further events. GOLD uses one hospitalization to define a patient at high risk of future exacerbations, recognizing the importance of event severity, which influences the time to recovery (75). RCTs assessing the effects of drugs on exacerbation rates have historically used one exacerbation in the previous year as an inclusion criterion (13, 14). Current GOLD propositions assume that results from these studies predict the effects in patients with two or more exacerbations per year, but this mostly remains untested.

The positioning of LAMAs as a first-line option for frequent exacerbators is based on robust evidence demonstrating effects on exacerbations compared with placebo (18, 76). Furthermore, the INSPIRE study in patients with severe airflow obstruction and a history of exacerbations showed no difference in exacerbation rate after 2 years of treatment with tiotropium compared with fluticasone propionate/salmeterol (77). Systemic corticosteroid treatment for exacerbations was less frequent with ICS/LABA treatment, and antibiotic use was less frequent with tiotropium. This suggests that initial pharmacotherapy could be tailored to prevent exacerbation subtypes.

GOLD does not provide guidance on pharmacological strategies during follow up, when treatment may be adjusted according to the initial treatment response; this potentially includes stopping ineffective therapies. The comparative benefits of adding or switching therapies if patients remain symptomatic on initial therapy need to be better characterized.

The introduction of dual bronchodilator combinations raises the issue of the comparative efficacy of LABA/LAMAs versus ICS/LABAs. Indacaterol/glycopyrronium had a greater effect on exacerbations than salmeterol/fluticasone propionate in a subgroup of patients with one exacerbation in the previous year included in an RCT (78). The recently published FLAME (Fluoxetine for Motor Recovery after Acute Ischaemic Stroke) study recruited 3,362 patients with one or more exacerbations in the previous year to compare these combinations over 1 year (28). Indacaterol/glycopyrronium showed superiority on the rate of all exacerbations (11% reduction, P = 0.003), with moderate to severe exacerbations reduced by 17% (P < 0.001). There was evidence of significantly better FEV1 (62 ml) and health status and lower pneumonia incidence with indacaterol/glycopyrronium. Although INSPIRE showed similarity between LAMAs and ICS/LABAs for exacerbation reduction (77), FLAME now demonstrates a superiority for LABA/LAMAs in this regard, across different severities of exacerbation. ICS treatment has been perceived to be an essential part of exacerbation prevention strategies; FLAME shows an effective alternative strategy without ICS.

There is little evidence for exacerbation reduction when stepping up from two medications (either ICS/LABA or LAMA/LABA) to triple therapy (79), although there are benefits for lung function and patient-reported outcomes (80, 81). An RCT comparing ICS/LABA to LABA allowed concomitant tiotropium use; a subgroup analysis showed a 28% reduction in exacerbations comparing triple therapy to LABA plus LAMA (13). RCTs with triple therapy in a single inhaler are ongoing and will provide relevant data.

The phosphodiesterase 4 inhibitor roflumilast has broad antiinflammatory effects on different cell types (82). Roflumilast reduces exacerbation rates in patients with COPD with chronic bronchitis, severe airflow obstruction, and a previous history of exacerbations (83, 84). This precision medicine approach (3) targets a subgroup most likely to benefit. The biological rationale for this differential effect remains unclear, and the nature of this effect is under evaluation (85). Roflumilast improves FEV1 by approximately 50 to 80 ml in patients with COPD (86, 87) but without consistent benefits on symptoms (84, 87). Roflumilast can cause nausea, reduced appetite, gastrointestinal disturbance, and weight loss, so it is usually prescribed after better-tolerated inhaled treatments. A recent RCT confirmed that roflumilast decreased exacerbations in patients with COPD with chronic bronchitis on multiple inhaled medications (87), and in real life roflumilast may decrease readmission rates in patients hospitalized for COPD (88). Further work is needed to improve our understanding of the narrowly defined patient populations where the clinical benefit of roflumilast is greatest, and attempts at altering the dosage regimen to minimize side effects are ongoing (89).

Macrolides have immunomodulatory and antibacterial effects (90, 91). Two systematic reviews of COPD RCTs confirmed a significant reduction in exacerbation rates with macrolide therapy (92, 93). The most compelling data are for azithromycin therapy (94, 95), although the optimal dosage is unclear, as daily and three times weekly dosing both demonstrate efficacy (90). The patient population most likely to benefit has not been identified (93). A post hoc analysis of the largest trial suggests an increased likelihood of benefit in older patients with milder disease and ex-smokers (96). The potential risks include hearing loss (94) and prolonged QTc interval, raising concerns about cardiovascular safety (97). Population-based studies have provided contradictory evidence regarding cardiovascular safety (98, 99). Some have suggested that chronic macrolide therapy be avoided in patients with COPD at increased risk for arrhythmia (90, 97). Long-term azithromycin therapy may result in new azithromycin-resistant nasopharyngeal bacterial strains (94) and cause increased azithromycin resistance in sputum bacterial isolates after just 3 months’ treatment (100). A practical approach is to use macrolides in patients with ongoing exacerbations despite triple therapy (95). However, this strategy does not target a likely responder subgroup or address concerns regarding antibiotic resistance.

RCTs evaluating mucolytics have varied greatly in their inclusion criteria (e.g., presence of chronic bronchitis, use of inhaled treatments) and exacerbation definition. Nevertheless, a systematic review suggests an effect on exacerbation reduction (101). Important questions remain regarding the effect of mucolytics in non-Asian populations (102), at varying doses (103), and when associated to optimal concomitant therapies (104).

An FEV1-free approach appears reasonable (provided that the diagnosis is confirmed using spirometry), targeting pharmacotherapy toward symptoms (impact) and exacerbations (activity). These are clinically recognizable treatable traits (105). Personalized approaches targeting uncontrolled treatable traits can be further developed to include biomarker measurements that provide information on underlying mechanisms (endotypes) and/or disease activity. The historic and current approaches to COPD pharmacotherapy have used FEV1 and clinical phenotyping, respectively, to guide treatment choices (5); Figure 3 summarizes the evolution to a more personalized approach on the basis of treatable traits plus biomarkers.

Let us consider the example of persistent bacterial colonization (an endotype) associated with increased exacerbations (clinical phenotype, disease activity marker, and treatable trait); biomarker development to identify patients who would respond best to pharmacotherapies such as macrolides would be of value. Similarly, identifying patients with repeated exacerbations of a specific endotype (e.g., bacterial infection vs. eosinophilic inflammation) may allow more effective targeting of preventive treatments (i.e., bronchodilators ± macrolides vs. ICS-containing regimen). This may prove difficult, because exacerbation mechanisms can change from one exacerbation to the next. Another example is emphysema (clinical phenotype and treatable trait); the development of biomarkers, possibly sRAGE (39), may identify patients with greater disease activity who would benefit from future pharmacological treatments targeting specific mechanisms (endotypes) involved in tissue destruction.

COPD RCTs have not generally enrolled patients with GOLD stage I disease (FEV1 > 80% predicted). There is a high symptom burden in some patients with GOLD I disease (106) and some smokers without airflow obstruction (107). The efficacy of COPD treatments within this subgroup should be addressed to develop personalized approaches.

The new inhaled therapies for patients with COPD in recent years have been confined to existing classes (LAMA, LABA, ICS). Although it is disappointing that no novel classes have been introduced, there is scope to develop a more personalized use of these existing medicines within our current practice. This is helped by evidence from head-to-head studies of different classes (28, 71, 72, 77, 78), which are changing the way that we view bronchodilators and ICS. New evidence suggesting that LABA/LAMA combinations may be more effective than ICS/LABAs for exacerbation prevention make the differential diagnosis between asthma and COPD even more important (28), because ICSs remain the cornerstone of asthma maintenance therapy. Physicians should not label a patient as having asthma–COPD overlap without performing the required investigations.

In the near future, we need measurements of endotypes and disease activity for the development of COPD drugs with novel mechanisms of action. These drugs will likely only show a satisfactory benefit-versus-risk ratio in narrowly defined subgroups, and we need to develop the tools to define these subgroups.

1. Agusti A, Calverley PM, Celli B, Coxson HO, Edwards LD, Lomas DA, MacNee W, Miller BE, Rennard S, Silverman EK, et al.; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010;11:122.
2. Agusti A. The path to personalised medicine in COPD. Thorax 2014;69:857864.
3. Woodruff PG, Agusti A, Roche N, Singh D, Martinez FJ. Current concepts in targeting chronic obstructive pulmonary disease pharmacotherapy: making progress towards personalised management. Lancet 2015;385:17891798.
4. Han MK, Agusti A, Calverley PMA, Celli BR, Criner G, Curtis JL, Fabbri LM, Goldin JG, Jones PW, Macnee W, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med 2010;182:598604.
5. Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013;187:347365.
6. Miravitlles M, Vogelmeier C, Roche N, Halpin D, Cardoso J, Chuchalin AG, Kankaanranta H, Sandström T, Śliwiński P, Zatloukal J, et al. A review of national guidelines for management of COPD in Europe. Eur Respir J 2016;47:625637.
7. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med 2015;372:793795.
8. Jones PW, Donohue JF, Nedelman J, Pascoe S, Pinault G, Lassen C. Correlating changes in lung function with patient outcomes in chronic obstructive pulmonary disease: a pooled analysis. Respir Res 2011;12:161.
9. Martin AL, Marvel J, Fahrbach K, Cadarette SM, Wilcox TK, Donohue JF. The association of lung function and St. George’s respiratory questionnaire with exacerbations in COPD: a systematic literature review and regression analysis. Respir Res 2016;17:40.
10. Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C; TRial of Inhaled STeroids ANd long-acting β2 agonists study group. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003;361:449456.
11. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775789.
12. Calverley PMA, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 2003;22:912919.
13. Wedzicha JA, Singh D, Vestbo J, Paggiaro PL, Jones PW, Bonnet-Gonod F, Cohuet G, Corradi M, Vezzoli S, Petruzzelli S, et al.; FORWARD Investigators. Extrafine beclomethasone/formoterol in severe COPD patients with history of exacerbations. Respir Med 2014;108:11531162.
14. Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J, Wachtel A, Martinez FJ, Barnhart F, Sanford L, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med 2013;1:210223.
15. Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, Miller B, Lomas DA, Agusti A, Macnee W, et al.; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010;363:11281138.
16. Han MK, Muellerova H, Curran-Everett D, Dransfield M, Washko G, Regan EA, Bowler R, Beaty TH, Hokanson JE, Lynch DA, et al. GOLD 2011 disease severity classification in COPDGene: a prospective cohort study. Lancet Respir Med 2013;1:4350.
17. Beeh KM, Singh D, Di Scala L, Drollmann A. Once-daily NVA237 improves exercise tolerance from the first dose in patients with COPD: the GLOW3 trial. Int J Chron Obstruct Pulmon Dis 2012;7:503513.
18. Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M, Investigators US; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359:15431554.
19. Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP; UPLIFT investigators. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet 2009;374:11711178.
20. Decramer M, Dahl R, Kornmann O, Korn S, Lawrence D, McBryan D. Effects of long-acting bronchodilators in COPD patients according to COPD severity and ICS use. Respir Med 2013;107:223232.
21. Bleecker ER, Emmett A, Crater G, Knobil K, Kalberg C. Lung function and symptom improvement with fluticasone propionate/salmeterol and ipratropium bromide/albuterol in COPD: response by beta-agonist reversibility. Pulm Pharmacol Ther 2008;21:682688.
22. Hanania NA, Sharafkhaneh A, Celli B, Decramer M, Lystig T, Kesten S, Tashkin D. Acute bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT trial. Respir Res 2011;12:6.
23. Singh D, Zhu CQ, Sharma S, Church A, Kalberg CJ. Daily variation in lung function in COPD patients with combined albuterol and ipratropium: results from a 4-week, randomized, crossover study. Pulm Pharmacol Ther 2015;31:8591.
24. Agusti A, Fabbri LM. Inhaled steroids in COPD: when should they be used? Lancet Respir Med 2014;2:869871.
25. Soriano JB, Lamprecht B, Ramírez AS, Martinez-Camblor P, Kaiser B, Alfageme I, Almagro P, Casanova C, Esteban C, Soler-Cataluña JJ, et al. Mortality prediction in chronic obstructive pulmonary disease comparing the GOLD 2007 and 2011 staging systems: a pooled analysis of individual patient data. Lancet Respir Med 2015;3:443450.
26. Agusti A, Gea J, Faner R. Biomarkers, the control panel and personalized COPD medicine. Respirology 2016;21:2433.
27. Agustí A, Celli B. Avoiding confusion in COPD: from risk factors to phenotypes to measures of disease characterisation. Eur Respir J 2011;38:749751.
28. Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, Thach C, Fogel R, Patalano F, Vogelmeier CF; FLAME Investigators. Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med 2016;374:22222234.
29. Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE, Sandström T, Taylor AF, D’Andrea P, Arrasate C, Chen H, Banerji D. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med 2013;1:199209.
30. Vestbo J, Edwards LD, Scanlon PD, Yates JC, Agusti A, Bakke P, Calverley PM, Celli B, Coxson HO, Crim C, et al.; ECLIPSE Investigators. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med 2011;365:11841192.
31. Lange P, Celli B, Agustí A, Boje Jensen G, Divo M, Faner R, Guerra S, Marott JL, Martinez FD, Martinez-Camblor P, et al. Lung-function trajectories leading to chronic obstructive pulmonary disease. N Engl J Med 2015;373:111122.
32. Celli BR, Thomas NE, Anderson JA, Ferguson GT, Jenkins CR, Jones PW, Vestbo J, Knobil K, Yates JC, Calverley PM. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit Care Med 2008;178:332338.
33. Vestbo J, Anderson JA, Brook RD, Calverley PM, Celli BR, Crim C, Martinez F, Yates J, Newby DE, Investigators S; SUMMIT Investigators. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial. Lancet 2016;387:18171826.
34. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002;57:847852.
35. Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS, Conway WA Jr, Enright PL, Kanner RE, O’Hara P, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1: the Lung Health Study. JAMA 1994;272:14971505.
36. Miller BE, Tal-Singer R, Rennard SI, Furtwaengler A, Leidy N, Lowings M, Martin UJ, Martin TR, Merrill DD, Snyder J, et al.; Perspective of the Chronic Obstructive Pulmonary Disease Biomarker Qualification Consortium. Plasma fibrinogen qualification as a drug development tool in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2016;193:607613.
37. Park HY, Churg A, Wright JL, Li Y, Tam S, Man SF, Tashkin D, Wise RA, Connett JE, Sin DD. Club cell protein 16 and disease progression in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;188:14131419.
38. Lomas DA, Silverman EK, Edwards LD, Miller BE, Coxson HO, Tal-Singer R; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators. Evaluation of serum CC-16 as a biomarker for COPD in the ECLIPSE cohort. Thorax 2008;63:10581063.
39. Yonchuk JG, Silverman EK, Bowler RP, Agustí A, Lomas DA, Miller BE, Tal-Singer R, Mayer RJ. Circulating soluble receptor for advanced glycation end products (sRAGE) as a biomarker of emphysema and the RAGE axis in the lung. Am J Respir Crit Care Med 2015;192:785792.
40. Agustí A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE, Vestbo J, Lomas DA, Calverley PM, Wouters E, et al.; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS One 2012;7:e37483.
41. Celli BR, Locantore N, Yates J, Tal-Singer R, Miller BE, Bakke P, Calverley P, Coxson H, Crim C, Edwards LD, et al.; ECLIPSE Investigators. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;185:10651072.
42. Thomsen M, Ingebrigtsen TS, Marott JL, Dahl M, Lange P, Vestbo J, Nordestgaard BG. Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease. JAMA 2013;309:23532361.
43. Singh D. New combination bronchodilators for chronic obstructive pulmonary disease: current evidence and future perspectives. Br J Clin Pharmacol 2015;79:695708.
44. Singh D, Jones PW, Bateman ED, Korn S, Serra C, Molins E, Caracta C, Gil EG, Leselbaum A. Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study. BMC Pulm Med 2014;14:178.
45. Bateman ED, Ferguson GT, Barnes N, Gallagher N, Green Y, Henley M, Banerji D. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J 2013;42:14841494.
46. Donohue JF, Maleki-Yazdi MR, Kilbride S, Mehta R, Kalberg C, Church A. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med 2013;107:15381546.
47. Jones PW, Beeh KM, Chapman KR, Decramer M, Mahler DA, Wedzicha JA. Minimal clinically important differences in pharmacological trials. Am J Respir Crit Care Med 2014;189:250255.
48. Singh D, Ferguson GT, Bolitschek J, Grönke L, Hallmann C, Bennett N, Abrahams R, Schmidt O, Bjermer L. Tiotropium + olodaterol shows clinically meaningful improvements in quality of life. Respir Med 2015;109:13121319.
49. Mahler DA, Decramer M, D’Urzo A, Worth H, White T, Alagappan VK, Chen H, Gallagher N, Kulich K, Banerji D. Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study. Eur Respir J 2014;43:15991609.
50. Bateman ED, Chapman KR, Singh D, D’Urzo AD, Molins E, Leselbaum A, Gil EG. Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT). Respir Res 2015;16:92.
51. Bafadhel M, McKenna S, Terry S, Mistry V, Reid C, Haldar P, McCormick M, Haldar K, Kebadze T, Duvoix A, et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med 2011;184:662671.
52. Wedzicha JA, Decramer M, Seemungal TA. The role of bronchodilator treatment in the prevention of exacerbations of COPD. Eur Respir J 2012;40:15451554.
53. Festic E, Scanlon PD. Incident pneumonia and mortality in patients with chronic obstructive pulmonary disease: a double effect of inhaled corticosteroids? Am J Respir Crit Care Med 2015;191:141148.
54. Crim C, Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J, Wachtel A, Martinez FJ, Barnhart F, et al. Pneumonia risk with inhaled fluticasone furoate and vilanterol compared with vilanterol alone in patients with COPD. Ann Am Thorac Soc 2015;12:2734.
55. Dong YH, Chang CH, Lin Wu FL, Shen LJ, Calverley PM, Löfdahl CG, Lai MS, Mahler DA. Use of inhaled corticosteroids in patients with COPD and the risk of TB and influenza: a systematic review and meta-analysis of randomized controlled trials. a systematic review and meta-analysis of randomized controlled trials. Chest 2014;145:12861297.
56. Lee CH, Kim K, Hyun MK, Jang EJ, Lee NR, Yim JJ. Use of inhaled corticosteroids and the risk of tuberculosis. Thorax 2013;68:11051113.
57. Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and the risks of diabetes onset and progression. Am J Med 2010;123:10011006.
58. Loke YK, Cavallazzi R, Singh S. Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies. Thorax 2011;66:699708.
59. Wang JJ, Rochtchina E, Tan AG, Cumming RG, Leeder SR, Mitchell P. Use of inhaled and oral corticosteroids and the long-term risk of cataract. Ophthalmology 2009;116:652657.
60. Pauwels RA, Löfdahl CG, Laitinen LA, Schouten JP, Postma DS, Pride NB, Ohlsson SV; European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med 1999;340:19481953.
61. Brightling CE, McKenna S, Hargadon B, Birring S, Green R, Siva R, Berry M, Parker D, Monteiro W, Pavord ID, et al. Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease. Thorax 2005;60:193198.
62. Brightling CE, Monteiro W, Ward R, Parker D, Morgan MD, Wardlaw AJ, Pavord ID. Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2000;356:14801485.
63. Singh D, Kolsum U, Brightling CE, Locantore N, Agusti A, Tal-Singer R; ECLIPSE investigators. Eosinophilic inflammation in COPD: prevalence and clinical characteristics. Eur Respir J 2014;44:16971700.
64. Siddiqui SH, Guasconi A, Vestbo J, Jones P, Agusti A, Paggiaro P, Wedzicha JA, Singh D. Blood eosinophils: a biomarker of response to extrafine beclomethasone/formoterol in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015;192:523525.
65. Pavord ID, Lettis S, Locantore N, Pascoe S, Jones PW, Wedzicha JA, Barnes NC. Blood eosinophils and inhaled corticosteroid/long-acting β-2 agonist efficacy in COPD. Thorax 2016;71:118125.
66. Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord ID. Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med 2015;3:435442.
67. Watz H, Tetzlaff K, Wouters EF, Kirsten A, Magnussen H, Rodriguez-Roisin R, Vogelmeier C, Fabbri LM, Chanez P, Dahl R, et al. Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial. Lancet Respir Med 2016;4:390398.
68. Barnes NC, Sharma R, Lettis S, Calverley PM. Blood eosinophils as a marker of response to inhaled corticosteroids in COPD. Eur Respir J 2016;47:13741382.
69. Vedel-Krogh S, Nielsen SF, Lange P, Vestbo J, Nordestgaard BG. Blood eosinophils and exacerbations in chronic obstructive pulmonary disease: the Copenhagen General Population Study. Am J Respir Crit Care Med 2016;193:965974.
70. Dransfield MT, Bailey W, Crater G, Emmett A, O’Dell DM, Yawn B. Disease severity and symptoms among patients receiving monotherapy for COPD. Prim Care Respir J 2011;20:4653.
71. Singh D, Worsley S, Zhu CQ, Hardaker L, Church A. Umeclidinium/vilanterol versus fluticasone propionate/salmeterol in COPD: a randomised trial. BMC Pulm Med 2015;15:91.
72. Vogelmeier CF, Bateman ED, Pallante J, Alagappan VK, D’Andrea P, Chen H, Banerji D. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respir Med 2013;1:5160.
73. Jones PW, Lamarca R, Chuecos F, Singh D, Agustí A, Bateman ED, de Miquel G, Caracta C, Garcia Gil E. Characterisation and impact of reported and unreported exacerbations: results from ATTAIN. Eur Respir J 2014;44:11561165.
74. Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:14181422.
75. Donaldson GC, Law M, Kowlessar B, Singh R, Brill SE, Allinson JP, Wedzicha JA. Impact of prolonged exacerbation recovery in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015;192:943950.
76. Bateman E, Singh D, Smith D, Disse B, Towse L, Massey D, Blatchford J, Pavia D, Hodder R. Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies. Int J Chron Obstruct Pulmon Dis 2010;5:197208.
77. Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA, Investigators I; INSPIRE Investigators. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med 2008;177:1926.
78. Zhong N, Wang C, Zhou X, Zhang N, Humphries M, Wang L, Thach C, Patalano F, Banerji D, Investigators L; LANTERN Investigators. LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD. Int J Chron Obstruct Pulmon Dis 2015;10:10151026.
79. Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M, O’Donnell D, McIvor A, Sharma S, et al.; Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2007;146:545555.
80. Frith PA, Thompson PJ, Ratnavadivel R, Chang CL, Bremner P, Day P, Frenzel C, Kurstjens N, Group GS; Glisten Study Group. Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN study, a randomised controlled trial. Thorax 2015;70:519527.
81. Singh D, Brooks J, Hagan G, Cahn A, O’Connor BJ. Superiority of “triple” therapy with salmeterol/fluticasone propionate and tiotropium bromide versus individual components in moderate to severe COPD. Thorax 2008;63:592598.
82. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol 2011;163:5367.
83. Rennard SI, Calverley PM, Goehring UM, Bredenbröker D, Martinez FJ. Reduction of exacerbations by the PDE4 inhibitor roflumilast: the importance of defining different subsets of patients with COPD. Respir Res 2011;12:18.
84. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ; M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374:685694.
85. Barnes NC, Saetta M, Rabe KF. Implementing lessons learned from previous bronchial biopsy trials in a new randomized controlled COPD biopsy trial with roflumilast. BMC Pulm Med 2014;14:9.
86. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF; M2-127 and M2-128 study groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009;374:695703.
87. Martinez FJ, Calverley PM, Goehring UM, Brose M, Fabbri LM, Rabe KF. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet 2015;385:857866.
88. Fu AZ, Sun SX, Huang X, Amin AN. Lower 30-day readmission rates with roflumilast treatment among patients hospitalized for chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2015;10:909915.
89. Hwang H, Shin JY, Park KR, Shin JO, Song KH, Park J, Park JW. Effect of a dose-escalation regimen for improving adherence to roflumilast in patients with chronic obstructive pulmonary disease. Tuberc Respir Dis (Seoul) 2015;78:321325.
90. Parameswaran GI, Sethi S. Long-term macrolide therapy in chronic obstructive pulmonary disease. CMAJ 2014;186:11481152.
91. Gualdoni GA, Lingscheid T, Schmetterer KG, Hennig A, Steinberger P, Zlabinger GJ. Azithromycin inhibits IL-1 secretion and non-canonical inflammasome activation. Sci Rep 2015;5:12016.
92. Donath E, Chaudhry A, Hernandez-Aya LF, Lit L. A meta-analysis on the prophylactic use of macrolide antibiotics for the prevention of disease exacerbations in patients with chronic obstructive pulmonary disease. Respir Med 2013;107:13851392.
93. Ni W, Shao X, Cai X, Wei C, Cui J, Wang R, Liu Y. Prophylactic use of macrolide antibiotics for the prevention of chronic obstructive pulmonary disease exacerbation: a meta-analysis. PLoS One 2015;10:e0121257.
94. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, et al.; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689698.
95. Uzun S, Djamin RS, Kluytmans JA, Mulder PG, van’t Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2014;2:361368.
96. Han MK, Tayob N, Murray S, Dransfield MT, Washko G, Scanlon PD, Criner GJ, Casaburi R, Connett J, Lazarus SC, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med 2014;189:15031508.
97. Albert RK, Schuller JL, Network CCR; COPD Clinical Research Network. Macrolide antibiotics and the risk of cardiac arrhythmias. Am J Respir Crit Care Med 2014;189:11731180.
98. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012;366:18811890.
99. Svanström H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med 2013;368:17041712.
100. Brill SE, Law M, El-Emir E, Allinson JP, James P, Maddox V, Donaldson GC, McHugh TD, Cookson WO, Moffatt MF, et al. Effects of different antibiotic classes on airway bacteria in stable COPD using culture and molecular techniques: a randomised controlled trial. Thorax 2015;70:930938.
101. Cazzola M, Calzetta L, Page C, Jardim J, Chuchalin AG, Rogliani P, Matera MG. Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis. Eur Respir Rev 2015;24:451461.
102. Cazzola M, Matera MG. N-acetylcysteine in COPD may be beneficial, but for whom? Lancet Respir Med 2014;2:166167.
103. Shen Y, Cai W, Lei S, Zhang Z. Effect of high/low dose N-acetylcysteine on chronic obstructive pulmonary disease: a systematic review and meta-analysis. COPD 2014;11:351358.
104. Turner RD, Bothamley GH. N-acetylcysteine for COPD: the evidence remains inconclusive. Lancet Respir Med 2014;2:e3.
105. Agusti A, Bel E, Thomas M, Vogelmeier C, Brusselle G, Holgate S, Humbert M, Jones P, Gibson PG, Vestbo J, et al. Treatable traits: toward precision medicine of chronic airway diseases. Eur Respir J 2016;47:410419.
106. Mannino DM, Doherty DE, Sonia Buist A. Global Initiative on Obstructive Lung Disease (GOLD) classification of lung disease and mortality: findings from the Atherosclerosis Risk in Communities (ARIC) study. Respir Med 2006;100:115122.
107. Woodruff PG, Barr RG, Bleecker E, Christenson SA, Couper D, Curtis JL, Gouskova NA, Hansel NN, Hoffman EA, Kanner RE, et al.; SPIROMICS Research Group. Clinical significance of symptoms in smokers with preserved pulmonary function. N Engl J Med 2016;374:18111821.
Correspondence and requests for reprints should be addressed to Dave Singh, M.D., Centre for Respiratory Medicine and Allergy, Medicines Evaluation Unit, University of Manchester and University Hospital of South Manchester, Manchester M23 9QZ, UK. E-mail:

Originally Published in Press as DOI: 10.1164/rccm.201606-1179PP

Author disclosures are available with the text of this article at


No related items
Comments Post a Comment

New User Registration

Not Yet Registered?
Benefits of Registration Include:
 •  A Unique User Profile that will allow you to manage your current subscriptions (including online access)
 •  The ability to create favorites lists down to the article level
 •  The ability to customize email alerts to receive specific notifications about the topics you care most about and special offers
American Journal of Respiratory and Critical Care Medicine

Click to see any corrections or updates and to confirm this is the authentic version of record