Mol Diagn Ther DOI 10.1007/s40291-014-0100-9

REVIEW ARTICLE

Defining Phenotypes in COPD: An Aid to Personalized Healthcare Andrea Segreti • Emanuele Stirpe Paola Rogliani • Mario Cazzola

•

Ó Springer International Publishing Switzerland 2014

Abstract The diagnosis of chronic obstructive pulmonary disease (COPD) is based on a post-bronchodilator fixed forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) \70 % ratio and the presence of symptoms such as shortness of breath and productive cough. Despite the simplicity in making a diagnosis of COPD, this morbid condition is very heterogeneous, and at least three different phenotypes can be recognized: the exacerbator, the emphysema–hyperinflation and the overlap COPD–asthma. These subgroups show different clinical and radiological features. It has been speculated that there is an enormous variability in the response to drugs among the COPD phenotypes, and it is expected that subjects with the same phenotype will have a similar response to each specific treatment. We believe that phenotyping COPD patients would be very useful to predict the response to a treatment and the progression of the disease. This personalized approach allows identification of the right treatment for each COPD patient, and at the same time, leads to improvement in the effectiveness of therapies, avoidance of treatments not indicated, and reduction in the onset of adverse effects. The objective of the present review is to report the current knowledge about different COPD phenotypes, focusing on specific treatments for each subgroup. However, at present, COPD phenotypes have not been studied by

randomized clinical trials and therefore we hope that well designed studies will focus on this topic.

Key Points Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease or disorder. It is important to classify and group patients, as subjects within the same subgroup/phenotype are likely to have a similar progression of disease and response to treatments. There are three different COPD phenotypes: the exacerbator, the emphysema–hyperinflation and the overlap COPD–asthma. The development of different pharmacological and non-pharmacological treatment options has proven that clinical response differs according to the characteristics of the disease. Although a specific therapy may not yet be identified for each phenotype, there is a clear need to move toward personalized treatment of COPD.

1 Introduction

A. Segreti
E. Stirpe
P. Rogliani
M. Cazzola (&) Unit of Respiratory Medicine, Department of System Medicine, University of Rome Tor Vergata, via Montpellier 1, 00131 Rome, Italy e-mail: [email protected]

Chronic obstructive pulmonary disease (COPD), a complex syndrome with many pulmonary and extra-pulmonary components, includes different phenotypes, defined as ‘‘a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression, or

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death)’’ [1]. As recommended by Global Initiative for Chronic Obstructive Lung Diseases (GOLD) guidelines, diagnosis of COPD is very easy because it is based on a reduced post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio below the fixed value of 70 % [2]. However, COPD is a heterogeneous disease, likely a disorder. Celli and colleagues hypothesized that FEV1 is not enough to estimate severity of COPD, and that a multidimensional approach would better grade the disease and predict the outcome with respect to the use of the FEV1 alone [3]. Therefore, it is important to group patients in phenotypes because subjects included in the same subgroup/phenotype are expected to have similar disease, progression of disease and response to treatments. According to classification of Miravitlles and colleagues, it is possible to identify at least three different COPD phenotypes: the exacerbator, the emphysema– hyperinflation and the overlap COPD–asthma [1]. Frequent exacerbators are patients that experience two or more exacerbations of COPD per year [4], and have typically chronic bronchitis, defined clinically as chronic productive cough for 3 months in each of 2 successive years in a patient in whom other causes of productive chronic cough have been excluded [5]. The emphysema–hyperinflation phenotype is characterized by parenchymal destruction with consequent hyperinflation, and dyspnea and intolerance to exercise are the predominating symptoms [1]. Emphysema is defined pathologically as the presence of permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis [6]. The third phenotype, COPD–asthma overlap syndrome, is characterized by incompletely reversible airflow obstruction (COPD), i.e., reduced post-bronchodilator FEV1, in addition to an increased variability of airflow, which can be determined by increased bronchodilator responsiveness or bronchial hyper-responsiveness [7]. It has been speculated that clinical features of different COPD phenotypes may be associated with morphological changes at chest high-resolution computed tomography (HRCT) and a different response to treatments, including inhaled corticosteroids (ICSs) and bronchodilators [8]. As a matter of fact, Kitaguchi and colleagues demonstrated that COPD patients with A phenotype (without emphysema) and M phenotype (emphysema with bronchial wall thickening), compared with E phenotype (emphysema without bronchial wall thickening), were significantly associated with reversibility response to treatment with ICSs and sputum eosinophilia, suggesting that the morphological phenotypes of COPD show several clinical characteristics and different responsiveness to pharmacological treatments [9]. A summary of principal features of each phenotype is reported in Table 1.

2 Phenotyping Chronic Obstructive Pulmonary Disease (COPD) 2.1 Frequent Exacerbator Phenotype Exacerbations of COPD have an important role in the natural history of the disease. An exacerbation of COPD is defined as ‘‘a sustained worsening of the patient’s condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD’’ [10]. Exacerbations in 50–70 % of cases are due to respiratory infections (including bacteria, atypical organisms and respiratory viruses), in 10 % are due to environmental pollution (depending on season and geographical placement), and up to 30 % are of unknown etiology [11]. In the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) observational study, exacerbations were more frequent and more severe with the progression of COPD, and the variable most strongly associated with exacerbations during the first year of follow-up was a history of exacerbations [4]. According to GOLD guidelines, patients in group C and D are at high risk of exacerbations. Both groups typically include patients with severe and very severe airflow limitation, but patients in group D have more symptoms than those included in group C [2]. However, the ECLIPSE study has documented that frequent exacerbations can also be present in those patients with an FEV1 higher than 50 % predicted [4]. The pathophysiology underlying the frequent exacerbator phenotype includes increased airway and systemic inflammation, dynamic lung hyperinflation, changes in lower airway bacterial colonization, increased susceptibility to viral infection and increased risk from comorbid extrapulmonary diseases [12]. A post-hoc analysis of the POET-COPD (Prevention Of Exacerbations with Tiotropium in COPD) trial showed that the frequent exacerbator phenotype was closely associated with exacerbation-related hospitalizations, which in turn were associated with poorer survival [13]. These data suggest that it is mandatory to properly treat this distinct clinical subgroup, to reduce the risk of future exacerbations. In accordance with GOLD guidelines, the first-choice treatment of patients at high risk of exacerbations includes a fixed combination of ICS plus long-acting b2-agonist (LABA) and/or long-acting muscarinic antagonist (LAMA) [2]. ICSs are indicated in patients with more severe disease and frequent exacerbations, and their use in stable COPD improves lung function, decreases the rate of exacerbations, and seems to improve the survival when combined with bronchodilators, but must be weighed against the potential for increased vulnerability to pneumonia [14].

COPD Phenotypes Table 1 Principal characteristics of COPD phenotypes Phenotype

Pathophysiological features

Imaging features

Frequent exacerbator

Two or more exacerbations of COPD per year

Bronchial wall thickening

Key treatments Inhaled corticosteroids Bronchodilators

Presence of chronic bronchitis

Roflumilast Bacterial lysates

Emphysema–hyperinflated

Parenchymal destruction with consequent hyperinflation

Emphysema

Bronchodilators Lung volume reduction surgery

Dyspnea and intolerance to exercise are the predominating symptoms

Pulmonary rehabilitation programs

Reduced diffusing capacity (KCO) Low rate of exacerbations Asthma–COPD overlap

Incompletely reversible airflow obstruction (COPD) Increased variability of airflow Increased levels of sputum eosinophils

Mixed features of asthma and COPD, i.e., bronchial wall thickening and emphysema

Bronchodilators Inhaled corticosteroids Other therapies generally used for treatment of asthma and COPD (e.g., omalizumab, antileukotrienes and theophyllines)

Preserved diffusing capacity (KCO) Low rate of exacerbations COPD chronic obstructive pulmonary disease, KCO carbon monoxide transfer coefficient

Bronchodilators are used to improve COPD symptoms such as dyspnea, and reduce hyperinflation secondary to airflow limitation. However, recent studies suggest that bronchodilators may also decrease the risk of COPD exacerbations, reducing the lung hyperinflation and increasing inspiratory capacity, and it is also possible that they exert direct or indirect effects on lung inflammation [15]. Another treatment option for this subgroup of patients might be the administration of roflumilast. This oral antiinflammatory drug is a highly selective phosphodiesterase4 (PDE-4) inhibitor, and its use is indicated for treatment of severe COPD associated with chronic bronchitis and frequent exacerbations, as an add-on to bronchodilators [16]. Two placebo-controlled, double-blind, randomized clinical trials have shown that roflumilast 500 lg daily can reduce the rate of exacerbations in COPD patients with severe airflow limitation [17]. In a post-hoc analysis of pooled data from two 1-year, placebo-controlled roflumilast (500 lg once daily) studies in patients with symptomatic COPD and severe airflow obstruction published by Wedzicha and colleagues, 32 % of COPD patients treated with roflumilast still experienced frequent exacerbations at year 1 compared with 40.8 % of patients treated with placebo. The authors concluded that treatment with roflumilast may shift patients from the frequent to the more stable infrequent exacerbator state [18]. This finding could question the existence of a frequent exacerbator phenotype. Another important aspect to consider is that lower airway bacterial colonization in stable COPD patients can

induce bronchial inflammation and infections, and consequently can modulate the character and frequency of exacerbations [19]. For this reason, a long-term administration of antibacterials to prevent exacerbations of COPD has been advocated. Different clinical trials have demonstrated that floroquinolones and macrolides have antinflammatory and immunomodulatory effects, and their administration was associated with a reduction in COPD exacerbations [20–24]. However, currently there is inadequate evidence to recommend routine prophylactic longterm antibacterial therapy in this group of patients to prevent exacerbations [25]. The analysis of literature also suggests that the use of bacterial lysates represents a potentially effective approach in preventing exacerbations of COPD, but almost all trials conducted to date have been of poor quality and, above all, poorly designed [26]. 2.2 COPD–Emphysema Phenotype Emphysema is defined pathologically as the presence of permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis [6]. Subjects with documented emphysema have lower FEV1, FEV1/FVC ratio, and lower carbon monoxide transfer coefficient (KCO) compared with subjects without emphysema and, in chest radiograph and HRCT scan, emphysema scores are higher and, conversely, chronic bronchitis scores are lower. Dyspnea, exercise intolerance and lower body mass index (BMI) are the clinical hallmarks of this phenotype [27].

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Hyperinflation is usually considered to be an elevation above normal values of resting functional residual capacity (FRC) or end expiratory lung volume (EELV), and is caused by both static and dynamic processes. The reduction in elastic recoil due to emphysema is responsible for static hyperinflation, while dynamic hyperinflation occurs when minute ventilation is enhanced to accommodate increased respiratory demands [28]. The phenotype characterized by emphysema without bronchial wall thickening presents a lower rate of exacerbations compared with COPD phenotypes characterized by emphysema with bronchial wall thickening, and bronchial wall thickening in absence of emphysema [8]. These data indicate that the COPD–emphysema phenotype is less prone to experiencing exacerbations of COPD unless it is present simultaneously with bronchial wall thickening, a feature of chronic bronchitis. Furthermore, it has been demonstrated that pulmonary hyperinflation is associated with low grade systemic inflammation. In fact, inspiratory capacity reduction, an index of an increase in residual volume, is associated with high serum levels of C Reactive Protein (CRP) in stable COPD patients [29]. Bronchodilators induce a relaxation of smooth muscle tone in airways and consequently reduce the flow limitation and promote lung emptying, as demonstrated by increase in inspiratory capacity and reduction of residual volume at spirometry [30]. Long-acting bronchodilators are the foundation of the pharmacological treatment of COPD because they improve symptoms, exercise capacity and, consequently, improve the state of health as perceived by the patient [31]. Other treatments such as pulmonary rehabilitation programs reduce lung hyperinflation and improve tolerance, gas exchange and perceived symptoms during effort [32]. The current guidelines recommend the use of more than one bronchodilator in order to achieve an additional effect, without increasing adverse effects in patients with poorly controlled symptoms in spite of treatment with a bronchodilator [2]. In COPD–emphysema phenotype patients, the use of double bronchodilator therapy versus bronchodilator monotherapy offers an added functional benefit with reduction of the rescue medication needed, and improvement of symptoms and quality of life [33]. Anti-inflammatory treatment with ICSs and roflumilast has not been shown to be as effective in the emphysema–hyperinflation phenotype [34, 35]. Lung volume reduction surgery (LVRS) may be particularly indicated in COPD patients with emphysema–hyperinflation. The NETT (National Emphysema Treatment Trial) has provided substantial evidence that treating hyperinflation in emphysema can improve exercise tolerance, quality of life, and survival [36]. Lastly, pulmonary rehabilitation programs in patients with emphysema significantly improve exercise capacity, symptoms and quality of life [37].

2.3 Asthma–COPD Overlap Syndrome Phenotype Zeki and colleagues analyzed the prevalence of the various obstructive airway diseases in a small cohort of general pulmonary clinic patients and found that prevalence of asthma–COPD overlap syndrome was 15.8 % [38]. In another study, the utilization of a simple questionnaire showed that the overlap between asthma and COPD comprised about 20 % of patients with COPD, and that this syndrome included a higher proportion of COPD patients with atopy and smoking asthmatics [39]. It has been demonstrated that subjects with the overlapping diagnoses of COPD and asthma have increased disease severity, are more than three times as likely to be frequent exacerbators and nearly twice as likely to experience severe respiratory exacerbations, and have more gas trapping on expiratory chest CT scans and greater subsegmental wall area on inspiratory CT scans, compared with subjects with COPD alone [40]. Furthermore, patients with the overlap syndrome, in comparison with subjects with COPD alone, have higher peripheral and sputum eosinophil counts, preserved diffusing capacity, higher prevalence of bronchial thickening on chest HRCT and better reversibility response to treatment with ICS. In particular, the increases in FEV1 after treatment with ICS correlated significantly with sputum eosinophil counts and the grade of bronchial wall thickening [41]. COPD is characterized by neutrophilic inflammation, macrophages and CD4? and CD8?T cells [42]. However, it has been observed that in some patients with COPD (e.g., asthma-COPD overlap syndrome), the eosinophilic inflammation plays an important role as well. A randomized, double-blind, crossover study investigated whether the sputum characteristics of COPD patients were correlated with the response to 2 weeks of treatment with prednisolone. The authors of this study reported that patients with eosinophilic airway inflammation had a good response to corticosteroids [43], indicating that eosinophilic inflammation in COPD patients may be predictive of a response to steroid therapy. This hypothesis is supported by the observation that the minimization of the eosinophilic airway inflammation is associated with a reduction in severe exacerbations of COPD [44].

3 COPD Phenotypes and Biomarkers ‘‘A biomarker refers to the measurement of any molecule or material (e.g., cells, tissue) that reflects the disease process’’ [45]. An ideal biomarker should be lung-specific, reproducible, easy to assess in large numbers of patients, and validated in a large, well characterized cohort of patients and controls [46]. The identification of biomarkers

COPD Phenotypes

specific for each phenotype would facilitate the classification of COPD patients and would provide prognostic information and predict drug response [47]. The application of the -OMIC approach such as genomics, proteomics and metabolomics for the collection and analysis of data, might allow identification of robust, reliable and reproducible biomarkers in many human diseases, including COPD [48, 49]. In effect, the application of proteomics and metabolomics in COPD is already available and, in combination with genomic studies, will likely identify novel candidate biomarkers [50]. In the lungs of COPD patients there is an imbalance between oxidants and antioxidants, with resultant defective repair processes, DNA damage and lung injury [51]. The metabolomics profiles of volatile organic compounds (VOCs) were examined in the breath by an electronic nose, among the different COPD phenotypes. This study demonstrated that exhaled molecular profiling, combined with clinical features, functional parameters, and chest CT scanning, was able to distinguish between the different COPD subphenotypes [52]. Moreover, in another study, ultra-high-performance liquid chromatography/quadrupletime-of-flight mass spectrometry techniques were used to identify a large number of metabolite markers among different COPD phenotypes, and these predictive models were able to differentiate very accurately the subjects with the emphysematous phenotype of COPD from those with COPD without emphysema [53]. Another study performed in COPD patients assessed the association between serum concentrations of biomarkers with CT findings. Particularly, the presence of airway thickening was directly associated with levels of interleukin (IL)-6, IL-13, IL-2 receptor, interferon-gamma (IFNc) and CRP, but inversely correlated with epidermal growth factor receptor (EGFR) and regulated on activation normal T cell expressed and secreted (RANTES). Instead, biomarkers directly associated with the presence of emphysema were IL-6 and matrix metalloproteinase-7 (MMP-7), while tumor necrosis factoralpha (TNFa) was inversely related to emphysema severity [54]. Also, the number of eosinophils, MMP-9 and the MMP-9/tissue inhibitor of metalloproteinase-1 (TIMP-1) ratio in sputum were higher in COPD patients with HRCTconfirmed emphysema, compared with those without emphysema [55]. Moreover, patients with emphysema presented elevated concentrations of markers of systemic inflammation (i.e., serum systemic oxidative stress and plasma fibrinogen levels), compared with COPD patients without emphysema [56]. In the ECLIPSE study, some biomarkers, inter alia, an increase in platelet count, white-cell count, neutrophil count, and serum fibrinogen, high-sensitivity CRP, chemokine ligand 18 (CCL-18) and surfactant protein D (SPD), have been shown to predict acute exacerbations of

COPD [4]. In the same study, it was demonstrated that white-cell count and the systemic levels of IL-6, CRP, IL8, fibrinogen, CCL-18/pulmonary and activation-regulated chemokine (PARC) and SP-D were higher in patients who died during the 3-year period of follow-up. Moreover, nonsurvivors were older and had more severe airflow limitation, increased dyspnea, higher BODE score (BMI, airflow obstruction, dyspnea and exercise), more emphysema, and higher rates of comorbidities and history of hospitalizations [57]. Another interesting finding is that patients with asthma–COPD overlap syndrome had significantly lower blood concentrations of nitrites/nitrates (NOx), indicating decreased systemic oxidant activity in this group of patients compared with other phenotypes of COPD [58]. Again, in COPD patients, sputum concentrations of IL-5 were associated with sputum eosinophilia, a marker of asthma–COPD overlap syndrome, and were attenuated after oral corticosteroid therapy [59]. All these results confirm the usefulness of biomarkers in clinical practice, because they contribute to the classification of COPD patients into phenotypes, and help to predict response to therapy, disease progression and mortality.

4 Conclusions International guidelines try to simplify the diagnosis and treatment of patients affected by COPD. However, there is an enormous variability in the response to drugs between patients suffering from this morbid condition. In our opinion, the classification of COPD patients into subgroups provides prognostic information and it is expected that subjects with the same phenotype will have a similar response to each specific treatment. Publication of large trials such as TORCH (TOwards a Revolution in COPD Health) and UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) has refocused attention away from simply treating current symptoms and improving quality of life (current control) to focusing on preventing future exacerbations, reducing mortality and preventing disease progression (prevention of future risk) [60]. The GOLD and National Institute for Health and Care Excellence (NICE) guidelines estimate disease severity on the basis of multi-dimensional assessment. Inhaled bronchodilators are the cornerstone of pharmacotherapy in both sets of guidelines, with combined ICS/LABA inhalers being reserved for more severe disease. Smoking cessation and pulmonary rehabilitation remain key interventions, with NICE recommending pulmonary rehabilitation at hospital discharge after an acute exacerbation of COPD [2, 61]. The concept of phenotype applied to COPD focuses on the definition of different types of patients with prognostic

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and therapeutic significance: the varied host response and heterogeneous nature of COPD can explain failure of treatment. Identification and targeted treatment of clinical and pathological phenotypes within the broad spectrum of COPD may therefore improve the outcomes [62]. The goal of phenotyping is to identify patient groups with unique prognostic or therapeutic characteristics. Although this approach represents an ideal construct, it is known that each phenotype may be etiologically heterogeneous and that any individual may manifest multiple phenotypes [63]. For this reason, it is fundamental to identify the characteristics of patients that predict response to drugs used to manage COPD. Individualized therapy allows administration of the right treatment to the right patient, increasing, in this way, the subject’s response to therapy, avoiding treatments not indicated and reducing the onset of adverse effects. The development of different pharmacological and nonpharmacological treatment options has demonstrated that the clinical response can be different according to the characteristics of the disease [1]. Although a specific therapy may not be ultimately identified for each phenotype, there is a clear need to move toward personalized treatment in COPD, although we must honestly admit that, unlike in asthma, in COPD the need for personalized medicines is not currently clearly defined [64]. A better understanding of the multiple dimensions of COPD and its relationship to other diseases is very relevant and of high current interest. Recent theoretical (scale-free networks), technological (high-throughput technology, biocomputing) and analytical improvements (systems biology) provide tools capable of addressing the complexity of COPD. The information obtained from the integrated use of those techniques will be eventually incorporated into routine clinical practice [65]. Because the diversity of phenotypes of each condition is better understood, clinicians will be presented with opportunities to evolve from a ‘one size fits all’ approach to personalized approaches, with the ultimate goal of improving care and reducing potential adverse effects from unnecessary therapies [66]. This means that we might take on a more personalized treatment not only according to the severity of the airflow obstruction, but also conditioned by the clinical phenotype. Actually, international guidelines, a part the recent Spanish guidelines [67], do not differentiate COPD patients into phenotypes and tend to homogenize patients with different diseases, thus reaching different results. Unfortunately, there are no randomized clinical studies that evaluated the influence of COPD phenotypes in terms of response to treatment and disease progression. This

means that there is an urgent need for well designed clinical studies focused on COPD phenotypes. Acknowledgements and Disclosures

None.

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