key: cord-0771197-aprh5q3x
authors: Segal, Leopoldo N.; Martinez, Fernando J.
title: COPD subpopulations and phenotyping
date: 2018-06-01
journal: Journal of Allergy and Clinical Immunology
DOI: 10.1016/j.jaci.2018.02.035
sha: 99f8fe83ec882a7dd8dc34c703efe186e175c9d6
doc_id: 771197
cord_uid: aprh5q3x

The diagnosis and treatment of Chronic Obstructive Pulmonary Disease (COPD) has been largely based on a “one size fits all” approach. Diagnosis of COPD is based on meeting the physiological criteria of fixed obstruction in forced expiratory flows and treatment focus on symptomatic relief with limited effect on the overall prognosis. However, patients with COPD have distinct features that determine very different evolution of the disease. In this review, we highlight distinct subgroups of COPD characterized by unique pathophysiological derangements, response to treatment and disease progression. It is likely that identification of subgroups of COPD will lead to discovery of highly needed disease modifying therapeutic approaches. We argue that a precision approach that integrates multiple dimensions (clinical, physiological, imaging and endotyping) is needed to move the field forward in this disease.

CAT: COPD Assessment Test COPD: Chronic obstructive pulmonary disease CT: Computed tomography FLAME: Effect of Indacaterol Glycopyronium Vs. Fluticasone Salmeterol on COPD Exacerbations FVC: Forced vital capacity GOLD: Global Initiative for Chronic Obstructive Lung Disease SPIROMICS: Subpopulations and Intermediate Outcome Measures in COPD Study when the so-called Dutch hypothesis was introduced. This hypothesis argued that bronchodilator responsiveness was an overlapping feature shared by various forms of obstructive lung diseases, including asthma. In contrast, the British hypothesis argued that bronchodilator responsiveness in patients with COPD was due to concomitant asthma. 1, 2 In 1959, during the Ciba Guest Symposium, the scientific community began to recognize the problems of poor phenotyping and published an article in Thorax under the title of ''Terminology, definitions, and classification of chronic pulmonary emphysema and related conditions.'' 3 That report stated the following: ''At present, the diagnosis of 'chronic bronchitis,' 'asthma,' and 'emphysema' are used without any general agreement about the clinical conditions to which they refer. Any one (or more) of these words may be used by different clinicians to describe the condition of the same patient. It appears that chronic bronchitis is often used in Great Britain to describe cases that would be called asthma or emphysema in the Unites States.'' Importantly, this remains an ongoing controversy in clinical practice. This blurred vision of disease was represented as a nonproportional Venn diagram of COPD, one of the most famous diagrams in pulmonary medicine. 4 For many years, a unifying view of COPD influenced physicians to take a one-size-fits-all approach to patients with COPD. This was applied to diagnostic approaches in which physicians rely on spirometry with bronchodilator responsiveness, as well as therapeutic management. In these approaches, first-line medications have been applied consistently once COPD is diagnosed without much consideration of possible distinct phenotypes of COPD.

However, several lines of investigation have demonstrated that subgroups of COPD can have distinct pathophysiologic derangements, response to treatment, and disease progression. 5 Thus a precision approach to this disease is needed to overcome the many years of stagnant therapeutic advances by identifying novel treatable traits and treating them at a stage at which disease-modifying approaches are more likely to succeed. 6 This review will focus on the state of the art and knowledge gaps of COPD subpopulations and phenotyping.

COPD is defined by airflow obstruction (postbronchodilator FEV 1 /forced vital capacity [FVC] ratio <0.7) that is not fully reversible after bronchodilator administration. 7 FEV 1 has been used to quantify and grade obstruction severity. This criterion does not consider the multiplicity of pathophysiologic derangements and heterogeneous histopathologic conditions that lead to airway obstruction. Both decrease in elastic recoil and decrease in cross-sectional airway diameter (independent of [and frequently concomitant with] each other) will lead to an increase in airway resistance during expiration, leading to airflow limitation. 8 This ramification increases further if one considers the multiple molecular derangements that lead to loss of elastic recoil and airway damage. This definition also leaves a large proportion of subjects with physiologic abnormalities, respiratory symptoms, or both that do not reach COPD diagnostic criteria. For example, use of 0.7 as a cut point for FEV 1 /FVC ratio excludes a significant portion of subjects (many of them with ratios of less than the predictive lower limit of normal values) that have significant symptoms. 9 In addition, the lower limit of normal for FEV 1 /FVC ratio decreases with age. Thus the accuracy of these diagnostic criteria also changes with age, affecting the establishment of early diagnosis in this disease among younger patients. 10 Furthermore, the use of a fixed cut point might misclassify some older patients as having COPD. Although using the lower limit of normal would be a more desirable parameter, this value is dependent on the reference population and is unlikely to accurately reflect the normality of many different ethnic groups. In addition, FEV 1 normally decreases with age, and the rate of decrease is an important spirometric indicator of disease progression in patients with COPD. However, the rate of lung function decrease is not considered for diagnosing or staging the disease.

The current approach to diagnosis and staging of COPD is based on spirometric values, even though disease is believed generally to begin in the small airways, 8 an area classically labelled as the ''quiet zone'' because it cannot be easily assessed by means of spirometry alone. 11 A large proportion of patients at risk for COPD have significant respiratory symptoms but without the spirometric abnormalities required to meet COPD criteria. Accordingly, there are several forms of smoke-related lung diseases, even with an FEV 1 /FVC ratio of greater than 0.7, 12 including chronic bronchitis (based on frequency of cough and sputum production), emphysema (based on computed tomography [CT]), small-airway disease (based on specialized lung function or imaging), or asthma (based on symptom characteristics, bronchodilator response, or both). In addition, some patients present with overlap within these broad entities, whereas others do not fit any of the available definitions.

The lack of clear agreement on how to define the above entities has delayed pathophysiologic understanding of these disease states. Several multicenter cohorts have been developed that allow study of these smoke-related lung diseases. Examples include the COPDGene, 13 Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), 14 Canadian Cohort Obstructive Lung Diseases (canCOLD) study, 15 and the Copenhagen City Heart Study 16 cohorts. Overall, these smoke-related lung diseases are very common, with significant morbidity and possible risk for progression to COPD, as defined by using spirometric criteria. For example, in the COPDGene cohort, smokers without spirometric criteria for COPD have worse health status when assessed by using the St George Respiratory Questionnaire. 17 In the SPIROMICS cohort, respiratory symptoms are present in half of smokers with preserved pulmonary function; when compared with asymptomatic smokers, these symptomatic subjects had greater limitation of physical activity, impaired pulmonary function (although still within the limits considered as normal), and evidence of airway wall thickening on CT imaging of the chest. 9 Importantly, smokers with preserved lung function and respiratory symptoms had higher rates of exacerbations than asymptomatic smokers (COPD Assessment Test [CAT] score <10).

In addition, the coexistence of asthma with other smoke-related lung diseases in subjects that do not fit the spirometric criteria for COPD has significant health implications. For example, coexistence of asthma with chronic bronchitis is associated with poor symptom control and a greater decrease in FEV 1 . 16, 18 The inflammatory changes observed in the airways of smokers with asthma are distinct from hose in never-smokers with asthma. In smokers with asthma, there are fewer eosinophils, increased numbers of cytotoxic T lymphocytes, and goblet cell hyperplasia. 19, 20 Of note, there are no clear treatment guidelines for this group of symptomatic smokers who have no spirometric criteria for COPD. However, a large proportion (between 20% and 42%) receive respiratory treatment with inhaled medications, 9, 17 despite data that smokers with asthma might be poorly responsive to corticosteroid therapy. 21 The above considerations indicate that more research is needed to define the phenotypic changes and pathophysiologic derangements of smoke-related lung disease before meeting the spirometric definition for COPD.

In patients with COPD, early pathologic derangements occur in bronchioles less than 2 mm in diameter, followed by parenchymal remodeling, 22, 23 leading to a minimal increase in total lung resistance. The 2-mm cutoff used to define small airways is based on experiments using retrograde catheters inserted into open lungs of dogs performed by Macklem and Mead 11 more than 50 years ago. As such, the physiologic abnormalities occur in a large silent region, and spirometric abnormalities become significant only later in disease development. Direct measurement of the distribution of resistance in the lower respiratory tract has confirmed that the small airways (ie, <2 mm in internal diameter) are the major sites in which obstruction starts in patients with emphysema. 24, 25 Micro-CT of surgical specimens from patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I COPD further demonstrated airway narrowing and loss of the small conducting airways. 23 Therefore it is not surprising that respiratory symptoms and structural changes in the lung are frequently discordant with spirometric results.

There is an increasing need to consider novel approaches using earlier indicators that would uncover underlying parenchymal and airway injury before meeting spirometric COPD criteria. Examples of such approaches include imaging methods, such as specialized CT methods, 26 and measurements of small-airway physiology, such as the forced oscillation technique. 8 

Newer CT techniques can evaluate changes in lung density between inspiration and expiration to perform parametric response mapping, which suggests differentiation between small-airways disease and emphysema. 27 This methodology demonstrated the widespread presence of functional smallairway disease, even within smokers with GOLD 0 and those with early GOLD 1 COPD, suggesting a role for assessment of small-airway disease in COPD phenotyping. Moreover, additional data have strongly suggested that functional small-airways abnormalities identified by using this technique are associated with rate of FEV 1 decrease. 28 In addition, CT can provide a measure of airway count, a parameter shown recently to be an earlier marker of COPD and associated independently with rapid lung function decrease. 29 Expiratory central airway collapse can be identified by bronchoscopic visualization or expiratory CT and has been suggested to be associated with significant respiratory morbidity. [30] [31] [32] 

The forced oscillation technique applies an oscillating signal at the airway opening during tidal breathing and measures changes in flow and pressure to compute the respiratory system impedance that reflects the mechanical properties of the respiratory system. 33 Using mathematic modeling, impedance can be partitioned into resistance and reactance. Resistance reflects predominately the frictional forces related to airflow within the airways. Reactance reflects the elastic properties and inhomogeneities of ventilation across the respiratory system. Higher oscillation frequencies (approximately 20 Hz) reflect large airways, and lower oscillation frequencies (<10 Hz) reflect properties of the entire respiratory system, including the small airways. Thus in the presence of normal forced airflows (as noted by normal FEV 1 and FEV 1 / FVC ratio), abnormalities present in low oscillation frequencies can be attributed to small-airway dysfunction.

Based on the above considerations, numerous studies have used the forced oscillation technique to evaluate small-airway function in patients with lower respiratory symptoms after toxic environmental inhalation. 34, 35 Of importance, respiratory symptoms in many of these subjects were unexplained by using routine clinical evaluation because chest radiographs and spirometric measures of airflow and lung volume were within the normal range, despite the presence of new-onset respiratory symptoms. Data demonstrated the presence of small-airways dysfunction despite normal airflow on spirometry. 36, 37 The clinical relevance of the small-airway dysfunction was demonstrated in multiple domains. Smallairway dysfunction was correlated with magnitude of inhaled toxin exposure, development/severity of respiratory symptoms, response to therapy, presence of systemic inflammation, and histologic abnormalities within the small airways. [38] [39] [40] Additional studies have evaluated the clinical relevance of small-airway assessment in cigarette smoke-induced lung disease. For smokers at risk for COPD (ie, at a time point when airflow remains normal when assessed by means of spirometry), the presence of peripheral airway dysfunction and its response to bronchodilator was correlated with the severity of peripheral lung inflammation. 41 In addition, longitudinal data from patients with established COPD suggest that expiratory flow limitation, as assessed by using the forced oscillation technique, predicts clinically relevant outcomes, including exercise performance, exacerbations, and possibly mortality. 42 Further longitudinal investigations of large cohorts are needed to evaluate the use of these early physiologic markers to both understand the progression to clinically evident COPD and provide insight into mechanisms for disease progression once COPD is established.

Multiple-breath nitrogen washout is another technique used to evaluate small-airway physiology. By using a mathematic model of gas mixing in the lung, one can obtain parameters that described inhomogeneity of gas mixing within the convectiondependent and diffusion-dependent airways. [43] [44] [45] In patients with COPD, physiologic dysfunction of the small airways can be detected by diffusion-dependent airways at early stages, whereas the convection airway physiology (convection-dependent airways) seems to be less affected. 46 In patients with COPD, abnormalities in diffusion capacity can occur as a consequence of either loss of alveolar capillary membrane surface area caused by emphysema and/or heterogeneity of regional ventilation caused by airway obstruction. 47 In patients with established COPD, the diffusing capacity of the lungs for carbon monoxide is frequently reduced by one or both of these mechanisms. Although distinguishing these phenotypes might be of interest, the relative contribution of airway heterogeneity versus parenchymal destruction is not readily quantifiable, and both mechanisms coexist frequently in an individual patient. Of interest, either of these factors could also produce a reduction in diffusing capacity of the lungs for carbon monoxide in the presence of normal spirometry, raising the possibility that measurement of diffusion could have a role in early diagnosis. 48, 49 

Multivariable approaches to address disease might provide relevant information that can characterize different subtypes of COPD. These multiple dimensions can include clinical, physiologic, imaging, and endotyping dimensions (Fig 1) . Within each of them, data support the relevance of specific variables to COPD diagnosis and prognosis. Very few and limited combinations of these variables and dimensions have been studied and validated. Examples include questionnaires directed toward understanding symptoms and quality of life, such as CAT scores and St George Respiratory Questionnaire scores. 50, 51 Other approaches combine variables to create indices that correlate with patient outcomes, including body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE); age, dyspnea, and airflow obstruction (ADO); and dyspnea, airflow obstruction, smoking, and exacerbation (DOSE) indices. [52] [53] [54] As depicted in Fig 1, much less is known about the value of multiple other variables combined from different dimensions for what future investigations are needed to achieve a more holistic view of subjects with COPD to understand relevant subtypes amenable for different therapeutic approaches. Below is the status of the current knowledge showing that identification of COPD subtypes is relevant in this disease.

The recent recognition of the need to characterize COPD phenotypes led to the creation of several large multicenter cohort studies. Although each of these have unique focuses and aims, they all share the premise that a multidimensional approach to evaluating this disease using large multicenter cohorts will help identify distinct phenotypes. Classification into groups of distinct phenotypes can provide pathophysiologic insights that would guide a more precise therapeutic approach and prognostic relevance for clinically meaningful outcomes. Here we propose that although some commonalities can be relevant to understand COPD, identification of distinct subpopulations might lead to a defined taxonomic annotation, with implications for prognosis and treatment (Fig 2) . Below are some of the most commonly cited and known COPD phenotypes and endotypes.

As noted earlier, micro-CT studies have shown that in early stages there is a reduction in total bronchiolar area and a reduction in the number of small conducting airways. 23 The small-airway remodeling observed in patients with COPD is characterized by goblet cell hyperplasia, mucous gland enlargement, peribronchiolar wall infiltration with inflammatory cells, and bronchiolar smooth muscle hypertrophy. 55, 56 Small-airways disease, although characteristic of early stages of COPD, becomes more widespread over time as the disease progresses to more severe COPD. The therapeutic relevance of this phenotype can include use of therapies that allow the small airways to be targeted pharmacologically. 57 a 1 -Antitrypsin deficiency This condition affects less than 5% of patients with COPD and presents in younger subjects compared with the rest of the COPD population. 58 Mutation of the a 1 -antitrypsin gene leads to a much higher risk of COPD in smokers and workers exposed to particulate matter. 59 Homozygous a 1 -antitrypsin deficiency occurs in 1% to 4.5% of patients with COPD, and the heterozygous form, with less severe protein deficiency, occurs in 17.8% of patients with COPD. 60 a 1 -Antitrypsin is a proteinase inhibitor that protects lung tissue from damage by neutrophil elastase. Thus subjects with this condition experience an imbalance between proteinases and antiproteinases, leading to destruction of elastin fibers, which affects the elastic recoil of the lung and results in parenchymal destruction. This imbalance between proteinases and antiproteinases seems to be less evident in patients with other forms of emphysema. The therapeutic relevance of recognizing this phenotype is the benefit observed especially in subjects with severe deficiency through intravenous augmentation with pooled human a 1 -antitrypsin. 61 Emphysema Emphysema occurs in a significant proportion of smokers that might not fit the COPD spirometric criteria. 26 Multiple biological pathways have been implicated in this phenotype. Both macrophage and neutrophil numbers are increased with release of matrix metalloproteinases, elastases, and collagenases that degrade the parenchymal matrix. 62 In addition, parenchymal destruction has been associated with increased apoptosis, probably through downregulation of the vascular endothelial growth factor pathway. 63, 64 Multiple different phenotypes of emphysema have been described, including centrilobular, panlobular, and paraseptal phenotypes. Some differences can be noted among these phenotypes. For example, the centrilobular phenotype is associated with greater smoking history, whereas the panlobular phenotype is associated with reduced body mass index independently from FEV 1 . 65 Paraseptal emphysema seems to be associated with fewer symptoms and less physiologic impairment. However, it is still not clear what determines the distribution of the emphysema. Careful phenotyping of the anatomic distribution also has important therapeutic implications. This is shown by the survival benefit for lung volume reduction surgery among patients with upper lobe emphysema and low exercise capacity. 66 Similarly, a significant clinical effect can be achieved by means of regional reduction by endobronchial valves based on identification of affected lobes without collateral ventilation. 67 On the basis of a model of the tree of life used to annotate living organisms, we represented our conceptualization of how subpopulations of COPD might be related but differentiated. In this review we proposed the need to define subpopulations of COPD that can share common variables (eg, physiologic and clinical variables) but that also had distinct features (eg, defined airway/parenchymal abnormalities, specific inflammatory pathways, and/or dysbiotic microbiota) that lead to a different natural history of disease and potential therapeutic targets.

This phenotype is characterized by chronic cough with sputum production. Prior data suggested this phenotype was associated with a more rapid decrease in lung function and exacerbations. 68, 69 However, analysis of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) data showed that this phenotype was not independently associated with exacerbations in multivariate analysis. 70 The airway inflammation present in patients with this phenotype is characterized by increased neutrophil, macrophage, and cytotoxic CD8 1 lymphocyte counts. 71 Colonization with potential pathogenic microorganisms leads to further neutrophilic response. 72 In addition, patients with COPD frequently have microaspiration associated with gastroesophageal reflux caused by lack of coordination between breathing and swallowing. [73] [74] [75] Smoking impairs mucociliary clearance and reduces the ability to clear oral microbes from the lower airways, exacerbating inflammation. 76 This leads to chronic cough with progressive incoordination of breathing with swallowing. Therefore it is not surprising that newer culture-independent techniques used to characterize the lower airway microbiota demonstrate the presence of upper airway commensals such as Streptococcus, Prevotella, and Veillonella species. 77 Importantly, this phenotype is associated with greater extent of dyspnea, greater frequency of exacerbations, greater airway obstruction, and increased airway wall thickening. 78 It is also associated with cardiovascular comorbidities and sleep apnea. 79 The clear therapeutic relevance is reflected in the phosphodiesterase 4 inhibitor roflumilast, which appears to have the greatest clinical benefit in patients with such a clinical phenotype. 80, 81 Frequent exacerbators Frequent exacerbators are a group of subjects with 2 or more exacerbations per year. 70, 82 Although recent data suggest that the frequent exacerbator phenotype is quite infrequent in a large cohort study, this phenotype seems to be quite stable over time because the best predictor for exacerbations is past history of exacerbations. 83 Other circulating biomarkers have been examined as part of the SPIROMICS and COPDGene cohorts to characterize this phenotype, and except for high levels of decorin and a 2 -macroglobulin, none have proved to be robust enough to be replicated across cohorts. 84 Interestingly, gastroesophageal reflux has been suggested by one group to be associated independently with exacerbations, suggesting that chemical and/or microbial challenge, as a result of microaspiration, can contribute to development of this phenotype. 70 During the course of a COPD exacerbation, two thirds of patients have bacteria, viruses, or both cultured from lower airway secretions, in which aerobic bacteria are isolated in half of patients, respiratory viruses are isolated in one third, and bacterial/viral coinfection is present in one fourth. 85, 86 Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis are the bacterial pathogens most commonly isolated during COPD exacerbations. Acquisition of a new bacterial strain commonly precede exacerbations. [87] [88] [89] [90] [91] Among viruses, rhinovirus is the virus most frequently associated with exacerbations, 85, 92, 93 whereas coronavirus, parainfluenza, adenovirus, influenza virus, and human metapneumovirus are less prevalent. 92, 94 Coinfections with viruses and bacteria produce higher bacterial burden, more sputum eosinophils, greater lung function impairment, and longer hospitalization. 85, 94 This vicious cycle could explain the association of poor oral health, increased airway bacterial load, COPD exacerbations, and reduced lung function. [95] [96] [97] [98] [99] Overall, frequent exacerbators generally experience more severe airway obstruction, as well as other multisystem parameters for evaluation of disease severity (eg, the Medical Research Council dyspnea scale and the body mass index, airflow obstruction, dyspnea, and exercise index). 100 In addition, exacerbations are particularly important because they are associated with accelerated lung function decrease and have a negative effect on quality of life and mortality. 101 Each exacerbation has negative short-and long-term effects on patients with COPD, including psychological effects. 102 The therapeutic relevance of the recognition of this phenotype is highlighted by multiple trials showing that inhaled steroids and phosphodiesterase 4 inhibitors provide therapeutic benefit in patients with this phenotype. 80, 103, 104 In addition, macrolides, such as erythromycin, clarithromycin, and azithromycin, are effective at reducing exacerbations and hospitalizations. [105] [106] [107] [108] Macrolides have direct anti-inflammatory effects, with data showing that they decrease proinflammatory cytokine production, adhesion molecule levels, and reactive oxygen species levels. 109, 110 However, the mechanisms for the beneficial effects of macrolides can go beyond their direct anti-inflammatory effect because newer data showed that they also induce changes in the lower airway microbiota with increased production of bacterial metabolites with anti-inflammatory properties. 111

According to both GOLD and the Global Initiative for Asthma, asthma-COPD overlap is ''characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.'' 7, 112 This concept remains quite controversial. [113] [114] [115] In asthmatic patients the classical pathophysiologic derangements described are inflammation of the large airways with a T H 2 phenotype and eosinophilic inflammation. 116 In contrast, airway inflammation in patients with COPD occurs initially in the small airways and is characterized by neutrophilic inflammation and inflammation with CD8 lymphocytes. 116 However, although these 2 phenotypes seem quite distinct, there is increasing awareness of the involvement of the small airways and non-T H 2 type of inflammation in asthma, as well as involvement of the large airways and eosinophils in patients with COPD. In asthmatic patients irreversible airway obstruction with airway remodeling occurs as disease progresses, whereas in patients with COPD, bronchodilator response to b 2 -agonist occurs in approximately 45% of patients with COPD 117 and might be less common with an emphysema-dominant phenotype. 118 Genetic variation of the b 2 -adrenergic receptor might explain why some patients with COPD have better response to this type of drug. 119 Although the relevance of identification of this phenotype is still unclear, airway hyperresponsiveness has been associated with lung function decrease. 5 Furthermore, patients with asthma-COPD overlap have more severe disease burden when compared with other patients with COPD. 120 The implications of this phenotype in the current therapeutic approach likely involve better understanding of the endotype, 121 and this is an area of active investigation for the use of biologics (eg, anti-IgE and anti-IL-5). 122 For now, both GOLD and the Global Initiative for Asthma recommend treatment of asthma-COPD overlap according to the most dominant phenotype. 7, 112 Table I describes some of the differences and similarities between these subtypes of COPD and asthma.

Eosinophilic airway inflammation has been described in approximately 15% to 40% of patients with COPD. 123 In patients with low blood eosinophil counts (<340 cells/mL), inflammation tend to remain stable, whereas in those with high eosinophil counts, levels tend to fluctuate over time. 124 Importantly, during exacerbations, there is an increase in eosinophil numbers in sputum. 125 The highly eosinophilic phenotype has been proposed to be associated with the patient's responsiveness to corticosteroids during both acute exacerbations and stable disease. [126] [127] [128] [129] In addition, a meta-analysis that included 10 large trials suggested that use of corticosteroids in patients with low eosinophil counts (<2%) was associated with an increased risk of pneumonia. 130 The value of blood eosinophil counts has been questioned in the presence of significant emphysema (defined as >15% of pulmonary parenchyma affected in a high-resolution CT scan). 131 Data suggest that this phenotype is characterized by low eosinophil counts, with no significant association with exacerbation phenotype. It is possible that the presence of high eosinophil counts represents a biomarker of a distinct host endotype with predominance of a T H 2 phenotype and thus more responsive to corticosteroids. 132 However, eosinophil counts vary across compartments. For example, blood eosinophil counts do not correlate with levels present in the airways or lung parenchyma in smokers with and without COPD. 133 More recent data have questioned the value of using eosinophils as a biomarker. [133] [134] [135] In the Effect of Indacaterol Glycopyronium Vs. Fluticasone Salmeterol on COPD Exacerbations (FLAME) trial, the therapeutic response to a combination of a secondgeneration long-acting b-agonist (indacaterol) and long-acting muscarinic agonist (glycopyrronium) was similar to that to a combination of inhaled corticosteroids and long-acting b-agonist (fluticasone/salmeterol), even in the predefined group of subjects with high blood eosinophil counts. Mepolizumab, an anti-IL-5 agent that affects proliferation, differentiation, and migration of eosinophils, was evaluated recently in patients with COPD, showing no significant differences in the annual rate of moderate or severe exacerbations. 136 However, in a subgroup of patients with defined blood eosinophil counts (> _150 cells/mm 3 at screening or > _300/ mm 3 during the previous year), a dose of 100 mg of mepolizumab (but not 300 mg) was associated with a small but statistically significant lower annual rate of moderate or severe exacerbations. Whether eosinophil levels alone are sufficient as biomarkers to identify a treatable distinct trait of COPD requires further longitudinal investigation. 137 Phenotyping beyond the lungs: Role of the comorbidome Patients with COPD experience a high prevalence of other nonpulmonary conditions. 138 This is important because approximately two thirds of patients with COPD die from these other diseases, and comorbidities have a significant effect on COPD. [139] [140] [141] Recent investigations using network analysis of comorbidities in patients with COPD reveals the presence of hubs of comorbid conditions highly associated with this disease beyond lung cancer and cardiovascular disease, in which common pathophysiologic pathways have been more clearly established. 142 For example, COPD was found to be associated with behavioral risk factors (eg, substance abuse), hepatitis, and pancreatitis. The relevance of identifying these subpopulations of patients with COPD is that it might lead to therapeutic interventions targeting the nonpulmonary comorbidity, with a significant effect on patients' health.

Although here we outlined some more or less well-defined subtypes, much is unknown about how to stratify and taxonomically annotate subtypes of COPD. Table II depicts some of the still unanswered questions that we foresee as a focus for future investigations. It is possible that COPD represents more of a syndrome rather than a defined disease entity, and we are at a point of redefining what this means. By enclosing different entities under the umbrella of COPD, we are committing our pathophysiologic investigations and therapeutic discoveries to fail because of multiple confounders. This is now increasingly accepted in asthmatic patients, in whom relabeling asthma and identification of treatable traits is at the forefront of current investigations. [143] [144] [145] In patients with COPD, it is clear that novel endotyping approaches combined with small-airways physiologic evaluation and imaging are needed to define these different subpopulations of COPD. In addition, multidimensional systembased approaches that integrate symptoms, pulmonary function (beyond FEV 1 ), imaging, microbiology, and immunology profiling should provide a holistic view of this heterogeneous disease.

As our ability to understand how these multiple variables help define subgroups of COPD, we will need a tailored precision medicine approach. [146] [147] [148] These distinct clusters of COPD phenotype will likely lead to identification of new drug targets, as well as new end points for clinical trials.

What do we know? d COPD is a heterogeneous disease in which we are starting to recognize distinct phenotypes associated with different prognosis and potential therapeutic targets.

d Different pathophysiologic derangements lead to the physiologic abnormalities that define COPD.

What is still unknown? d A biomarker approach that would identify subjects at higher risk for progression d Well-defined treatable traits for each subgroup of COPD

Against the Dutch hypothesis: asthma and chronic obstructive pulmonary disease are distinct diseases

Asthma and chronic obstructive pulmonary disease exhibit common origins in any country

Terminology, definitions, and classification of chronic pulmonary emphysema and related conditions. A report of the conclusions of a Ciba guest symposium

Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease phenotypes: the future of COPD

Current concepts in targeting chronic obstructive pulmonary disease pharmacotherapy: making progress towards personalised management

Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary

The contribution of small airway obstruction to the pathogenesis of chronic obstructive pulmonary disease

Clinical significance of symptoms in smokers with preserved pulmonary function

Underestimation of airflow obstruction among young adults using FEV1/FVC <70% as a fixed cut-off: a longitudinal evaluation of clinical and functional outcomes

Resistance of central and peripheral airways measured by a retrograde catheter

Asthma and smoking-induced airway disease without spirometric COPD

A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci

Design of the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS)

Canadian Cohort Obstructive Lung Disease (CanCOLD): fulfilling the need for longitudinal observational studies in COPD

A 15-year follow-up study of ventilatory function in adults with asthma

Clinical and radiologic disease in smokers with normal spirometry

Chronic cough and sputum production are associated with worse clinical outcomes in stable asthma

Airway epithelial changes in smokers but not in ex-smokers with asthma

CD8(1) T cells characterize early smoking-related airway pathology in patients with asthma

Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma

Pathology of emphysema in chronic obstructive pulmonary disease

Small-airway obstruction and emphysema in chronic obstructive pulmonary disease

Site and nature of airway obstruction in chronic obstructive lung disease

Site of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressure

The role of chest computed tomography in the evaluation and management of the patient with chronic obstructive pulmonary disease

Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression

Association between functional small airway disease and FEV1 decline in chronic obstructive pulmonary disease

Total airway count on computed tomography and the risk of COPD progression: findings from a population-based study

Tracheobronchomalacia and excessive dynamic airway collapse

Prevalence of tracheal collapse in an emphysema cohort as measured with end-expiration CT

Association between expiratory central airway collapse and respiratory outcomes among smokers

Oscillation mechanics of lungs and chest in man

Distal airway function in symptomatic subjects with normal spirometry following World Trade Center dust exposure

Oscillometry complements spirometry in evaluation of subjects following toxic inhalation

Isolated small airway reactivity during bronchoprovocation as a mechanism for respiratory symptoms in WTC dust-exposed community members

Disparity between proximal and distal airway reactivity during methacholine challenge

Systemic inflammation associated with world trade center dust exposures and airway abnormalities in the local community

Lung pathologic findings in a local residential and working community exposed to World Trade Center dust, gas, and fumes

Case-control study of lung function in World Trade Center Health Registry area residents and workers

Distal airway dysfunction identifies pulmonary inflammation in asymptomatic smokers

The association of tidal EFL with exercise performance, exacerbations, and death in COPD

Convection-and diffusiondependent ventilation maldistribution in normal subjects

Model simulations of gas mixing and ventilation distribution in the human lung

Noninvasive assessment of airway alterations in smokers: the small airways revisited

Conductive and acinar lung-zone contributions to ventilation inhomogeneity in COPD

Determination of D-CO by the single breath method in inhomogeneous lungs: theory

Nitric oxide diffusing capacity versus spirometry in the early diagnosis of emphysema in smokers

Risk of COPD with obstruction in active smokers with normal spirometry and reduced diffusion capacity

A self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire

Development and first validation of the COPD Assessment Test

The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease

Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: the updated BODE index and the ADO index

Derivation and validation of a composite index of severity in chronic obstructive pulmonary disease: the DOSE Index

Remodeling in response to infection and injury. Airway inflammation and hypersecretion of mucus in smoking subjects with chronic obstructive pulmonary disease

The pathology of chronic obstructive pulmonary disease

Extrafine beclomethasone/formoterol compared to fluticasone/salmeterol combination therapy in COPD

Serum elastase inhibitor deficiency and alpha 1-antitrypsin deficiency in patients with obstructive emphysema

Accelerated spirometric decline in New York City firefighters with alpha(1)-antitrypsin deficiency

European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency

Intravenous augmentation treatment and lung density in severe alpha1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial

Release and activity of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by alveolar macrophages from patients with chronic obstructive pulmonary disease

Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema

Correlation of lung surface area to apoptosis and proliferation in human emphysema

Pulmonary emphysema subtypes on computed tomography: the MESA COPD study

A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema

A randomized study of endobronchial valves for advanced emphysema

The chronic bronchitic phenotype of COPD: an analysis of the COPDGene Study

Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease

Susceptibility to exacerbation in chronic obstructive pulmonary disease

Severity of airflow limitation is associated with severity of airway inflammation in smokers

Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis

Laryngeal penetration and aspiration in individuals with stable COPD

Oropharyngeal deglutition in stable COPD

Role of gastroesophageal reflux symptoms in exacerbations of COPD

Effects of cigarette smoking intensity on the mucociliary clearance of active smokers

Analysis of the lung microbiome in the ''healthy'' smoker and in COPD

Clinical and computed tomographic predictors of chronic bronchitis in COPD: a cross sectional analysis of the COPDGene study

Prevalence and characteristics of three clinical phenotypes of chronic obstructive pulmonary disease (COPD)

Reduction of exacerbations by the PDE4 inhibitor roflumilast-the importance of defining different subsets of patients with COPD

Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials

Defining the ''frequent exacerbator'' phenotype in COPD: a hypothesis-free approach

Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort

Biomarkers Predictive of Exacerbations in the SPIROMICS and COPDGene Cohorts

Effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of COPD

Bacterial infection in chronic obstructive pulmonary disease. A study of stable and exacerbated outpatients using the protected specimen brush

Airway bacterial concentrations and exacerbations of chronic obstructive pulmonary disease

Airway inflammation and bronchial bacterial colonization in chronic obstructive pulmonary disease

New strains of bacteria and exacerbations of chronic obstructive pulmonary disease

Pseudomonas aeruginosa in chronic obstructive pulmonary disease

Molecular diagnosis of respiratory tract infection in acute exacerbations of chronic obstructive pulmonary disease

Prevalence of viral infection detected by PCR and RT-PCR in patients with acute exacerbation of COPD: a systematic review

Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease

Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations

Respiratory pathogen colonization of the dental plaque of institutionalized elders

The association between alveolar bone loss and pulmonary function: the VA Dental Longitudinal Study

Potential associations between chronic respiratory disease and periodontal disease: analysis of National Health and Nutrition Examination Survey III

Associations between oral conditions and respiratory disease in a national sample survey population

Systematic review of the association between respiratory diseases and oral health

Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease

Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease

Physiological changes during symptom recovery from moderate exacerbations of COPD

Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease

Efficacy of roflumilast in the COPD frequent exacerbator phenotype

Long-term azithromycin therapy in patients with severe COPD and repeated exacerbations

Erythromycin and common cold in COPD

Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations

Azithromycin for prevention of exacerbations of COPD

Mechanisms of action and clinical application of macrolides as immunomodulatory medications

Antibiotics as immunomodulant agents in COPD

Randomised, double-blind, placebo-controlled trial with azithromycin selects for antiinflammatory microbial metabolites in the emphysematous lung

Global strategy for asthma management and prevention: GINA executive summary

What is asthma-COPD overlap syndrome? Towards a consensus definition from a round table discussion

Do we really need asthma-chronic obstructive pulmonary disease overlap syndrome?

American Thoracic Society/National Heart, Lung, and Blood Institute Asthma-Chronic Obstructive Pulmonary Disease Overlap Workshop Report

Immunology of asthma and chronic obstructive pulmonary disease

Bronchodilator responsiveness in patients with COPD

Is the short-term response to inhaled beta-adrenergic agonist sensitive or specific for distinguishing between asthma and COPD?

Beta2-adrenergic receptor genetic polymorphisms and short-term bronchodilator responses in patients with COPD

COPD assessment test and severity of airflow limitation in patients with asthma, COPD, and asthma-COPD overlap syndrome

Asthma-COPD overlap. Clinical relevance of genomic signatures of type 2 inflammation in chronic obstructive pulmonary disease

Therapeutic approaches to asthma-chronic obstructive pulmonary disease overlap syndromes

Eosinophilic airway inflammation in COPD

Stability of blood eosinophils in patients with chronic obstructive pulmonary disease and in control subjects, and the impact of sex, age, smoking, and baseline counts

Airways inflammation and treatment during acute exacerbations of COPD

Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial

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

Blood eosinophils: a biomarker of response to extrafine beclomethasone/formoterol in chronic obstructive pulmonary disease

Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial

Blood eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level metaanalysis

Emphysematous phenotype is characterized by low blood eosinophils: a cross-sectional study

Blood eosinophils as a marker of response to inhaled corticosteroids in COPD

Blood eosinophilia does not reflect tissue eosinophils nor worsen clinical outcomes in COPD

Blood eosinophils and response to maintenance chronic obstructive pulmonary disease treatment. Data from the FLAME Trial

Relationship between blood eosinophils, clinical characteristics, and mortality in patients with COPD

Mepolizumab for eosinophilic chronic obstructive pulmonary disease

New anti-eosinophil drugs for asthma and COPD: targeting the trait

The prevalence of clinically-relevant comorbid conditions in patients with physician-diagnosed COPD: a cross-sectional study using data from NHANES 1999-2008

Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease

Role of comorbidities in a cohort of patients with COPD undergoing pulmonary rehabilitation

Independent effect of depression and anxiety on chronic obstructive pulmonary disease exacerbations and hospitalizations

COPD comorbidities network

The asthmas in 2015 and beyond: a Lancet commission

After asthma: redefining airways diseases

After asthma: airways diseases need a new name and a revolution

Treatable traits: toward precision medicine of chronic airway diseases

The challenges of precision medicine in COPD

A new approach to the classification and management of airways diseases: identification of treatable traits