TRANSATLANTIC AIRWAY CONFERENCE Phenotypes and Disease Characterization in Chronic Obstructive Pulmonary Disease Toward the Extinction of Phenotypes? Alvar Agust´ı1 1
Thorax Institute, Hospital Clinic, IDIBAPS, Universitat de Barcelona and CIBER Enfermedades Respiratorias, FISIB, Mallorca, Spain
Abstract Chronic obstructive pulmonary disease (COPD) is a complex, heterogeneous disease. The severity of airflow limitation, traditionally used to guide therapy in patients with COPD, does not describe this complexity properly. As a result, over the past few years there has been a great deal of interest in characterizing COPD more precisely and identifying homogeneous groups of patients who respond to specific therapeutic interventions
(i.e., phenotypes). This review summarizes a presentation at the Transatlantic Airway Conference held in Lucerne on January 31, 2013 on this topic. It addresses the following questions: (1) What do we mean by “phenotypes”? (2) Why do we care about them? (3) Are phenotypes the best strategy to understand COPD heterogeneity? and (4) How can we progress in this field? Keywords: chronic bronchitis; emphysema; smoking; systems medicine; network medicine
(Received in original form March 23, 2013; accepted in final form June 24, 2013 ) Correspondence and requests for reprints should be addressed to Alvar Agustı´, M.D., Ph.D., Institut del Torax, ` Hospital Cl´ınic, Universitat de Barcelona, Villarroel 170, Escala 3, Planta 5, 08036 Barcelona, Spain. E-mail: [email protected] Ann Am Thorac Soc Vol 10, Supplement, pp S125–S130, Dec 2013 Copyright © 2013 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201303-055AW Internet address: www.atsjournals.org
The severity of airflow limitation (i.e., FEV1) has been traditionally used as the key variable to assess and guide therapy in patients with chronic obstructive pulmonary disease (COPD) (1). It is now clear that FEV1 is poorly related to other clinically relevant characteristics of the disease and cannot describe its complexity (2). As a result, over the past few years there has been a great deal of interest in characterizing COPD more precisely and to identify homogeneous groups of patients who respond to specific therapeutic interventions (i.e., phenotypes). This has been acknowledged by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), which recommends assessing patients with COPD according to three dimensions: level of symptoms, FEV1, and previous history of exacerbations (3). This is a very important step toward a more personalized treatment of COPD, but it is unlikely to be the last one (4) because the
complexity of COPD goes well beyond these three domains (5–9). In the future, the proper assessment, treatment, and monitoring of patients with COPD will likely have to incorporate other variables (4). This paper summarizes a presentation at the Transatlantic Airway Conference held in Lucerne on January 31, 2013 on this topic. It addresses the following questions: (1) What do we mean by “phenotypes”? (2) Why do we care about them? (3) Are phenotypes the best strategy to understand COPD heterogeneity? and (4) How can we progress in this field?
What Do We Mean by “Phenotypes”? A phenotype is any observed quality of an organism, such as its morphology, development, or behavior, as opposed to its genotype (i.e., the inherited instructions it
Agust´ı: Phenotypes and Disease Characterization in COPD
carries, which may or may not be expressed) (10, 11). A phenotype is composed of traits or characteristics. Some traits are controlled entirely by the individual’s genes, some are controlled by the environment, and others are controlled by the interaction between genes and environmental factors (10, 11). Therefore, in essence, a phenotype is the end result of the interaction between the genotype, the environment, and some degree of random variation that facilitates and/or limits these gene–environment interactions (10, 11). According to this definition, having brown eyes or red hair are phenotypes. Yet, in clinical practice these “phenotypes” are irrelevant. Because of this, a recent consensus definition indicates that a “clinical phenotype” is “a single or combination of disease attributes (i.e., phenotypic traits) that describe differences between individuals with the disease of interest (in this case, COPD) as they relate to clinically S125
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Figure 1. Comorbidities are prevalent in chronic obstructive pulmonary disease (COPD) (left), but they also occur in many other age-related chronic diseases, so, following Nicolaus Copernicus’ proposal (it is the sun, not the earth, that is at the center of the solar system), aging should occupy the center of the diagram (right). CVD = cardiovascular disease.
meaningful outcomes (such as symptoms, exacerbations, response to therapy, rate of disease progression or death)” (12). This definition has several implications. First, a “clinical phenotype” cannot be a universal feature of the disease (e.g., airflow limitation) because then it would lack discriminant power to separate different groups of individuals within that particular disease. Second, any clinical phenotype has to be related to (i.e., predict) at least one clinically relevant outcome. This necessarily implies that any clinical phenotype requires prospective validation. This is important because most published papers describing “COPD phenotypes” only describe the crosssectional prevalence of a number of phenotypic traits but do not relate them to any meaningful clinical outcome. However, things are changing, and over the past few years at least three different COPD studies with adequate longitudinal validation have been published (6, 13, 14). This definition of a “clinical phenotype” has several caveats that need to be considered (12). First, certain attributes, such as dyspnea or rate of exacerbations, are clinically relevant outcomes, but, depending on the context, they can also be relevant phenotypic traits. Second, some “phenotypes” may change during the S126
course of the disease because of disease progression or in response to therapy. Third, the severity of a given disease is not a phenotype, although it may be the consequence of a particularly aggressive phenotype (15). Likewise, the severity of a disease should be differentiated from its level of biological activity (see below) (15, 16). Furthermore, some of the “attributes” (or phenotypic traits) that may constitute a given phenotype may not be immediately visible. For instance, there is evidence that the persistence of systemic inflammation (which requires specific laboratory measurements) fulfills the requirements of a “clinical COPD phenotype” (6). The terms “endotype” (17) or “intermediate patho-phenotype” (18) are often used in the literature to describe this type of “biological” phenotype.
Why Do We Care about Phenotypes in COPD? Diseases have been traditionally defined on the basis of the principal organ system in which symptoms and signs are manifest and in which gross anatomic pathology and histopathology are correlated (19). This so-called “Oslerian formalism” has been helpful to clinicians because it establishes syndromic patterns that limit the number of potential patho-phenotypes they may need to consider, but it vastly overgeneralizes them, does not take into consideration susceptibility states or preclinical disease manifestations, and cannot be used to individualize disease diagnosis or therapy (19). In the case of COPD, the disease is defined by the presence of “persistent airflow limitation
Figure 2. Phenotypes are a necessary but intermediate step from the classical approach (“one size [FEV1] fits all”) to the future personalized treatment of chronic obstructive pulmonary disease. It is likely that the concept of “phenotypes” will be abandoned.
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Figure 3. Conceptualization of the different pathobiological mechanisms underlying the complex clinical presentation of chronic obstructive pulmonary disease. Modified by permission from B. Celli (personal communication).
that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases” (20). According to this definition, a number of patients commonly encountered in clinical practice cannot be diagnosed with COPD, including smokers with symptoms (chronic bronchitis) and normal spirometry, smokers with emphysema seen on computed tomography (CT) of the thorax but with normal spirometry, smokers with CT evidence of emphysema and pulmonary fibrosis (a biological conundrum because this situation requires simultaneous tissue loss [emphysema] and tissue gain [fibrosis]), and never smokers with non–fully reversible airflow limitation (chronic asthma?). On the other hand, the current definition of COPD emphasizes that “comorbidities contribute to the overall severity in individual patients” (20). There is firm evidence to support this statement because comorbidities are very prevalent in COPD (21) and increase the risk of mortality at each level of airflow limitation severity (22). Yet, whether these are “concomitant diseases” that occur by chance or appear because they share risk factors with COPD (e.g., aging, smoking,
and sedentarism) and/or because they are an integral part of pulmonary disease is unclear (23). Comorbidities also occur in many other age-related chronic diseases (24), so, following the example of Nicolaus Copernicus who in the 17th century proposed that it was the Sun, not the Earth, that was at the center of the Solar System, perhaps we should consider that aging, not COPD, should occupy the center of the comorbidome (Figure 1). Because of these uncertainties, caveats, and unknowns, it has been suggested that the identification and validation of clinically relevant phenotypes is the way to “the future” of COPD (12).
Are Phenotypes the Best Strategy to Understand COPD Heterogeneity? To answer this question, we need to consider the following aspects: (1) the ultimate fate of “the perfect phenotype” (i.e., a “phenotype” that occurs only in some individuals with the disease) that can be clearly identified in clinical practice by one or more biomarkers and that has a specific treatment is to become
Agust´ı: Phenotypes and Disease Characterization in COPD
an independent disease (e.g., a1 antitrypsin deficiency); (2) other “less perfect” phenotypes are not mutually exclusive and can occur simultaneously in the same patient, so they behave more like “phenotypic traits” than like isolated, independent, well-defined “phenotypes.” This is not a semantic issue. On the contrary, it has clinical implications because the diagnosis and treatment of one of such “phenotypes” should not exclude the search (and eventual treatment) of other potentially coexisting ones and because each of them may be associated with different biomarker(s). Having highlighted the potential limitations of the “phenotype” concept, it is fair to say that they are a necessary but intermediate step toward personalized medicine (Figure 2). When we progress further in the field (see below), it is likely that the concept of “phenotypes” will no longer be needed and might be abandoned.
How Can We Progress in this Field? To progress from the current situation of “stratified medicine” (i.e., phenotype-based) to a more “personalized” approach, a threeS127
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Figure 4. Diagram illustrating the different levels of complexity of chronic obstructive pulmonary disease (COPD) and the outcomes of potential clinical relevance that may be ideally derived from each of them (right). CVD = cardiovascular disease; GWAS = genome-wide association studies; miDNA = mitochondrial DNA; miRNA = microRNA; ncRNA = noncoding RNA. Reproduced with permission from Reference 30.
phase strategy can be conceived as follows, keeping in mind, however, that this is a sort of iterative strategy where each step enriches and facilitates the next, with the last phase influencing the first one. Phase 1
We need to understand the pathobiology of the disease better. As shown in Figure 3, the clinical presentation of the disease is only the “tip of the iceberg.” We need to understand the complex relationships between the genetic background of the individual and a large number of environmental factors that can influence gene expression through epigenetic changes (25–28) or that have direct toxic effects (Figure 3). This will lead to the activation of one or more biological processes (endotypes [11, 17, 29] or intermediate pathophenotypes [2, 18, 30]) that, in turn, will be responsible for the specific anatomical changes occurring in a given patient (e.g., the presence or absence of emphysema) and for the degree of activation of a number of biological process (i.e., the biological activity of the disease) (15, 16). Both mechanisms eventually S128
influence the severity of the disease (understood as the amount of functional reserve left) (15). Likewise, the combination of all these elements determines the clinical presentation and impact of the disease in any given patient (Figure 3). We need to understand each of the elements of this system and how they influence each other to be able to understand the complexity of COPD (Figure 4) (2, 30). This approach may lead to a new taxonomy of the disease (18). The value of this network strategy (31) has been recently shown by Agusti and coworkers using data from the ECLIPSE cohort (5) to define the systemic inflammatory response associated with smoking and COPD (6).
Phase 2
Using this new taxonomy and network approach, we need to identify and validate specific therapeutic alternatives for specific disease subtypes (now diseases?), an endeavor that requires the cooperation of the pharmaceutical industry.
Phase 3
We need to identify and validate a number of clinical, radiological, or biological biomarkers that can be incorporated into a “COPD control panel,” which may include at least three different modules addressing relevant domains of the disease (severity, activity, and impact) (Figure 5). Each of these modules will display information on different elements of the disease (i.e., biomarkers) with potential prognostic value and/or with specific therapeutic requirements (4). All this information can be easily incorporated into an “app” for daily use in clinical practice (4). Careful history taking and clinical examinations are, and will continue to be, key elements of clinical practice. However, given that the use of electronic health records is becoming standard in most institutions around the world, the direct link of this e-information to an algorithm included in an app can theoretically be automated and can help clinicians to make the most appropriate and cost-efficient decision through the so called “clinical decision support systems” (32).
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Figure 5. Proposal for a chronic obstructive pulmonary disease control panel. 6MWD = 6-minute-walk distance; CAT = Chronic Obstructive Pulmonary Disease Assessment Test; Exacerb = frequency of previous exacerbations; IC/TLC = inspiratory capacity to total lung capacity ratio; mMRC = modified Medical Research Council Dyspnea Scale. Reproduced with permission from Reference 4.
Conclusions COPD is a complex disease. We need to understand this complexity better to provide better care to our patients. The identification and validation of clinically relevant phenotypes (i.e., groups of patients who
have different prognoses and/or require different therapeutic approaches) will facilitate a better understanding of the pathobiology of COPD, and hence the development of novel treatment alternatives, and facilitate the progress toward more personalized and better
References 1 Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, et al.; Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176:532–555. 2 Agusti A, Sobradillo P, Celli B. Addressing the complexity of chronic obstructive pulmonary disease: from phenotypes and biomarkers to scale-free networks, systems biology, and P4 medicine. Am J Respir Crit Care Med 2011;183:1129–1137. 3 Vestbo J, Hurd SS, Agust´ı 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;187:347–365. 4 Agusti A, MacNee W. The COPD control panel: towards personalised medicine in COPD. Thorax 2013;68:687–690. 5 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;11:122–136. 6 Agust´ı A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE, Vestbo J, Lomas DA, Calverley PMA, Wouters E, et al.; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Persistent systemic inflammation is
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associated with poor clinical outcomes in COPD: a novel phenotype. PLoS ONE 2012;7:e37483. Hurst JR, Vestbo J, Anzueto A, Locantore N, Mullerova ¨ 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: 1128–1138. Vestbo J, Edwards LD, Scanlon PD, Yates JC, Agusti A, Bakke P, Calverley PMA, 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;365:1184–1192. Coxson HO, Dirksen A, Edwards L, Yates JC, Agusti A, Bakke P, Calverley PMA, Celli B, Crim C, Lomas DA, et al. Change in lung density measured using computed tomography in chronic obstructive pulmonary disease. The Lancet Respiratory (In press) Freimer N, Sabatti C. The human phenome project. Nat Genet 2003; 34:15–21. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012;18:716–725. Han MK, Agusti A, Calverley PM, 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;182:598–604. Garcia-Aymerich J, Gomez ´ FP, Anto´ JM; en nombre del Grupo Investigador del Estudio PAC-COPD. [Phenotypic characterization and course of chronic obstructive pulmonary disease in the PAC-COPD Study: design and methods]. Arch Bronconeumol 2009;45:4–11.
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TRANSATLANTIC AIRWAY CONFERENCE 14 Burgel PR, Paillasseur JL, Peene B, Dusser D, Roche N, Coolen J, Troosters T, Decramer M, Janssens W. Two distinct chronic obstructive pulmonary disease (COPD) phenotypes are associated with high risk of mortality. PLoS ONE 2012;7:e51048. 15 Agust´ı A, Celli B. Avoiding confusion in COPD: from risk factors to phenotypes to measures of disease characterisation. Eur Respir J 2011;38:749–751. 16 Vestbo J, Rennard S. Chronic obstructive pulmonary disease biomarker(s) for disease activity needed—urgently. Am J Respir Crit Care Med 2010;182:863–864. 17 Lotvall ¨ J, Akdis CA, Bacharier LB, Bjermer L, Casale TB, Custovic A, Lemanske RF Jr, Wardlaw AJ, Wenzel SE, Greenberger PA. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 2011;127: 355–360. 18 Loscalzo J, Kohane I, Barabasi AL. Human disease classification in the postgenomic era: a complex systems approach to human pathobiology. Mol Syst Biol 2007;3:124. 19 Loscalzo J, Barabasi AL. Systems biology and the future of medicine. Wiley Interdiscip Rev Syst Biol Med 2011;3:619–627. 20 Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, et al. Global initiative for the diagnosis, management, and prevention of chronic obstructive lung disease [updated 2013; accessed June 22, 2013]. www.goldcopd.org. 21 Vanfleteren LE, Spruit MA, Groenen M, Gaffron S, van Empel VP, Bruijnzeel PL, Rutten EP, Op ’t Roodt J, Wouters EF, Franssen FM. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;187:728–735. 22 Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J 2008;32:962–969.
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23 Hidalgo CA, Blumm N, Barabasi ´ AL, Christakis NA. A dynamic network approach for the study of human phenotypes. PLOS Comput Biol 2009;5:e1000353. 24 Bousquet J, Anto JM, Sterk PJ, Adcock IM, Chung KF, Roca J, Agusti A, Brightling C, Cambon-Thomsen A, Cesario A, et al. Systems medicine and integrated care to combat chronic noncommunicable diseases. Genome Med 2011;3:43. 25 Feinberg AP. Phenotypic plasticity and the epigenetics of human disease. Nature 2007;447:433–440. 26 Qiu W, Baccarelli A, Carey VJ, Boutaoui N, Bacherman H, Klanderman B, Rennard S, Agusti A, Anderson W, Lomas DA, et al. Variable DNA methylation is associated with chronic obstructive pulmonary disease and lung function. Am J Respir Crit Care Med 2012;185: 373–381. 27 Cho MH, Castaldi PJ, Wan ES, Siedlinski M, Hersh CP, Demeo DL, Himes BE, Sylvia JS, Klanderman BJ, Ziniti JP, et al.; ICGN Investigators; ECLIPSE Investigators; COPDGene Investigators. A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13. Hum Mol Genet 2012;21:947–957. 28 Wan ES, Qiu W, Baccarelli A, Carey VJ, Bacherman H, Rennard SI, Agusti A, Anderson W, Lomas DA, Demeo DL. Cigarette smoking behaviors and time since quitting are associated with differential DNA methylation across the human genome. Hum Mol Genet 2012; 21:3073–3082. 29 Wilkinson T. From disease heterogeneity through patient endotype to “microtype”: the future for chronic obstructive pulmonary disease research? Am J Respir Crit Care Med 2012;185:686–687. 30 Agust´ı A, Vestbo J. Current controversies and future perspectives in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2011;184:507–513. 31 Barabasi ´ AL, Gulbahce N, Loscalzo J. Network medicine: a networkbased approach to human disease. Nat Rev Genet 2011;12:56–68. 32 Hood L, Balling R, Auffray C. Revolutionizing medicine in the 21st century through systems approaches. Biotechnol J 2012;7: 992–1001.
AnnalsATS Volume 10 Supplement
| December 2013
Thorax Institute, Hospital Clinic, IDIBAPS, Universitat de Barcelona and CIBER Enfermedades Respiratorias, FISIB, Mallorca, Spain
Abstract Chronic obstructive pulmonary disease (COPD) is a complex, heterogeneous disease. The severity of airflow limitation, traditionally used to guide therapy in patients with COPD, does not describe this complexity properly. As a result, over the past few years there has been a great deal of interest in characterizing COPD more precisely and identifying homogeneous groups of patients who respond to specific therapeutic interventions
(i.e., phenotypes). This review summarizes a presentation at the Transatlantic Airway Conference held in Lucerne on January 31, 2013 on this topic. It addresses the following questions: (1) What do we mean by “phenotypes”? (2) Why do we care about them? (3) Are phenotypes the best strategy to understand COPD heterogeneity? and (4) How can we progress in this field? Keywords: chronic bronchitis; emphysema; smoking; systems medicine; network medicine
(Received in original form March 23, 2013; accepted in final form June 24, 2013 ) Correspondence and requests for reprints should be addressed to Alvar Agustı´, M.D., Ph.D., Institut del Torax, ` Hospital Cl´ınic, Universitat de Barcelona, Villarroel 170, Escala 3, Planta 5, 08036 Barcelona, Spain. E-mail: [email protected] Ann Am Thorac Soc Vol 10, Supplement, pp S125–S130, Dec 2013 Copyright © 2013 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201303-055AW Internet address: www.atsjournals.org
The severity of airflow limitation (i.e., FEV1) has been traditionally used as the key variable to assess and guide therapy in patients with chronic obstructive pulmonary disease (COPD) (1). It is now clear that FEV1 is poorly related to other clinically relevant characteristics of the disease and cannot describe its complexity (2). As a result, over the past few years there has been a great deal of interest in characterizing COPD more precisely and to identify homogeneous groups of patients who respond to specific therapeutic interventions (i.e., phenotypes). This has been acknowledged by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), which recommends assessing patients with COPD according to three dimensions: level of symptoms, FEV1, and previous history of exacerbations (3). This is a very important step toward a more personalized treatment of COPD, but it is unlikely to be the last one (4) because the
complexity of COPD goes well beyond these three domains (5–9). In the future, the proper assessment, treatment, and monitoring of patients with COPD will likely have to incorporate other variables (4). This paper summarizes a presentation at the Transatlantic Airway Conference held in Lucerne on January 31, 2013 on this topic. It addresses the following questions: (1) What do we mean by “phenotypes”? (2) Why do we care about them? (3) Are phenotypes the best strategy to understand COPD heterogeneity? and (4) How can we progress in this field?
What Do We Mean by “Phenotypes”? A phenotype is any observed quality of an organism, such as its morphology, development, or behavior, as opposed to its genotype (i.e., the inherited instructions it
Agust´ı: Phenotypes and Disease Characterization in COPD
carries, which may or may not be expressed) (10, 11). A phenotype is composed of traits or characteristics. Some traits are controlled entirely by the individual’s genes, some are controlled by the environment, and others are controlled by the interaction between genes and environmental factors (10, 11). Therefore, in essence, a phenotype is the end result of the interaction between the genotype, the environment, and some degree of random variation that facilitates and/or limits these gene–environment interactions (10, 11). According to this definition, having brown eyes or red hair are phenotypes. Yet, in clinical practice these “phenotypes” are irrelevant. Because of this, a recent consensus definition indicates that a “clinical phenotype” is “a single or combination of disease attributes (i.e., phenotypic traits) that describe differences between individuals with the disease of interest (in this case, COPD) as they relate to clinically S125
TRANSATLANTIC AIRWAY CONFERENCE
Figure 1. Comorbidities are prevalent in chronic obstructive pulmonary disease (COPD) (left), but they also occur in many other age-related chronic diseases, so, following Nicolaus Copernicus’ proposal (it is the sun, not the earth, that is at the center of the solar system), aging should occupy the center of the diagram (right). CVD = cardiovascular disease.
meaningful outcomes (such as symptoms, exacerbations, response to therapy, rate of disease progression or death)” (12). This definition has several implications. First, a “clinical phenotype” cannot be a universal feature of the disease (e.g., airflow limitation) because then it would lack discriminant power to separate different groups of individuals within that particular disease. Second, any clinical phenotype has to be related to (i.e., predict) at least one clinically relevant outcome. This necessarily implies that any clinical phenotype requires prospective validation. This is important because most published papers describing “COPD phenotypes” only describe the crosssectional prevalence of a number of phenotypic traits but do not relate them to any meaningful clinical outcome. However, things are changing, and over the past few years at least three different COPD studies with adequate longitudinal validation have been published (6, 13, 14). This definition of a “clinical phenotype” has several caveats that need to be considered (12). First, certain attributes, such as dyspnea or rate of exacerbations, are clinically relevant outcomes, but, depending on the context, they can also be relevant phenotypic traits. Second, some “phenotypes” may change during the S126
course of the disease because of disease progression or in response to therapy. Third, the severity of a given disease is not a phenotype, although it may be the consequence of a particularly aggressive phenotype (15). Likewise, the severity of a disease should be differentiated from its level of biological activity (see below) (15, 16). Furthermore, some of the “attributes” (or phenotypic traits) that may constitute a given phenotype may not be immediately visible. For instance, there is evidence that the persistence of systemic inflammation (which requires specific laboratory measurements) fulfills the requirements of a “clinical COPD phenotype” (6). The terms “endotype” (17) or “intermediate patho-phenotype” (18) are often used in the literature to describe this type of “biological” phenotype.
Why Do We Care about Phenotypes in COPD? Diseases have been traditionally defined on the basis of the principal organ system in which symptoms and signs are manifest and in which gross anatomic pathology and histopathology are correlated (19). This so-called “Oslerian formalism” has been helpful to clinicians because it establishes syndromic patterns that limit the number of potential patho-phenotypes they may need to consider, but it vastly overgeneralizes them, does not take into consideration susceptibility states or preclinical disease manifestations, and cannot be used to individualize disease diagnosis or therapy (19). In the case of COPD, the disease is defined by the presence of “persistent airflow limitation
Figure 2. Phenotypes are a necessary but intermediate step from the classical approach (“one size [FEV1] fits all”) to the future personalized treatment of chronic obstructive pulmonary disease. It is likely that the concept of “phenotypes” will be abandoned.
AnnalsATS Volume 10 Supplement
| December 2013
TRANSATLANTIC AIRWAY CONFERENCE
Figure 3. Conceptualization of the different pathobiological mechanisms underlying the complex clinical presentation of chronic obstructive pulmonary disease. Modified by permission from B. Celli (personal communication).
that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases” (20). According to this definition, a number of patients commonly encountered in clinical practice cannot be diagnosed with COPD, including smokers with symptoms (chronic bronchitis) and normal spirometry, smokers with emphysema seen on computed tomography (CT) of the thorax but with normal spirometry, smokers with CT evidence of emphysema and pulmonary fibrosis (a biological conundrum because this situation requires simultaneous tissue loss [emphysema] and tissue gain [fibrosis]), and never smokers with non–fully reversible airflow limitation (chronic asthma?). On the other hand, the current definition of COPD emphasizes that “comorbidities contribute to the overall severity in individual patients” (20). There is firm evidence to support this statement because comorbidities are very prevalent in COPD (21) and increase the risk of mortality at each level of airflow limitation severity (22). Yet, whether these are “concomitant diseases” that occur by chance or appear because they share risk factors with COPD (e.g., aging, smoking,
and sedentarism) and/or because they are an integral part of pulmonary disease is unclear (23). Comorbidities also occur in many other age-related chronic diseases (24), so, following the example of Nicolaus Copernicus who in the 17th century proposed that it was the Sun, not the Earth, that was at the center of the Solar System, perhaps we should consider that aging, not COPD, should occupy the center of the comorbidome (Figure 1). Because of these uncertainties, caveats, and unknowns, it has been suggested that the identification and validation of clinically relevant phenotypes is the way to “the future” of COPD (12).
Are Phenotypes the Best Strategy to Understand COPD Heterogeneity? To answer this question, we need to consider the following aspects: (1) the ultimate fate of “the perfect phenotype” (i.e., a “phenotype” that occurs only in some individuals with the disease) that can be clearly identified in clinical practice by one or more biomarkers and that has a specific treatment is to become
Agust´ı: Phenotypes and Disease Characterization in COPD
an independent disease (e.g., a1 antitrypsin deficiency); (2) other “less perfect” phenotypes are not mutually exclusive and can occur simultaneously in the same patient, so they behave more like “phenotypic traits” than like isolated, independent, well-defined “phenotypes.” This is not a semantic issue. On the contrary, it has clinical implications because the diagnosis and treatment of one of such “phenotypes” should not exclude the search (and eventual treatment) of other potentially coexisting ones and because each of them may be associated with different biomarker(s). Having highlighted the potential limitations of the “phenotype” concept, it is fair to say that they are a necessary but intermediate step toward personalized medicine (Figure 2). When we progress further in the field (see below), it is likely that the concept of “phenotypes” will no longer be needed and might be abandoned.
How Can We Progress in this Field? To progress from the current situation of “stratified medicine” (i.e., phenotype-based) to a more “personalized” approach, a threeS127
TRANSATLANTIC AIRWAY CONFERENCE
Figure 4. Diagram illustrating the different levels of complexity of chronic obstructive pulmonary disease (COPD) and the outcomes of potential clinical relevance that may be ideally derived from each of them (right). CVD = cardiovascular disease; GWAS = genome-wide association studies; miDNA = mitochondrial DNA; miRNA = microRNA; ncRNA = noncoding RNA. Reproduced with permission from Reference 30.
phase strategy can be conceived as follows, keeping in mind, however, that this is a sort of iterative strategy where each step enriches and facilitates the next, with the last phase influencing the first one. Phase 1
We need to understand the pathobiology of the disease better. As shown in Figure 3, the clinical presentation of the disease is only the “tip of the iceberg.” We need to understand the complex relationships between the genetic background of the individual and a large number of environmental factors that can influence gene expression through epigenetic changes (25–28) or that have direct toxic effects (Figure 3). This will lead to the activation of one or more biological processes (endotypes [11, 17, 29] or intermediate pathophenotypes [2, 18, 30]) that, in turn, will be responsible for the specific anatomical changes occurring in a given patient (e.g., the presence or absence of emphysema) and for the degree of activation of a number of biological process (i.e., the biological activity of the disease) (15, 16). Both mechanisms eventually S128
influence the severity of the disease (understood as the amount of functional reserve left) (15). Likewise, the combination of all these elements determines the clinical presentation and impact of the disease in any given patient (Figure 3). We need to understand each of the elements of this system and how they influence each other to be able to understand the complexity of COPD (Figure 4) (2, 30). This approach may lead to a new taxonomy of the disease (18). The value of this network strategy (31) has been recently shown by Agusti and coworkers using data from the ECLIPSE cohort (5) to define the systemic inflammatory response associated with smoking and COPD (6).
Phase 2
Using this new taxonomy and network approach, we need to identify and validate specific therapeutic alternatives for specific disease subtypes (now diseases?), an endeavor that requires the cooperation of the pharmaceutical industry.
Phase 3
We need to identify and validate a number of clinical, radiological, or biological biomarkers that can be incorporated into a “COPD control panel,” which may include at least three different modules addressing relevant domains of the disease (severity, activity, and impact) (Figure 5). Each of these modules will display information on different elements of the disease (i.e., biomarkers) with potential prognostic value and/or with specific therapeutic requirements (4). All this information can be easily incorporated into an “app” for daily use in clinical practice (4). Careful history taking and clinical examinations are, and will continue to be, key elements of clinical practice. However, given that the use of electronic health records is becoming standard in most institutions around the world, the direct link of this e-information to an algorithm included in an app can theoretically be automated and can help clinicians to make the most appropriate and cost-efficient decision through the so called “clinical decision support systems” (32).
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Figure 5. Proposal for a chronic obstructive pulmonary disease control panel. 6MWD = 6-minute-walk distance; CAT = Chronic Obstructive Pulmonary Disease Assessment Test; Exacerb = frequency of previous exacerbations; IC/TLC = inspiratory capacity to total lung capacity ratio; mMRC = modified Medical Research Council Dyspnea Scale. Reproduced with permission from Reference 4.
Conclusions COPD is a complex disease. We need to understand this complexity better to provide better care to our patients. The identification and validation of clinically relevant phenotypes (i.e., groups of patients who
have different prognoses and/or require different therapeutic approaches) will facilitate a better understanding of the pathobiology of COPD, and hence the development of novel treatment alternatives, and facilitate the progress toward more personalized and better
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