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CHICAGO – Accurate phenotyping, in the ascendant over the last decade, equates with more effectively targeted treatments for chronic obstructive pulmonary disease, according to a proponent of personalized pulmonary medicine.
"We know that COPD is not the same, but right now we are treating these patients as though one size fits all," Dr. Nicola A. Hanania of the Baylor College of Medicine, Houston, said in a packed session on COPD at the annual meeting of the American College of Chest Physicians.
Because phenotypes describe differences in individuals, they should have relevance to clinically meaningful outcomes. "In COPD, that relates to symptoms, exacerbation, disease progression, response to therapy, and survival," he said.
Potential phenotypes that have been identified according to clinical, physiologic, and radiologic criteria include chronic bronchitis, asthma/COPD overlap, frequent exacerbator, radiologic CT, and persistent systemic inflammation.
Chronic bronchitis
Chronic bronchitis tends to occur more in younger people who smoke. It also is characterized by more wheezing and thicker airway walls. Data presented by Dr. Hanania also showed that this phenotype has more frequent acute exacerbations (Chest 2011;140:1107-8).
In one study, 290 subjects deemed chronically bronchitic – chronic cough and phlegm lasting 3 months of every year for 2 consecutive years – were compared with 771 subjects who were not chronically bronchitic. Investigators found that patients in the first group had more frequent exacerbations per patient: 1.21-1.62 vs. 0.63-1.12 (P < .027). The first group also reported more severe exacerbations: 26.6% vs. 20% (P < .024) (Chest 2011;140:626-33).
Asthma/COPD overlap
"This is a phenotype that deserves more attention. We all have patients where we scratch our head, ‘Is this asthma, or is this COPD?’ " said Dr. Hanania. "We don’t really know because these patients are notoriously excluded from both asthma and COPD studies." He cited estimates suggesting that 13%-20% of COPD patients overlap with asthma (Arch. Bronconeumol. 2012;48:331-7).
Proposed diagnostic criteria for the overlap syndrome phenotype may include two major criteria: marked response to bronchodilators (>15% and >400 mL in forced expiratory volume in 1 second [FEV1]), history of asthma if patient is younger than 40 years, and sputum eosinophilia. Overlap also can be diagnosed by one major criterion and two of the following: response to bronchodilation at least two separate times (>12% and >200 mL in FEV1), history of atopy, and increased total serum IgE. At this time, he said, these criteria are based on expert opinion and on data, "but the clinical implications, once we do the homework, is that these patients deserve to be on antibiotics and corticosteroids early on."
Frequent exacerbator
Defined in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines as two or more exacerbations per year, the frequent exacerbator phenotype was explained in the ECLIPSE study (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), Dr. Hanania said, which showed that, although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype (N. Engl. J. Med. 2010; 363:1128-38).
Frequent exacerbators have higher-stage COPD, more severe obstruction, and more hospitalizations, Dr. Hanania noted.
In addition, the ECLIPSE investigators found that, in 2,138 patients, frequent exacerbator types had an odds ratio of 5.72 of having had an exacerbation in the previous year
Although there other risk factors implicating this phenotype, "the most important question to ask the patient is whether they have had an exacerbation in the previous year," he said. Chronic cough is another factor.
The clinical benefit to identifying the frequent exacerbator, according to Dr. Hanania, is that this group has a greater range of comorbidities, including more inflammation, heightened viral susceptibility, and increased cardiovascular risk, among other susceptibilities.
Using CT for phenotyping
Noting that radiologic phenotyping in COPD is more advanced than in asthma at this time, Dr. Hanania said that quantitative and visual assessment of CT radiographs is "promising" and has helped identify COPD subphenotypes such as emphysema because of accurate assessment of lung inflation, wall thickness, and other factors.
Identifying patients with bronchiectasis, pulmonary arterial enlargement, and acute exacerbations in COPD is also possible with CT radiography, making it possible to predict the different outcomes in each situation. "The clinical implication is that these patients tend to have more frequent exacerbation, worse lung function, and infection," he said, noting that nascent research using imaging to determine biomarkers in functional small airways disease also is occurring.
Systemic inflammation
In the ECLIPSE study, 2,164 COPD patients had an odds ratio of 2.23 for being a current smoker and had higher levels of inflammation, as determined using biomarkers such as C-reactive protein, compared with 337 smokers without COPD and 245 nonsmokers. At the 3-year follow-up, this group with persistently higher inflammation also was classified as having significantly higher all-cause mortality than the group with less inflammation (13% vs. 2%); exacerbation rates in this group were also persistently higher (1.5 vs. 0.9) (PLoS ONE 2012;7:e37483).
Therapeutic implications
Coupling these phenotypes with molecular descriptions of mechanisms and their underlying pathologies can lead to accurate, personalized treatment of COPD. "Phenotypes without clear implications for prognosis and treatment are of little clinical use," Dr. Hanania said, noting that longitudinal studies to validate these phenotypes are necessary.
"Research can help identify mechanisms and courses in different phenotypes, including gender differences," he concluded. "Examining therapeutic responses to different phenotypes can lead to future interventions."
Dr. Hanania disclosed several relationships with a variety of pharmaceutical and medical manufacturers, including Genentech, GlaxoSmithKline* and Astra Zeneca.
Beyond GOLD: A tale of two COPD guidelines
Both address severity and comorbidity, but only one COPD guideline takes into account the latest research on phenotyping in chronic obstructive pulmonary disease.
"The GOLD guidelines do not include clinical phenotypes," said Dr. Joan Soriano, a presenter at the meeting. "But the Spanish ones do."
In fact, there is really only one area where the two documents overlap, said Dr. Soriano: how they define COPD, and even that is not the same. "They both mention the fundamental aspect, which is airflow limitation, and also that the mechanism involved is inflammation," he said. The GOLD definition, however, recognizes the importance of comorbidities, which the Spanish guidelines address the role of tobacco and symptomology.
GOLD (Global Initiative for Chronic Obstructive Lung Disease) is an organization of health care professionals from around the world. "I am not a member of GOLD," Dr. Soriano told the packed session.
The Spanish guidelines are issued by SEPAR, the Spanish Society for Pneumology and Thoracic Surgery. Dr. Soriano is the director of epidemiology and clinical research at the International Center of Advanced Respiratory Medicine (CIMERA) in Palma, Spain.
How the two approach diagnosis also differs. The Spanish guidelines begin with the general COPD diagnosis, then move to the characterization and phenotype, then move to the severity of the disease. They are more specific about age (over 35 years), and have lower limit of normal (LLN) values for persons aged over 70 years and less than 50 years. The GOLD guidelines do not address LLN.
To characterize the disease specifically, the Spanish guidelines address the existence of phenotypes, according to Dr. Soriano, beginning with determining the frequency of exacerbation the patient has per year, and then classifying them eventually into four types: mixed, chronic bronchitis, emphysema, and exacerbator. The GOLD guidelines do not mention phenotypes.
When it comes to the multidimensional assessment of COPD, "the GOLD guidelines lump the mild with the severe spirometry. This is very hard for me to understand," he said. Other classification divergence includes that the Spanish guidelines consider the BODE index.
Treatment in the two guidelines begins similarly, but vectors off from there. "Basically, we are looking at the same trials, so the initial treatments should be short-acting bronchodilators," Dr. Soriano said, but because phenotyping allows for more targeted treatment, the Spanish guidelines offer more detailed treatment options.
In a paper coauthored by Dr. Soriano earlier this year, specific treatment per phenotype included phosphodiesterase-4 inhibitors only for those with chronic bronchitis, inhaled corticosteroids for overlap COPD-asthma, and bronchodilators for infrequent exacerbators (Eur. Respir. J. 2013;41:1252-6).
In the end, the guidelines might not follow the same trajectory, but each has value, he said. "Whatever guidelines you choose, don’t go back and forth. Pick one and use them."
Dr. Soriano reported relationships with Novartis Spain, AstraZeneca, Pfizer, and several other pharmaceutical and medical manufacturers.
*CORRECTION, 2/20/2014: An earlier version of this story misstated the name of GlaxoSmithKline.
CHICAGO – Accurate phenotyping, in the ascendant over the last decade, equates with more effectively targeted treatments for chronic obstructive pulmonary disease, according to a proponent of personalized pulmonary medicine.
"We know that COPD is not the same, but right now we are treating these patients as though one size fits all," Dr. Nicola A. Hanania of the Baylor College of Medicine, Houston, said in a packed session on COPD at the annual meeting of the American College of Chest Physicians.
Because phenotypes describe differences in individuals, they should have relevance to clinically meaningful outcomes. "In COPD, that relates to symptoms, exacerbation, disease progression, response to therapy, and survival," he said.
Potential phenotypes that have been identified according to clinical, physiologic, and radiologic criteria include chronic bronchitis, asthma/COPD overlap, frequent exacerbator, radiologic CT, and persistent systemic inflammation.
Chronic bronchitis
Chronic bronchitis tends to occur more in younger people who smoke. It also is characterized by more wheezing and thicker airway walls. Data presented by Dr. Hanania also showed that this phenotype has more frequent acute exacerbations (Chest 2011;140:1107-8).
In one study, 290 subjects deemed chronically bronchitic – chronic cough and phlegm lasting 3 months of every year for 2 consecutive years – were compared with 771 subjects who were not chronically bronchitic. Investigators found that patients in the first group had more frequent exacerbations per patient: 1.21-1.62 vs. 0.63-1.12 (P < .027). The first group also reported more severe exacerbations: 26.6% vs. 20% (P < .024) (Chest 2011;140:626-33).
Asthma/COPD overlap
"This is a phenotype that deserves more attention. We all have patients where we scratch our head, ‘Is this asthma, or is this COPD?’ " said Dr. Hanania. "We don’t really know because these patients are notoriously excluded from both asthma and COPD studies." He cited estimates suggesting that 13%-20% of COPD patients overlap with asthma (Arch. Bronconeumol. 2012;48:331-7).
Proposed diagnostic criteria for the overlap syndrome phenotype may include two major criteria: marked response to bronchodilators (>15% and >400 mL in forced expiratory volume in 1 second [FEV1]), history of asthma if patient is younger than 40 years, and sputum eosinophilia. Overlap also can be diagnosed by one major criterion and two of the following: response to bronchodilation at least two separate times (>12% and >200 mL in FEV1), history of atopy, and increased total serum IgE. At this time, he said, these criteria are based on expert opinion and on data, "but the clinical implications, once we do the homework, is that these patients deserve to be on antibiotics and corticosteroids early on."
Frequent exacerbator
Defined in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines as two or more exacerbations per year, the frequent exacerbator phenotype was explained in the ECLIPSE study (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), Dr. Hanania said, which showed that, although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype (N. Engl. J. Med. 2010; 363:1128-38).
Frequent exacerbators have higher-stage COPD, more severe obstruction, and more hospitalizations, Dr. Hanania noted.
In addition, the ECLIPSE investigators found that, in 2,138 patients, frequent exacerbator types had an odds ratio of 5.72 of having had an exacerbation in the previous year
Although there other risk factors implicating this phenotype, "the most important question to ask the patient is whether they have had an exacerbation in the previous year," he said. Chronic cough is another factor.
The clinical benefit to identifying the frequent exacerbator, according to Dr. Hanania, is that this group has a greater range of comorbidities, including more inflammation, heightened viral susceptibility, and increased cardiovascular risk, among other susceptibilities.
Using CT for phenotyping
Noting that radiologic phenotyping in COPD is more advanced than in asthma at this time, Dr. Hanania said that quantitative and visual assessment of CT radiographs is "promising" and has helped identify COPD subphenotypes such as emphysema because of accurate assessment of lung inflation, wall thickness, and other factors.
Identifying patients with bronchiectasis, pulmonary arterial enlargement, and acute exacerbations in COPD is also possible with CT radiography, making it possible to predict the different outcomes in each situation. "The clinical implication is that these patients tend to have more frequent exacerbation, worse lung function, and infection," he said, noting that nascent research using imaging to determine biomarkers in functional small airways disease also is occurring.
Systemic inflammation
In the ECLIPSE study, 2,164 COPD patients had an odds ratio of 2.23 for being a current smoker and had higher levels of inflammation, as determined using biomarkers such as C-reactive protein, compared with 337 smokers without COPD and 245 nonsmokers. At the 3-year follow-up, this group with persistently higher inflammation also was classified as having significantly higher all-cause mortality than the group with less inflammation (13% vs. 2%); exacerbation rates in this group were also persistently higher (1.5 vs. 0.9) (PLoS ONE 2012;7:e37483).
Therapeutic implications
Coupling these phenotypes with molecular descriptions of mechanisms and their underlying pathologies can lead to accurate, personalized treatment of COPD. "Phenotypes without clear implications for prognosis and treatment are of little clinical use," Dr. Hanania said, noting that longitudinal studies to validate these phenotypes are necessary.
"Research can help identify mechanisms and courses in different phenotypes, including gender differences," he concluded. "Examining therapeutic responses to different phenotypes can lead to future interventions."
Dr. Hanania disclosed several relationships with a variety of pharmaceutical and medical manufacturers, including Genentech, GlaxoSmithKline* and Astra Zeneca.
Beyond GOLD: A tale of two COPD guidelines
Both address severity and comorbidity, but only one COPD guideline takes into account the latest research on phenotyping in chronic obstructive pulmonary disease.
"The GOLD guidelines do not include clinical phenotypes," said Dr. Joan Soriano, a presenter at the meeting. "But the Spanish ones do."
In fact, there is really only one area where the two documents overlap, said Dr. Soriano: how they define COPD, and even that is not the same. "They both mention the fundamental aspect, which is airflow limitation, and also that the mechanism involved is inflammation," he said. The GOLD definition, however, recognizes the importance of comorbidities, which the Spanish guidelines address the role of tobacco and symptomology.
GOLD (Global Initiative for Chronic Obstructive Lung Disease) is an organization of health care professionals from around the world. "I am not a member of GOLD," Dr. Soriano told the packed session.
The Spanish guidelines are issued by SEPAR, the Spanish Society for Pneumology and Thoracic Surgery. Dr. Soriano is the director of epidemiology and clinical research at the International Center of Advanced Respiratory Medicine (CIMERA) in Palma, Spain.
How the two approach diagnosis also differs. The Spanish guidelines begin with the general COPD diagnosis, then move to the characterization and phenotype, then move to the severity of the disease. They are more specific about age (over 35 years), and have lower limit of normal (LLN) values for persons aged over 70 years and less than 50 years. The GOLD guidelines do not address LLN.
To characterize the disease specifically, the Spanish guidelines address the existence of phenotypes, according to Dr. Soriano, beginning with determining the frequency of exacerbation the patient has per year, and then classifying them eventually into four types: mixed, chronic bronchitis, emphysema, and exacerbator. The GOLD guidelines do not mention phenotypes.
When it comes to the multidimensional assessment of COPD, "the GOLD guidelines lump the mild with the severe spirometry. This is very hard for me to understand," he said. Other classification divergence includes that the Spanish guidelines consider the BODE index.
Treatment in the two guidelines begins similarly, but vectors off from there. "Basically, we are looking at the same trials, so the initial treatments should be short-acting bronchodilators," Dr. Soriano said, but because phenotyping allows for more targeted treatment, the Spanish guidelines offer more detailed treatment options.
In a paper coauthored by Dr. Soriano earlier this year, specific treatment per phenotype included phosphodiesterase-4 inhibitors only for those with chronic bronchitis, inhaled corticosteroids for overlap COPD-asthma, and bronchodilators for infrequent exacerbators (Eur. Respir. J. 2013;41:1252-6).
In the end, the guidelines might not follow the same trajectory, but each has value, he said. "Whatever guidelines you choose, don’t go back and forth. Pick one and use them."
Dr. Soriano reported relationships with Novartis Spain, AstraZeneca, Pfizer, and several other pharmaceutical and medical manufacturers.
*CORRECTION, 2/20/2014: An earlier version of this story misstated the name of GlaxoSmithKline.
CHICAGO – Accurate phenotyping, in the ascendant over the last decade, equates with more effectively targeted treatments for chronic obstructive pulmonary disease, according to a proponent of personalized pulmonary medicine.
"We know that COPD is not the same, but right now we are treating these patients as though one size fits all," Dr. Nicola A. Hanania of the Baylor College of Medicine, Houston, said in a packed session on COPD at the annual meeting of the American College of Chest Physicians.
Because phenotypes describe differences in individuals, they should have relevance to clinically meaningful outcomes. "In COPD, that relates to symptoms, exacerbation, disease progression, response to therapy, and survival," he said.
Potential phenotypes that have been identified according to clinical, physiologic, and radiologic criteria include chronic bronchitis, asthma/COPD overlap, frequent exacerbator, radiologic CT, and persistent systemic inflammation.
Chronic bronchitis
Chronic bronchitis tends to occur more in younger people who smoke. It also is characterized by more wheezing and thicker airway walls. Data presented by Dr. Hanania also showed that this phenotype has more frequent acute exacerbations (Chest 2011;140:1107-8).
In one study, 290 subjects deemed chronically bronchitic – chronic cough and phlegm lasting 3 months of every year for 2 consecutive years – were compared with 771 subjects who were not chronically bronchitic. Investigators found that patients in the first group had more frequent exacerbations per patient: 1.21-1.62 vs. 0.63-1.12 (P < .027). The first group also reported more severe exacerbations: 26.6% vs. 20% (P < .024) (Chest 2011;140:626-33).
Asthma/COPD overlap
"This is a phenotype that deserves more attention. We all have patients where we scratch our head, ‘Is this asthma, or is this COPD?’ " said Dr. Hanania. "We don’t really know because these patients are notoriously excluded from both asthma and COPD studies." He cited estimates suggesting that 13%-20% of COPD patients overlap with asthma (Arch. Bronconeumol. 2012;48:331-7).
Proposed diagnostic criteria for the overlap syndrome phenotype may include two major criteria: marked response to bronchodilators (>15% and >400 mL in forced expiratory volume in 1 second [FEV1]), history of asthma if patient is younger than 40 years, and sputum eosinophilia. Overlap also can be diagnosed by one major criterion and two of the following: response to bronchodilation at least two separate times (>12% and >200 mL in FEV1), history of atopy, and increased total serum IgE. At this time, he said, these criteria are based on expert opinion and on data, "but the clinical implications, once we do the homework, is that these patients deserve to be on antibiotics and corticosteroids early on."
Frequent exacerbator
Defined in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines as two or more exacerbations per year, the frequent exacerbator phenotype was explained in the ECLIPSE study (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), Dr. Hanania said, which showed that, although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype (N. Engl. J. Med. 2010; 363:1128-38).
Frequent exacerbators have higher-stage COPD, more severe obstruction, and more hospitalizations, Dr. Hanania noted.
In addition, the ECLIPSE investigators found that, in 2,138 patients, frequent exacerbator types had an odds ratio of 5.72 of having had an exacerbation in the previous year
Although there other risk factors implicating this phenotype, "the most important question to ask the patient is whether they have had an exacerbation in the previous year," he said. Chronic cough is another factor.
The clinical benefit to identifying the frequent exacerbator, according to Dr. Hanania, is that this group has a greater range of comorbidities, including more inflammation, heightened viral susceptibility, and increased cardiovascular risk, among other susceptibilities.
Using CT for phenotyping
Noting that radiologic phenotyping in COPD is more advanced than in asthma at this time, Dr. Hanania said that quantitative and visual assessment of CT radiographs is "promising" and has helped identify COPD subphenotypes such as emphysema because of accurate assessment of lung inflation, wall thickness, and other factors.
Identifying patients with bronchiectasis, pulmonary arterial enlargement, and acute exacerbations in COPD is also possible with CT radiography, making it possible to predict the different outcomes in each situation. "The clinical implication is that these patients tend to have more frequent exacerbation, worse lung function, and infection," he said, noting that nascent research using imaging to determine biomarkers in functional small airways disease also is occurring.
Systemic inflammation
In the ECLIPSE study, 2,164 COPD patients had an odds ratio of 2.23 for being a current smoker and had higher levels of inflammation, as determined using biomarkers such as C-reactive protein, compared with 337 smokers without COPD and 245 nonsmokers. At the 3-year follow-up, this group with persistently higher inflammation also was classified as having significantly higher all-cause mortality than the group with less inflammation (13% vs. 2%); exacerbation rates in this group were also persistently higher (1.5 vs. 0.9) (PLoS ONE 2012;7:e37483).
Therapeutic implications
Coupling these phenotypes with molecular descriptions of mechanisms and their underlying pathologies can lead to accurate, personalized treatment of COPD. "Phenotypes without clear implications for prognosis and treatment are of little clinical use," Dr. Hanania said, noting that longitudinal studies to validate these phenotypes are necessary.
"Research can help identify mechanisms and courses in different phenotypes, including gender differences," he concluded. "Examining therapeutic responses to different phenotypes can lead to future interventions."
Dr. Hanania disclosed several relationships with a variety of pharmaceutical and medical manufacturers, including Genentech, GlaxoSmithKline* and Astra Zeneca.
Beyond GOLD: A tale of two COPD guidelines
Both address severity and comorbidity, but only one COPD guideline takes into account the latest research on phenotyping in chronic obstructive pulmonary disease.
"The GOLD guidelines do not include clinical phenotypes," said Dr. Joan Soriano, a presenter at the meeting. "But the Spanish ones do."
In fact, there is really only one area where the two documents overlap, said Dr. Soriano: how they define COPD, and even that is not the same. "They both mention the fundamental aspect, which is airflow limitation, and also that the mechanism involved is inflammation," he said. The GOLD definition, however, recognizes the importance of comorbidities, which the Spanish guidelines address the role of tobacco and symptomology.
GOLD (Global Initiative for Chronic Obstructive Lung Disease) is an organization of health care professionals from around the world. "I am not a member of GOLD," Dr. Soriano told the packed session.
The Spanish guidelines are issued by SEPAR, the Spanish Society for Pneumology and Thoracic Surgery. Dr. Soriano is the director of epidemiology and clinical research at the International Center of Advanced Respiratory Medicine (CIMERA) in Palma, Spain.
How the two approach diagnosis also differs. The Spanish guidelines begin with the general COPD diagnosis, then move to the characterization and phenotype, then move to the severity of the disease. They are more specific about age (over 35 years), and have lower limit of normal (LLN) values for persons aged over 70 years and less than 50 years. The GOLD guidelines do not address LLN.
To characterize the disease specifically, the Spanish guidelines address the existence of phenotypes, according to Dr. Soriano, beginning with determining the frequency of exacerbation the patient has per year, and then classifying them eventually into four types: mixed, chronic bronchitis, emphysema, and exacerbator. The GOLD guidelines do not mention phenotypes.
When it comes to the multidimensional assessment of COPD, "the GOLD guidelines lump the mild with the severe spirometry. This is very hard for me to understand," he said. Other classification divergence includes that the Spanish guidelines consider the BODE index.
Treatment in the two guidelines begins similarly, but vectors off from there. "Basically, we are looking at the same trials, so the initial treatments should be short-acting bronchodilators," Dr. Soriano said, but because phenotyping allows for more targeted treatment, the Spanish guidelines offer more detailed treatment options.
In a paper coauthored by Dr. Soriano earlier this year, specific treatment per phenotype included phosphodiesterase-4 inhibitors only for those with chronic bronchitis, inhaled corticosteroids for overlap COPD-asthma, and bronchodilators for infrequent exacerbators (Eur. Respir. J. 2013;41:1252-6).
In the end, the guidelines might not follow the same trajectory, but each has value, he said. "Whatever guidelines you choose, don’t go back and forth. Pick one and use them."
Dr. Soriano reported relationships with Novartis Spain, AstraZeneca, Pfizer, and several other pharmaceutical and medical manufacturers.
*CORRECTION, 2/20/2014: An earlier version of this story misstated the name of GlaxoSmithKline.
EXPERT ANALYSIS FROM CHEST 2013
