Difficult Cases Is It Asthma or Is It COPD: The Overlap Syndrome Matthew C. Bell, MDa, and William W. Busse, MDb INFORMATION FOR CATEGORY 1 CME CREDIT Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI: In Practice Web site: www.jaci-inpractice.org/. The accompanying tests may only be submitted online at www. jaciinpractice.org/. Fax or other copies will not be accepted. Date of Original Release: July 1, 2015. Credit may be obtained for these courses until August 31, 2017. Copyright Statement: Copyright Ó 2015-2017. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity.
List of Design Committee Members: Matthew C. Bell, MD, and William W. Busse, MD Activity Objectives 1. To appreciate the clinical similarities and differences between asthma and chronic obstructive pulmonary disease (COPD). 2. To apply knowledge of pulmonary laboratory techniques (spirometry, DLCO, etc) to differentiate between asthma and COPD. 3. To recognize that many patients fall into an “overlap syndrome” category and display clinical features of both asthma and COPD. 4. To understand the limitations of current treatment guidelines when applied to this overlap syndrome population. Recognition of Commercial Support: This CME has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: M. C. Bell declares no relevant conflicts of interest. W. W. Busse is on the Merck Board; has received consultancy fees from Novartis, GlaxoSmithKline, Genentech, Roche, Pfizer, Boston Scientific, Circassia, ICON, AstraZeneca, Sanofi, Amgen, and MedImmune; has received research support from the NIH/NIAID and NIH/NHLBI; and receives royalties from UpToDate.
The Difficult Cases Feature is based on the Difficult Cases Course presented at the AAAAI Annual Meeting and coordinated by the AAAAI New Allergist-Immunologist Assembly (NAIA). View the entire presentation and obtain CME by visiting the JACI: In Practice homepage www.jaci-inpractice.org. Key words: Asthma; Chronic obstructive pulmonary disease
A 68-year-old woman presents with worsening cough, shortness of breath, and occasional wheezing of 6-month duration. She had a history of childhood asthma and allergic rhinitis, which have not been problematic in years. She had a a
Division of Allergy and Immunology, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Ark b Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis No funding was received for this work. Conflicts of interest: M. C. Bell declares no relevant conflicts of interest. W. W. Busse is on the Merck Board; has received consultancy fees from Novartis, GlaxoSmithKline, Genentech, Roche, Pfizer, Boston Scientific, Circassia, ICON, AstraZeneca, Sanofi, Amgen, and MedImmune; has received research support from the NIH/NIAID and NIH/NHLBI; and receives royalties from UpToDate. Received for publication September 29, 2014; revised October 31, 2014; accepted for publication November 3, 2014. Corresponding author: William W. Busse, MD, Professor of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI. E-mail: [email protected]. 2213-2198 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2014.11.003
15- to 20-pack-year smoking history, but quit 40 years ago. Her mother had a history of exercise-induced bronchospasm. Her physical examination is within normal limits and her body mass index is 29. In-office spirometry reveals a forced vital capacity (FVC) of 3.2 L (84% predicted), a forced expiratory volume in 1 second (FEV1) of 2 L (69% predicted), and an FEV1:FVC ratio of 63%. Because of her age of onset and smoking history, the decision is made to start on therapy for Global Initiative for Obstructive Lung Disease (GOLD) Group B chronic obstructive pulmonary disease (COPD) with tiotropium. The patient returns a month later with only mild symptom improvement and no change in lung function. A carbon monoxide diffusion capacity assay is performed that is normal. Spirometry after bronchodilator challenge reveals a 12% and 240 mL improvement in FEV1. The management of asthma is one of the cornerstones of the allergist’s practice. In adult patients, however, the clinical distinction between severe asthma and COPD is often difficult. In many patients, features of both diseases are seen, and a new clinical entity, the “overlap syndrome,” is becoming increasingly recognized and important for a number of reasons.1 641
642
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Asthma, by its purest definition, is a disease of reversible airflow obstruction, bronchial hyperresponsiveness, and underlying airway inflammation.2 Although the majority of patients with asthma have reversible airflow obstruction, a segment of patients with asthma can have severe compromises in lung function, and from the perspective of lung function, look much like patients with COPD. COPD shares features of the components of airflow obstruction, which is often progressive in severity, and elements of airway inflammation, but is historically linked to cigarette smoking. Furthermore, the airflow obstruction in COPD is usually incompletely reversible after the administration of bronchodilator medications. However, as patients with obstructive airway disease age, they often begin to take on characteristics of both diseases. Up to 50% of older patients with obstructive airway disease can be classified as having overlap syndrome, a cross between asthma and COPD.1,3 Clinically, the overlap syndrome is manifested in patients with symptoms of obstructive airway disease with incomplete bronchodilator reversibility and evidence of bronchial hyperresponsiveness on bronchoprovocation testing.1 These patients often present in different ways. Some patients with asthma show a proportionally greater decline in postbronchodilator FEV1 than prebronchodilator FEV1, which indicates a loss of reversibility over time, and have pulmonary functions usually associated with COPD.4 A significant proportion of patients with a diagnosis of COPD, in contrast, have evidence of bronchial hyperresponsiveness as measured by histamine or methacholine bronchoprovocation challenge.5,6 Thus, the once prevailing thought that asthma and COPD are distinct clinical entities has given way to the realization that although they do exist in their pure form in many patients, a significant number of patients straddle the line between these diseases. There are important differences between asthma and COPD. In contrast to COPD, those patients with severe asthma and profound obstructive lung disease do not require supplementary oxygen over time. In addition, the primary treatment in COPD is bronchodilator medications, whereas those with asthma benefit from anti-inflammatory treatment. The importance of recognizing an overlap syndrome extends beyond the clinic and into the research sphere. Guidelines for treatment of asthma and COPD were developed based on the findings of research studies with strict exclusion criteria. Patients who are current, and often former, smokers are excluded from most asthma trials. Both asthma and COPD trials have set strict limits for bronchodilator reversibility, excluding patients with excessive reversibility from COPD trials and those with minimal
J ALLERGY CLIN IMMUNOL PRACT JULY/AUGUST 2015
reversibility from asthma trials. Thus, patients with overlap syndrome are often treated according to guidelines based on studies that excluded patients with similar presentations to their own. This leads to an emerging diagnostic and therapeutic dilemma, which is only beginning to be approached. Asthma and COPD also share several important clinical features, including cough and breathlessness, as well as many pathophysiologic mechanisms, including bronchoconstriction, airway inflammation, and excess mucous production. It is no surprise, thus, that patients with one diagnosis can often show signs consistent with the other. One of the strongest risk factors, outside of cigarette smoking, for the future development of COPD remains a diagnosis of childhood asthma, indicating that the link between these diseases is likely a lifelong phenomenon.7 As our population ages, a larger number of patients with obstructive airway disease will be classified as having overlap syndrome. Further study is certainly warranted at this time to establish diagnostic and therapeutic guidelines that are specifically tailored to this growing subset of patients. Realizing that the overlap syndrome may represent a distinct phenotype of asthma is important for the clinician and ongoing investigation is necessary to more fully define this group of patients and discover what treatments are most effective for them. For more, please see the slide presentation in this article’s Online Repository at www.jaci-inpractice.org. REFERENCES 1. Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: what are its features and how important is it? Thorax 2009;64:728-35. 2. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Asthma Education and Prevention Program. Bethesda, MD: U.S. Department of Health and Human Services, National Heart, Lung, and Blood Institute; 2007. 3. Soriano JB, Davis KJ, Coleman B, Visick G, Mannino D, Pride NB. The proportional Venn diagram of obstructive lung disease: two approximations from the United States and the United Kingdom. Chest 2003;124:474-81. 4. Van Rensen EL, Sont JK, Evertse CE, Willems LN, Mauad T, Hiemstra PS, et al. Bronchial CD8 cell infiltrate and lung function decline in asthma. Am J Respir Crit Care Med 2005;172:837-41. 5. Postma DS, Kerstjens HA. Characteristics of airway hyperresponsiveness in asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;158:S187-92. 6. Yan K, Salome CM, Woolcock AJ. Prevalence and nature of bronchial hyperresponsiveness in subjects with chronic obstructive pulmonary disease. Am Rev Respir Dis 1985;132:25-9. 7. Shirtcliffe P, Marsh S, Travers J, Weatherall M, Beasley R. Childhood asthma and GOLD-defined chronic obstructive pulmonary disease. Intern Med J 2010; 42:83-8.
List of Design Committee Members: Matthew C. Bell, MD, and William W. Busse, MD Activity Objectives 1. To appreciate the clinical similarities and differences between asthma and chronic obstructive pulmonary disease (COPD). 2. To apply knowledge of pulmonary laboratory techniques (spirometry, DLCO, etc) to differentiate between asthma and COPD. 3. To recognize that many patients fall into an “overlap syndrome” category and display clinical features of both asthma and COPD. 4. To understand the limitations of current treatment guidelines when applied to this overlap syndrome population. Recognition of Commercial Support: This CME has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: M. C. Bell declares no relevant conflicts of interest. W. W. Busse is on the Merck Board; has received consultancy fees from Novartis, GlaxoSmithKline, Genentech, Roche, Pfizer, Boston Scientific, Circassia, ICON, AstraZeneca, Sanofi, Amgen, and MedImmune; has received research support from the NIH/NIAID and NIH/NHLBI; and receives royalties from UpToDate.
The Difficult Cases Feature is based on the Difficult Cases Course presented at the AAAAI Annual Meeting and coordinated by the AAAAI New Allergist-Immunologist Assembly (NAIA). View the entire presentation and obtain CME by visiting the JACI: In Practice homepage www.jaci-inpractice.org. Key words: Asthma; Chronic obstructive pulmonary disease
A 68-year-old woman presents with worsening cough, shortness of breath, and occasional wheezing of 6-month duration. She had a history of childhood asthma and allergic rhinitis, which have not been problematic in years. She had a a
Division of Allergy and Immunology, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Ark b Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis No funding was received for this work. Conflicts of interest: M. C. Bell declares no relevant conflicts of interest. W. W. Busse is on the Merck Board; has received consultancy fees from Novartis, GlaxoSmithKline, Genentech, Roche, Pfizer, Boston Scientific, Circassia, ICON, AstraZeneca, Sanofi, Amgen, and MedImmune; has received research support from the NIH/NIAID and NIH/NHLBI; and receives royalties from UpToDate. Received for publication September 29, 2014; revised October 31, 2014; accepted for publication November 3, 2014. Corresponding author: William W. Busse, MD, Professor of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI. E-mail: [email protected]. 2213-2198 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2014.11.003
15- to 20-pack-year smoking history, but quit 40 years ago. Her mother had a history of exercise-induced bronchospasm. Her physical examination is within normal limits and her body mass index is 29. In-office spirometry reveals a forced vital capacity (FVC) of 3.2 L (84% predicted), a forced expiratory volume in 1 second (FEV1) of 2 L (69% predicted), and an FEV1:FVC ratio of 63%. Because of her age of onset and smoking history, the decision is made to start on therapy for Global Initiative for Obstructive Lung Disease (GOLD) Group B chronic obstructive pulmonary disease (COPD) with tiotropium. The patient returns a month later with only mild symptom improvement and no change in lung function. A carbon monoxide diffusion capacity assay is performed that is normal. Spirometry after bronchodilator challenge reveals a 12% and 240 mL improvement in FEV1. The management of asthma is one of the cornerstones of the allergist’s practice. In adult patients, however, the clinical distinction between severe asthma and COPD is often difficult. In many patients, features of both diseases are seen, and a new clinical entity, the “overlap syndrome,” is becoming increasingly recognized and important for a number of reasons.1 641
642
BELL AND BUSSE
Asthma, by its purest definition, is a disease of reversible airflow obstruction, bronchial hyperresponsiveness, and underlying airway inflammation.2 Although the majority of patients with asthma have reversible airflow obstruction, a segment of patients with asthma can have severe compromises in lung function, and from the perspective of lung function, look much like patients with COPD. COPD shares features of the components of airflow obstruction, which is often progressive in severity, and elements of airway inflammation, but is historically linked to cigarette smoking. Furthermore, the airflow obstruction in COPD is usually incompletely reversible after the administration of bronchodilator medications. However, as patients with obstructive airway disease age, they often begin to take on characteristics of both diseases. Up to 50% of older patients with obstructive airway disease can be classified as having overlap syndrome, a cross between asthma and COPD.1,3 Clinically, the overlap syndrome is manifested in patients with symptoms of obstructive airway disease with incomplete bronchodilator reversibility and evidence of bronchial hyperresponsiveness on bronchoprovocation testing.1 These patients often present in different ways. Some patients with asthma show a proportionally greater decline in postbronchodilator FEV1 than prebronchodilator FEV1, which indicates a loss of reversibility over time, and have pulmonary functions usually associated with COPD.4 A significant proportion of patients with a diagnosis of COPD, in contrast, have evidence of bronchial hyperresponsiveness as measured by histamine or methacholine bronchoprovocation challenge.5,6 Thus, the once prevailing thought that asthma and COPD are distinct clinical entities has given way to the realization that although they do exist in their pure form in many patients, a significant number of patients straddle the line between these diseases. There are important differences between asthma and COPD. In contrast to COPD, those patients with severe asthma and profound obstructive lung disease do not require supplementary oxygen over time. In addition, the primary treatment in COPD is bronchodilator medications, whereas those with asthma benefit from anti-inflammatory treatment. The importance of recognizing an overlap syndrome extends beyond the clinic and into the research sphere. Guidelines for treatment of asthma and COPD were developed based on the findings of research studies with strict exclusion criteria. Patients who are current, and often former, smokers are excluded from most asthma trials. Both asthma and COPD trials have set strict limits for bronchodilator reversibility, excluding patients with excessive reversibility from COPD trials and those with minimal
J ALLERGY CLIN IMMUNOL PRACT JULY/AUGUST 2015
reversibility from asthma trials. Thus, patients with overlap syndrome are often treated according to guidelines based on studies that excluded patients with similar presentations to their own. This leads to an emerging diagnostic and therapeutic dilemma, which is only beginning to be approached. Asthma and COPD also share several important clinical features, including cough and breathlessness, as well as many pathophysiologic mechanisms, including bronchoconstriction, airway inflammation, and excess mucous production. It is no surprise, thus, that patients with one diagnosis can often show signs consistent with the other. One of the strongest risk factors, outside of cigarette smoking, for the future development of COPD remains a diagnosis of childhood asthma, indicating that the link between these diseases is likely a lifelong phenomenon.7 As our population ages, a larger number of patients with obstructive airway disease will be classified as having overlap syndrome. Further study is certainly warranted at this time to establish diagnostic and therapeutic guidelines that are specifically tailored to this growing subset of patients. Realizing that the overlap syndrome may represent a distinct phenotype of asthma is important for the clinician and ongoing investigation is necessary to more fully define this group of patients and discover what treatments are most effective for them. For more, please see the slide presentation in this article’s Online Repository at www.jaci-inpractice.org. REFERENCES 1. Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: what are its features and how important is it? Thorax 2009;64:728-35. 2. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Asthma Education and Prevention Program. Bethesda, MD: U.S. Department of Health and Human Services, National Heart, Lung, and Blood Institute; 2007. 3. Soriano JB, Davis KJ, Coleman B, Visick G, Mannino D, Pride NB. The proportional Venn diagram of obstructive lung disease: two approximations from the United States and the United Kingdom. Chest 2003;124:474-81. 4. Van Rensen EL, Sont JK, Evertse CE, Willems LN, Mauad T, Hiemstra PS, et al. Bronchial CD8 cell infiltrate and lung function decline in asthma. Am J Respir Crit Care Med 2005;172:837-41. 5. Postma DS, Kerstjens HA. Characteristics of airway hyperresponsiveness in asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;158:S187-92. 6. Yan K, Salome CM, Woolcock AJ. Prevalence and nature of bronchial hyperresponsiveness in subjects with chronic obstructive pulmonary disease. Am Rev Respir Dis 1985;132:25-9. 7. Shirtcliffe P, Marsh S, Travers J, Weatherall M, Beasley R. Childhood asthma and GOLD-defined chronic obstructive pulmonary disease. Intern Med J 2010; 42:83-8.
