The Asthma–Chronic Obstructive Pulmonary Disease Overlap Syndrome

Pharmacotherapeutic Considerations

Samuel Louie; Amir A Zeki; Michael Schivo; Andrew L Chan; Ken Y Yoneda; Mark Avdalovic; Brian M Morrissey; Timothy E Albertson

Disclosures

Expert Rev Clin Pharmacol. 2013;6(2):197-219.

Abstract and Introduction

Abstract

Asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is a commonly encountered yet loosely defined clinical entity. ACOS accounts for approximately 15–25% of the obstructive airway diseases and patients experience worse outcomes compared with asthma or COPD alone. Patients with ACOS have the combined risk factors of smoking and atopy, are generally younger than patients with COPD and experience acute exacerbations with higher frequency and greater severity than lone COPD. Pharmacotherapeutic considerations require an integrated approach, first to identify the relevant clinical phenotype(s), then to determine the best available therapy. The authors discuss the array of existing and emerging classes of drugs that could benefit those with ACOS and share their therapeutic approach. A consensus international definition of ACOS is needed to design prospective, randomized clinical trials to evaluate specific drug interventions on important outcomes such as lung function, acute exacerbations, quality of life and mortality.

Introduction

The asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is poorly recognized in part because clinical trials have consistently ignored this condition, as evidenced by strict inclusion and exclusion criteria that exclude either asthma patients from COPD studies or COPD patients from asthma studies. Asthmatic bronchitis was a term used to describe the overlapping conditions of asthma and COPD by the American Thoracic Society (ATS) in 1962,^[1] but no further attempts were made to expound on this clinical phenotype until recently.^[2–4] Guidelines from Canada, Japan and Spain attempt to describe this clinical phenotype and establish treatment options.^[5–7]

Asthma is a syndrome consisting of similar phenotypes with characteristic but nonspecific symptoms. COPD is a syndrome akin to asthma but with important differences, including tobacco smoke-induced pathobiology and pulmonary emphysema. An exploration of how best to define ACOS is beyond the scope of this article. However, a clinical definition is a necessary starting point for a review of potential pharmacotherapeutic approaches.

1 2 3 4 5 6 7

Next Section

Table 1. Comparing asthma, chronic obstructive pulmonary disease and asthma–chronic obstructive pulmonary disease overlap syndromes.
Syndrome	Asthma (severe) [105]	ACOS	COPD [106]
Demographics	>40 years Women > men Nonsmoker or <5 pack years Obesity Atopy typical Rhinosinusitis GERD Frequent albuterol use Exercise limited in between attacks Dependence on prednisone Hallmark problem: frequent exacerbations	>40 years; 50–65 years Past or current smoker >10 pack-years Atopy present Rhinosinusitis GERD Exercise very limited Hallmark problem: very frequent exacerbations > COPD alone	≥65 years if not younger Past or current smoker >10 pack-years No atopy GERD Multiple daily albuterol Exercise very limited Oxygen dependence Hallmark problem: exacerbations and exercise intolerance
Pathophysiology	Intermittent to chronic moderate-to-severe airflow obstructionyFEV₁/FVC <0.70 FEV₁ <68% predicted, ≥ or <65% after albuterol SARP cluster 3, 4 or 5 DLco normal FeNO >50 ppb ≥3% sputum eosinophils Exacerbations >3/year	Intermittent to chronic moderate-to-severe airflow obstruction FEV₁/FVC <0.70 FEV₁ <68% predicted, ≥ or <65% after albuterol DLco normal or low FeNO >25–50 ppb Static hyperinflation Exacerbations >3–5/year Frequent nocturnal awakenings ≥4/week	Chronic airflow obstruction moderate to severe (GOLD II–IV) FEV₁/FVC <0.70 DLco <80% predicted FeNO <25 ppb Static and dynamic hyperinflation Exacerbations >2/year after FEV₁ <50% Infrequent nocturnal awakenings Pulmonary HTN late
Pathobiology	Airway inflammation: eosinophils > neutrophils Mast cells CD4⁺ T lymphocytes Smooth muscle hyperplasia/hypertrophy No emphysema Basement membrane thickening IgE, IL-4, IL-5, IL-13, eotaxin	Airway inflammation: eosinophils + neutrophils, CD4⁺ T lymphocytes, CD8⁺ T lymphocytes Alveolar macrophages, smooth muscle hyperplasia/hypertrophy ± emphysema Peribronchiolar fibrosis IgE, IL-4, IL-5, IL-13, IL-1ß, IL-8, IL-6, TNF-α, eotaxin, proteases	Emphysema with alveolar destruction Airway inflammation: neutrophils>eosinophils CD4⁺ T lymphocytes, CD8⁺ T lymphocytes Alveolar macrophages Mast cells? Peribronchiolar fibrosis IL-1b, IL-8, IL-6, TNF-α, proteases
First-line pharmacotherapy and treatments	ICS ICS + LABA^†	ICS ± LAMA ± LABA Smoking cessation Pulmonary rehabilitation	Bronchodilators LAMA or LABA or both Smoking cessation Pulmonary rehabilitation
Current add-on pharmacotherapy	LABA^†, LAMA, LTRA, theophylline, omalizumab^†, prednisone	LABA, LAMA, LTRA, or roflumilast or theophylline, omalizumab^†, prednisone	ICS or roflumilast theophylline
Emerging treatments	Anti-IL-5, anti-IL-13 ICS + LABA^† once daily Azithromycin Vaccines Bronchial thermoplasty	Refer to asthma and COPD emerging treatments Consider using FeNO to endotype Bronchial thermoplasty	LAMA + LABA once daily Carbocisteine Azithromycin Anti-IL-8, p39 protein kinase inhibitors Haemophilus influenzae vaccine Endobronchial valves Lung transplantation

^†US FDA black box warning alert.
ACOS: Asthma–COPD overlap syndrome; COPD: Chronic obstructive pulmonary disease; DLco: Carbon monoxide diffusing capacity; FeNO: Fractional exhaled nitric oxide; FEV₁: Forced expiratory volume in 1 s; FVC: Forced vital capacity; GERD: Gastroesophageal reflux disease; HTN: Hypertension; ICS: Inhaled corticosteroids; LABA: Long-acting β₂ agonist; LAMA: Long-acting muscarinic receptor antagonist; LTRA: Leukotriene receptor antagonist; SARP: Severe Asthma Research Program.

Table 2. Number needed to treat to prevent acute moderate-to-severe exacerbations of asthma or chronic obstructive pulmonary disease.
Drug or treatment	NNT	Comment	Ref.
COPD study Tiotropium or placebo added to ongoing LABA ± ICS ± theophylline	8 to prevent one exacerbation per year + 14% reduction in exacerbation 7 to prevent one exacerbation per year in GOLD II COPD + 20% reduction in exacerbations	4-year study 62% on ICS 60% on LABA n = 5992 No change annual decline in FEV₁ across GOLD II, III and IV	[25]
COPD study Fluticasone 500 µg + salmeterol compared with salmeterol	2 to prevent one exacerbation per year 35% reduction in exacerbations	44-week study n = 998 Fluticasone/salmeterol 500 µg/50 µg No tiotropium used Theophylline permitted	[57]
COPD study Fluticasone 500 µg + salmeterol vs fluticasone alone vs salmeterol alone vs control	3 to prevent one exacerbation per year vs placebo 8 to prevent one exacerbation per year vs salmeterol 25% reduction in exacerbations	3-year study n = 6112 No anticholinergics	[24]
COPD study Fluticasone 250 µg + salmeterol vs salmeterol alone	2 to prevent one exacerbation per year vs salmeterol alone 30.5% reduction in exacerbations	1-year study n = 782 No anticholinergics or other maintenance drugs	[58]
COPD study Tiotropium or salmeterol added to usual care, including inhaled corticosteroids	24 to prevent one exacerbation per year vs salmeterol	1-year study	[50]
COPD study Tiotropium added to usual care COPD treatments	13 to prevent one exacerbation per year 38 to prevent one hospitalization per year	Nine trials n = 8002 Tiotropium reduced COPD exacerbations, hospitalizations, improved quality of life and symptoms and may have slowed the decline in FEV₁	[53]
COPD study Roflumilast vs placebo added to SABA (99–100%) ± SAMA (35–37%) ± LABA (44–45%)	4 to prevent one exacerbation per year 18% reduction in exacerbations 5 to prevent one exacerbation per year 15% reduction	1-year study n = 1571 No ICS during either trial 1-year study n = 1525	[70]
COPD study Theophylline vs LABA Theophylline vs ICS	9 to prevent one exacerbation per year with theophylline vs LABA 5 to prevent one exacerbation per year with ICS vs theophylline	n = 36,492 reconstructed from healthcare database in COPD patients aged ≥50 years	[74]
COPD study Azithromycin or placebo added to usual care COPD treatments	3 to prevent one exacerbation per year	Exacerbations reduced despite development of antibiotic resistancen = 1142	[77]
COPD study Carbocisteine added to usual care COPD treatments, including inhaled corticosteroids	6 to prevent 1 exacerbation per year	1-year study Mucolytic 1500 mg per day n = 709	[76]
Asthma study Fluticasone + salmeterol compared with fluticasone	15 to prevent one exacerbation per year	1-year study Fluticasone titrated for asthma control every 12 weeks n = 3421	[23]
Asthma study Omalizumab added to ICS + LABA + other controllers	3 to prevent one exacerbation per year 2 to prevent one severe exacerbation per year 2 to prevent one emergency visit	28-week study n = 419 Add-on omalizumab significantly reduced clinically significant exacerbation rates by 26%, severe exacerbation rates by 50% and emergency visit rates by 44%	[68]
Asthma study Omalizumab added to ICS + LABA	10 to prevent one exacerbation per year 33 to prevent one hospitalization per year 5 for one successful corticosteroid discontinuation	Eight trials n = 3429 US$12,000 per year Serious adverse effects omalizumab (3.8%) vs placebo (5.3%). No increased risk of malignancy, hypersensitivity or cardiovascular effects	[66]
Asthma study Salmeterol or montelukast added to ICS	38 to prevent one exacerbation per year for salmeterol vs LTRA	Seventeen trials n = 5895 Add-on LABA superior to LTRA in preventing exacerbations, symptom control and need for rescue albuterol	[87]
Asthma study Budesonide or placebo + usual therapy in mild persistent asthma	45 to prevent one exacerbation in 3 years	5-year study n = 7241 age 5–66 years	[88]
Asthma study Bronchial thermoplasty in severe persistent asthma despite step 5 of the NIH NAEPP EPR-3 treatment guidelines	6 to prevent one exacerbation per year 7 to improve quality of life	n = 288	[89]
COPD study Patient self-management vs usual care	2 to prevent one hospitalization per year 39.8% reduction in hospital admissions for COPD	1-year study Emergency department visits were reduced by 41.0% and unscheduled physician visits by 58.9%	[33]

NNT rounded to whole number. For comparison, NNT for primary prevention of nonfatal myocardial infarction or cardiovascular death is 69 for lipid-lowering drugs and NNT for cardiovascular events for statins is 17 and 30 for death [90].
COPD: Chronic obstructive pulmonary disease; FEV₁: Forced expiratory volume in 1 s; ICS: Inhaled corticosteroids; LABA: Long-acting β₂ agonists;
LTRA: Leukotriene receptor antagonist; NNT: Number needed to treat; SABA: Short-acting β₂ agonist; SAMA: Short-acting muscarinic receptor antagonist.

Box 1. Risk factors and symptoms related to asthma–chronic obstructive pulmonary disease overlap syndrome with suggested major and minor criteria for clincial recognition.
Risk factors Atopy; for example, hay fever, elevated total IgE, positive RAST testing or intradermal allergen testing History of current or past cigarette smoking (>10 pack-years) Severe persistent asthma during childhood Symptoms Chronic cough or wheezing with or without sputum (early symptom) Dyspnea or exercise intolerance (late symptom) Reduction in daily activities of living Frequent need for inhaled albuterol Frequent acute exacerbations despite adherence to standard pharmacotherapy Major criteria A physician diagnosis of asthma and chronic obstructive pulmonary disease in the same patient History or evidence of atopy; for example, hay fever, elevated total IgE Age ≥40 years Smoking >10 pack-years Postbronchodilator FEV₁<80% predicted and FEV₁/FVC < 70% Minor criteria ≥15% increase in FEV₁or ≥12% and ≥200 ml increase in FEV₁postbronchodilator treatment with albuterol
FEV₁: Forced expiratory volume in 1 s; FVC: Forced vital capacity; RAST: Radioallergosorbent test.

Box 2. Current and emerging drug treatments for asthma and chronic obstructive pulmonary disease and dual utility in asthma–chronic obstructive pulmonary disease overlap syndrome.
Smoking aids Nicotine replacement treatments^†‡§ Bupropion (Zyban®[GlaxoSmithKline, London, UK])^†‡§ Varenicline (Chantix®[Pfizer, NY, USA])^†‡§ Nicotine vaccines Bronchodilators Short-acting SABA, for example, racemic albuterol^§, levalbuterol (Xopenex®[Sunovion Pharmaceuticals, MA, USA])^§ SAMA, for example, ipratropium (Atrovent®[Boehringer Ingelheim, Ingelheim, Germany])^‡ Combination SABA + SAMA, that is, combination albuterol + ipratropium (Combivent®[Boehringer Ingelheim, Ingelheim, Germany])^‡ Long-acting LABA^#, for example, salmeterol (Serevent® [GlaxoSmithKline, London, UK])^‡§, formoterol ^{(Foradil® [Novartis, Basel, Switzerland])‡§}, arformoerol inhalation solution (Brovana® [Dainippon Sumitomo, Osaka, Japan]), formoterol inhalation solution (Perforomist® [Dey Pharma, NJ, USA]), indacaterol (Arcapta® [Novartis, Basel, Switzerland])^†, vilanterol, carmoterol, milveterol, BI-1744-CL, PF-00610355, LAS-100977 LAMA, for example, tiotropium (Spiriva® [Boehringer Ingelheim, Ingelheim, Germany])^‡§, aclidinium (Tudoraza® [Forest Pharmaceuticals, NY, USA] or Eklira® [Almirall, Barcelona, Spain])^‡, glycopyrronium, darotropium, dexpirronium, umeclidinum, QAT-370, TD-4208 Emerging treatments MABA – dual pharmacophore with long-acting musacrinic antagonist and β₂agonist pharmacology^†‡§ GSK-961081 (GlaxoSmithKline, London, UK), formerly TD-5959 THRX-200495 (Theravance, CA, USA) IL-4 inhibitor pitrakinra^† IL-5 inhibitors mepolizumab^†, reslizumab^† IL-13 inhibitor lebrikizumab^† Statins Simvastatin Other drugs Immunosuppressive agents, for example, cyclosporin A and antimetabolite methotrexate TNF-α inhibitor NF-κB inhibitors p38 MAPK inhibitors^†‡§ Proteinase inhibitors targeting matrix metalloproteinase and neutrophil elastase Antioxidants Inhaled corticosteroids (in order of increasing potency; equal efficacy when dose-adjusted)^†§ Triamincolone (Azmacort® [Abbott Laboratories, IL, USA]) Beclometasone (Qvar® [IVAX, FL, USA]) Budesonide (Pulmicort® [AstraZeneca, London, UK]) Ciclesonide (Zetonna® [Sunovion Pharmaceuticals, MA, USA]) Mometasone (Asmanex® [Merck, NJ, USA]) Fluticasone propionate (Flovent® [GlaxoSmithKline, London, UK]) Double therapy (ICS + LABA) in single delivery device^# Fluticasone proprionate + salmeterol (Seretide® [GlaxoSmithKline, London, UK] or Advair® [GlaxoSmithKline, London, UK])^‡§¶# Fluticasone furoate + vilanterol (Relovair® [GlaxoSmithKline, London, UK])^# Budesonide + formoterol (Symbicort® [AstraZeneca, London, UK])^‡§¶# Mometasone + formoterol (Dulera® [Merck, NJ, USA])^§†# Mometasone + indacaterol^# Double therapy (LABA + LAMA) in single delivery device^# Carmoterol + tiotropium Formoterol + aclidinium Formoterol + gycopyrronium Indacaterol + glycopyrronium Vilanterol + umeclidinium Milveterol + darotropium Vilanterol + darotropium Triple therapy (ICS + LABA + LAMA or PDE-4 inhibitor + LABA + LAMA) in single delivery device Mometasone + indacaterol^#+ glycopyrronium Fluticasone furoate + milveterol or vilanterol^#+ darotropium or umeclidinium Ciclesonide + formoterol^#+ tiotropium Leukotrine modifiers Leukotriene receptor antagonists^†§ Montelukast (Singulair®[Merck, NJ, USA]) Zafirlukast (Accolate®[AstraZeneca, London, UK]) Pranlukast (Azlaire®[Schering-Plough] or Onon®[Ono Pharmaceutical Co., Ltd.]) 5-lipoxygenase inhibitor^†§ Zileuton (Zyflo®) Phosphodiesterase-4 inhibitors Roflumilast (Daliresp®[Forest Pharmaceuticals, NY, USA] or Daxas® [Takeda, Zurich, Switzerland])^‡§ Methylxanthine Theophylline^†‡§ Monoclonal antibodies and immunomodulators Omalizumab (Xolair®[Novartis, Basel, Switzerland])^† Vaccines NTHi oral immunotherapeutic (HI-164OV) against Hemophilus influenzae ^‡ Pneumococcal vaccine Influenza vaccine Antibiotics Azithromycin^†‡§ Azole antifungal agents, itraconazole^† Mucoregulators Carbocisteine^‡
^†Asthma only. ^‡Chronic obstructive pulmonary disease only. ^§Both or asthma–chronic obstructive pulmonary disease overlap syndrome. ^¶Only fluticasone 250 µg/salmeterol 40 µg fixed combination dry powder inhaler and budesonide 160 µg/formoterol 4.5 µg fixed combination metered-dose inhaler are US FDA approved for chronic obstructive pulmonary disease in the USA. ^#FDA black box warning alert contraindicate their use as monotherapy in asthma patients and warning their use alone or in combination with other medications that cause asthma deaths. ICS: Inhaled corticosteroids; LABA: Long-acting b2 agonist; LAMA: Long-acting muscarinic receptor antagonist; SABA: Short-acting b2 agonist; SAMA: Short-acting muscarinic receptor antagonist.

processing....

The Asthma–Chronic Obstructive Pulmonary Disease Overlap Syndrome

Pharmacotherapeutic Considerations

Abstract and Introduction

Abstract

Introduction

Tables

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

Sidebar

Sidebar

Key Issues

Email This

Feedback