Asthma-COPD Overlap Syndrome

Rania Esteitie, M.D.
Samaan Rafeq, M.D.

Basic Information

Definition

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The asthma and chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is a recently recognized clinical entity of important significance. It identifies a subgroup of smokers with COPD that shares some pathogenic and inflammatory characteristics with asthma and that tends to have a more severe disease phenotype than just COPD alone. It has been defined as either:
1. ○
  
  Asthma with partially reversible airflow obstruction with or without emphysema or reduced carbon monoxide diffusing capacity (DLco) to <80% predicted.
2. ○
  
  Chronic obstructive pulmonary disease (COPD) with emphysema accompanied by reversible or partially reversible airflow obstruction, with or without environmental allergies or reduced DLco.

Synonyms

Bronchospasm
Reactive airway disease
Asthmatic bronchitis
Hyperreactive airways
Chronic obstructive pulmonary disease

ICD10-CM CODES
J45	Asthma
J42	Unspecified chronic bronchitis
J43	Emphysema
J44	COPD
J44.9	COPD, unspecified
M35.1	Other overlap syndromes

Epidemiology & Demographics

Prevalence

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COPD afflicts 14.2 million adults (a prevalence of 1 in 5) in the U.S.
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Twenty-five million Americans (18 million adults and 7 million children) have asthma (prevalence of 1 in 12 adults).
•

The prevalence of bronchial hyperresponsiveness among patients with COPD has been reported to be 60%.
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Reversibility of airway obstruction is frequently present in COPD as well; in two studies, reversibility was observed in up to 44% and 50% of patients with COPD.
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Among published studies, persons with ACOS have worse lung function, more respiratory symptoms, and a lower health-related quality of life than those with either disease alone. Those with ACOS are reported to experience more frequent health care utilization and more severe impairment than persons with COPD or asthma alone.
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In a recent study, 15-year mortality for ACOS was similar to that for COPD and worse than that for asthma and healthy controls. ACOS had a significant impact on physical performance, functional ability, and health-related quality of life.
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The prevalence of ACOS is between 15% and 25% in an adult population of obstructive airway diseases. ACOS is also more prevalent in the elderly, African Americans, and among individuals with greater disease severity.
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Epidemiologic studies report an estimated prevalence of 20%.

Predominant Sex and Age

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Sex: In a large, population-based sample, women were more likely than men to report ACOS.
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Age: The prevalence of overlap syndrome has been shown to increase with age (>60-70), which may reflect that with time asthmatics may develop fixed airway obstruction.
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Race: No published predilection for race/ethnicity noted.

Genetics

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No known genetic basis described. Genetic linkage studies and genome-wide association (GWA) studies have been of limited value in characterizing a link between asthma and COPD.
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Postma et al evaluated the paucity of GWA studies, assessing overlap syndrome and the focus on clearly defined outcomes that do not include overlap and that hamper the current insight that genetic studies provide. However, Hardin et al (2014) showed that the two most significant associations among non-Hispanic white overlap subjects include variants from the CSMD1 gene, which has been associated with emphysema, and within the SOX5 gene, which has previously been associated with COPD and may play a role in lung development.
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In a meta-analysis across the non-Hispanic white and African American groups, several variants in the GPR65 gene were identified that were associated with the overlap syndrome.

Risk Factors

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Smoking
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Atopy
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Genetics
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Childhood asthma
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Older age
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Allergies
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Infections (rhinovirus, influenza, mycoplasma)
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Higher body mass index (BMI)
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Patients with ACOS have the combined risk factors of smoking and atopy and are generally younger than patients with COPD.

Physical Findings & Clinical Presentation

Physical Examination

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May be normal
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Wheezing, rhonchi
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Hoover’s sign
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In severe cases, decreased airway entry, abdominal retractions, accessory muscle use, abdominal muscle use

Clinical Presentation

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Wheezing
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Shortness of breath
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Chest tightness
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History of repeated respiratory infections
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Chronic cough (typically productive)
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Episodic symptoms instigated by certain triggers (odors, temperatures, allergens)
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Decreased exercise tolerance

Etiology

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The pathophysiology of asthma involves a complex interaction among various environmental and genetic factors.
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Cigarette smoking interacts with the inflammation and remodeling that occur in asthma and COPD.
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No genetic basis identified thus far.

Diagnosis

ACOS should be considered when “a similar number of features listed for asthma and COPD are present.” This definition for ACOS is not yet very specific because it is recognized that a more detailed classification of patients with overlapping features of asthma and COPD is needed. Studies performed so far have generally based the diagnosis of ACOS on the pattern of symptoms, the presence of incompletely reversible airflow obstruction in ex- or current smokers or patients with asthma, the degree of bronchodilator reversibility, and bronchial hyperresponsiveness.

Differential Diagnosis

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Chronic obstructive pulmonary disease (COPD)
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Asthma
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Central airway obstruction
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Bronchiectasis
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Heart failure
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Obliterative bronchiolitis

Workup

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Patients must have demonstrated either one of these to be diagnosed with “overlap syndrome.”
1. ○
  
  Reversible airflow: increase in FEV1 or forced vital capacity (FVC) by ≥200 ml and 12% postbronchodilator challenge
2. ○
  
  Airway hyperresponsiveness (AHR): a positive methacholine challenge test
•

Asthma defined by the Global Initiative for Asthma (GINA) executive summary criteria, as a clinical syndrome with “variable airflow obstruction within the lung that is often reversible either spontaneously or with treatment.”
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COPD according to the American Thoracic Society/European Respiratory Society (ATS/ERS) joint task force: “a preventable and treatable disease state characterized by airflow limitation that is not fully reversible.”

Laboratory Tests

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Arterial blood gas (ABG)
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Complete blood count (CBC)
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Spirometry
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Methacholine challenge
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Peak expiratory flow rate (PEFR)
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Serum immunoglobulin E
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Sputum
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Allergy testing

Imaging Studies

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Chest x-ray
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Chest CT scan
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ECG

Treatment

There is little information about the response of ACOS patients to most of the current pharmacologic therapies because they have been systematically excluded from both COPD and asthma pharmacologic trials. The main interest in differentiating ACOS from COPD lies in the different response to inhaled corticosteroids (ICS). Some studies demonstrate that patients with COPD and eosinophilic inflammation treated with ICS present a significant improvement clinically and objectively by spirometry.

Nonpharmacologic Therapy

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Avoidance of environmental or occupational trigger factors
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Patient education regarding warning signs of an attack and proper use of medications (e.g., correct use of inhalers)
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Pulmonary rehabilitation

Acute General Rx

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At present, there are no randomized clinical trial data to help guide therapeutic interventions in overlap syndrome.
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Treatment typically is directed toward management of symptoms.
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For dynamic obstruction and/or hyperinflation, bronchodilators may provide the greatest benefit.
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Whether long-acting muscarinic antagonists (LAMAs) alone or in combination with long-acting beta-agonists (LABAs) are appropriate in overlap syndrome remains to be elucidated.
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For patients in whom bronchospasm is demonstrated, bronchodilators and ICSs are reasonable options.
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Clinical trials have shown efficacy for fluticasone furoate/vilanterole combination (the first once-daily ICS/LABA) versus twice-daily fluticasone propionate/salmeterol; it can provide substantial improvement in lung functions in a population of ACOS, indicating that this combination should be considered for the regular treatment of ACOS.
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A more recent study showed some efficacy with the use of omalizumab as an effective and safe therapy for patients with ACOS. However, this study included only 3 patients; therefore, larger randomized trials are needed.

Chronic Rx

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Earlier screening of the overlap syndrome is important in current or former smokers in their fifth decade of life who have partially reversible airway obstruction and progressive exercise intolerance and who have variable or no response to guideline-recommended asthma treatments. Smoking cessation, oxygen supplementation, pulmonary rehabilitation, and vaccines are all reasonable interventions.
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As the prevalence of overlap syndrome increases with age, targeting nonrespiratory age-related changes that may influence respiratory disease is paramount. This includes targeting nasal obstruction symptoms (due to nonallergic or allergic rhinitis, mucosal dryness, or vasomotor symptoms) with nasal irrigation, nasal steroids, and/or nasal anticholinergics.
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Treating comorbidities such as chronic aspiration, gastroesophageal reflux disease (GERD) or vocal cord dysfunction (VCD) is important.
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Evaluation for cardiovascular disease is important given the higher risk of cardiovascular disease in patients with asthma-COPD overlap syndrome even without the presence of comorbidities.

Complementary and Alternative Medicine

None

Referral

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Referral for expert advice and further diagnostic evaluation is necessary in the following contexts:
1. ○
  
  Persistent symptoms and/or exacerbations
2. ○
  
  Diagnostic uncertainty
3. ○
  
  Patients with asthma/COPD with atypical/additional symptoms such as hemoptysis, weight loss, night sweats, fevers, signs of bronchiectasis
4. ○
  
  Comorbidities that may interfere with assessment and management
5. ○
  
  No response to treatment

Pearls & Considerations

Prevention

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Smoking cessation
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Avoidance of triggers

Ferri – Asthma-COPD Overlap Syndrome