Asthma COPD Overlap

Asthma and chronic obstructive pulmonary disease (COPD) overlap (ACO) is a recently recognized clinical entity of important significance.

It identifies a subgroup of smokers with COPD that share some pathogenic and inflammatory characteristics with asthma and that tend to have a more severe disease phenotype than just COPD alone.

It has been defined as either:

•Asthma with partially reversible airflow obstruction with or without emphysema or reduced carbon monoxide diffusing capacity (DLco) to <80% predicted
•Chronic obstructive pulmonary disease (COPD) with emphysema accompanied by reversible or partially reversible airflow obstruction, with or without environmental allergies or reduced DLco
Patients with ACO, formerly known as asthma COPD overlap syndrome (ACOS), have varying phenotypes, such as COPD with eosinophilia, neutrophilic-predominant asthma with severe disease or who smoke, or asthma with largely irreversible airway obstruction due to structural changes. Given the heterogeneity, reframing ACOS as ACO was proposed and is now widely accepted as the more appropriate diagnostic terminology.

Synonyms

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

Epidemiology & Demographics

Prevalence

•COPD prevalence varies considerably by U.S. state, from <4% in Hawaii, Colorado, and Utah to >9% in Alabama, Tennessee, Kentucky, and West Virginia.
•Approximately 25 million Americans (19.2 million adults and 5.5 million children) have asthma.
•The prevalence of bronchial hyperresponsiveness among patients with COPD has been reported to be 50%, but up to 90% have bronchial hyperresponsiveness, especially among women with COPD.
•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.
•Among published studies, persons with ACO have worse lung function, more respiratory symptoms, and a lower health-related quality of life than those with either disease alone. Those with ACO are reported to experience more frequent health care utilization and more severe impairment than persons with COPD or asthma alone.
•In a recent study, 15-yr mortality for ACO was similar to that for COPD and worse than that for asthma and healthy controls. ACO had a significant impact on physical performance, functional ability, and health-related quality of life.
•The prevalence of ACO is between 15% and 25% in an adult population of obstructive airway diseases. ACO is also more prevalent in the elderly, African Americans, and among individuals with greater disease severity.
•Epidemiologic studies report an estimated prevalence of 20%.

Predominant Sex & Age

•Sex: In a large, population-based sample, women were more likely than men to have ACO.
•Age: The prevalence of ACO has been shown to increase with age (>60 yr), which may reflect that with time asthmatics may develop fixed airway obstruction.

Risk Factors

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

Genetics

No known genetic basis has been described. Genetic linkage studies and genome-wide association (GWA) studies have been of limited value in characterizing a link between asthma and COPD.
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 ACO.

Physical Findings & Clinical Presentation

Physical examination:

•May be normal
•Wheezing, rhonchi
•Hoover sign (inspiratory retraction of the lower intercostal spaces)
•In severe cases, decreased airway entry, abdominal retractions, accessory muscle use, abdominal muscle use

Clinical presentation:

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

Etiology

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

Diagnosis

ACO should be considered when “a similar number of features listed for asthma and COPD are present.” This definition for ACO is not yet very specific, recognizing 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 ACO 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

•COPD
•Asthma
•Central airway obstruction
•Bronchiectasis
•Heart failure
•Obliterative bronchiolitis

Workup

•Patients must have demonstrated either one of these to be diagnosed with “asthma-COPD overlap”:
- 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”
•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

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

Imaging Studies

•Chest x-ray
•Chest CT scan
•ECG

Treatment

There is little information about the response of ACO 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 ACO 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

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

Acute General Rx

•At present, there are no large randomized clinical trials to help guide therapeutic interventions in ACO.
•Treatment typically is directed toward management of symptoms.
•For dynamic obstruction and/or hyperinflation, bronchodilators may provide the greatest benefit.
•Whether long-acting muscarinic antagonists (LAMAs) alone or in combination with long-acting beta-agonists (LABAs) are appropriate in ACO remains to be elucidated, but according to the 2020 GINA guidelines, recommendations against giving LABA and/or LAMA alone without ICS was provided.
•For patients in whom bronchospasm is demonstrated, bronchodilators and ICSs are reasonable options.
•One clinical trial has shown efficacy for fluticasone furoate/vilanterol combination (once-daily ICS/LABA) in a population of ACO patients.
•The 2020 GINA guideline supports consideration of including an ICS in treatment regimens of patients with ACO. A well-designed case-control trial demonstrated newly prescribed ICS+LABA combination therapy in patients with a history of COPD and asthma was associated with lower composite risk of hospitalization or death compared with LABA treatment alone.
•A previous post hoc, exploratory analysis of clinical outcomes of adult patients with ACO treated with omalizumab in the Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab (Prospero) showed that ACO patients treated with omalizumab had similar outcomes to patients with asthma without ACO in ACT score and exacerbation frequency with preserved lung function after 48 wk of treatment.

Chronic Rx

•Earlier screening for ACO 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.
•As the prevalence of ACO 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.
•Treating comorbidities such as chronic aspiration, gastroesophageal reflux disease (GERD), or vocal cord dysfunction (VCD) is important.
•Evaluation for cardiovascular disease is important given the higher risk of cardiovascular disease in patients with ACO even without the presence of comorbidities.

Complementary & Alternative Medicine

None

Referral

Referral for expert advice and further diagnostic evaluation is necessary in the following contexts:

•Persistent symptoms and/or exacerbations
•Diagnostic uncertainty
•Patients with asthma/COPD with atypical/additional symptoms such as hemoptysis, weight loss, night sweats, fevers, signs of bronchiectasis
•Comorbidities that may interfere with assessment and management
•No response to treatment

Prevention

•Smoking cessation
•Avoidance of triggers

Asthma COPD Overlap