Asthma and chronic obstructive pulmonary disease (COPD) have historically been considered different diseases. However, studies consistently have shown that there are some overlapped patients with asthma and COPD. The Global Initiative for Asthma and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recently accepted the concept of asthma-COPD overlap syndrome (ACOS). However, a firm definition of ACOS is lacking. Thus, a large number of patients can be considered to have ACOS. An understanding of the pathophysiology of ACOS according to each subtype is very important. Phenotypic classification based on the underlying disease mechanism is needed for appropriate management of individual patients.

ACOS can be diagnosed by spirometric examination findings (Fig. 1) [1]. According to this definition, patients with both fixed airflow obstruction (AO; post-bronchodilator forced expiratory volume in 1 second [FEV₁]/forced vital capacity of < 0.7) and bronchodilator reversibility (BDR) or fixed AO and bronchial hyperresponsiveness (BHR) can be considered to have ACOS. This approach is easily applicable in clinical practice. Moreover, this definition is very clear-cut. Thus, it is easy even for general practitioners to diagnose ACOS. However, this definition has some limitations. First, this definition does not consider clinical characteristics, only spirometric criteria. Thus, many important features including a history of smoking, childhood asthma, and atopy are missing from this definition. Second, according to this definition, a large number of patients are classified as having ACOS. For example, even if a patient has relatively pure COPD (no history of asthma, allergic lung inflammation, or atopy), the patient can be classified as having ACOS only if BDR is present. As another example, even if a patient has relatively pure asthma (no history of smoking or biomass fuel exposure), the patient can be classified as having ACOS only if fixed AO is present.

Patients with ACOS diagnosed according to spirometric criteria are inevitably heterogeneous. A large number of patients with obstructive disease, from those with predominant asthma features to those with predominant COPD features, can be considered to have ACOS by these criteria. Consequently, there are several phenotypes of ACOS. Several factors should be considered in the classification of these phenotypes. Eosinophilic lung inflammation and a history of allergic disease are important asthma-related factors, while smoke exposure and emphysema are important COPD-related factors. ACOS can be classified into four categories according to different combinations of these factors (Figs. 2 and 3).

The main treatment option for phenotype A is asthma medication (Fig. 6). Because patients with phenotype A have typical asthma features and eosinophilic inflammation, inhaled corticosteroids (ICS) are a key treatment component. However, because these patients have lower lung function (fixed AO), ICS + a long-acting beta agonist (LABA) is recommended. Other asthma medications can also be used, such as a leukotriene antagonist (LTRA). If patients with phenotype A are not well controlled by ICS + LABA, a long-acting muscarinic antagonist (LAMA) can be added. A previous study showed that LAMAs are not inferior to LABAs in step-up therapy [23], and adding LAMA to an ICS + LABA regimen can decrease exacerbations of asthma [24]. Because patients with phenotype A have allergic lung inflammation, anti-IgE medications are likely to be effective.

The main treatment option for phenotype B is based on medication for severe asthma. ICS + LABA can be considered as first-line therapy. However, many patients with severe noneosinophilic asthma are not adequately controlled by ICS + LABA. Thus, adding a LAMA can be useful for patients with phenotype B. Iwamoto et al. [25] showed that tiotropium was effective for severe asthma with a noneosinophilic phenotype and that the treatment response was well correlated with the sputum neutrophil percentage. Because patients with phenotype B have noneosinophilic lung inflammation, macrolides can be considered for patients with uncontrolled disease. Simpson et al. [26] showed that clarithromycin therapy significantly reduced the airway concentrations of interleukin-8 and neutrophils and improved the quality-of-life scores compared with placebo. These reductions in inflammation were most substantial in patients with refractory noneosinophilic asthma. In a subgroup analysis of azithromycin for prevention of exacerbations of severe asthma [27], azithromycin effectively decreased the rate of severe exacerbations of severe noneosinophilic asthma.

The optimal therapy for phenotype C is ICS + LABA. Kitaguchi et al. [15] evaluated the effect of ICS treatment for ACOS and found that the increases in FEV₁ in response to treatment with ICS were significantly higher in patients with ACOS than in patients with only COPD. The authors found no significant difference in the increases in FEV₁ in response to a β2-agonist between the two groups. The response to ICS was strongly correlated with the sputum eosinophil concentration. LTRAs can also be a good therapeutic option for patients with phenotype C. Price et al. [28] showed that LTRAs can be relatively effective for smokers with asthma. Patients with a smoking history of ≤ 11 pack-years tended to show a greater benefit with fluticasone, whereas those with a smoking history of > 11 pack-years tended to show a greater benefit with montelukast. Because patients with phenotype C have a history of both asthma and smoking, LTRAs are expected to be helpful for these patients.

Treatment for phenotype D should be consistent with COPD guidelines. These patients have no history of asthma and have neutrophilic inflammation. Because the prognosis of COPD with BDR or BHR is poor, more intensive therapy should be administered. Few studies have compared patients with only COPD versus those with BDR or BHR. However, because these patients are likely to lose lung function rapidly, medication to prevent lung function decline is recommended. In a post hoc analysis of the Towards a Revolution in COPD Health (TORCH) study, salmeterol plus fluticasone reduced the rate of decline of FEV₁ in patients with moderate to severe COPD [29]. In a subgroup analysis of the UPLIFT trial, tiotropium reduced the rate of decline of post-bronchodilator FEV₁ in patients with GOLD stage II COPD [30]. Thus, these medications are likely to be beneficial. Because patients with phenotype D have neutrophilic inflammation, the addition of roflumilast may also be considered for patients with frequent exacerbations and chronic bronchitis. Albert et al. [31] and Uzun et al. [32] showed that azithromycin could be effective in reducing exacerbations of COPD. The addition of azithromycin can be also considered for patients with frequent exacerbations.

According to the spirometric definition of ACOS, many patients with asthma or COPD can be considered to have ACOS. Thus, a narrower definition of ACOS is needed. Spanish experts suggested a definition of ACOS based not only on spirometric criteria but also on clinical criteria [33]. This Spanish definition is more reasonable than a definition based on spirometric criteria alone. However, there has been little discussion of COPD in the Spanish definition; no diagnostic criteria for COPD have been provided. According to this Spanish definition, never-smokers with life-long allergic asthma can also be considered to have ACOS. Thus, as stated above, a narrower definition of ACOS is needed. A narrow and focused definition of ACOS should include both spirometric and clinical criteria. Inclusion of both asthma and COPD is also mandatory. A narrow definition of ACOS is illustrated in Fig. 7. Patients who meet all four criteria can be considered to have true ACOS. This definition is very compatible with phenotype C ACOS as described in the present article. A clinical trial is necessary to fully evaluate the efficacy of various medications for ACOS. However, without a simple and firm definition of ACOS, it is not possible to perform a high-quality clinical trial. Thus, a narrow definition of ACOS that includes both asthma and COPD is needed. The present report may serve as a baseline for establishment of such a definition, which will prompt the development of future clinical trials.

Many patients with asthma or COPD have overlapping characteristics of both diseases. Use of spirometric criteria may result in the classification of many patients with COPD as having ACOS. These patients with ACOS can be classified by phenotype. Each phenotype has different characteristics and prognoses. Treatment also should be tailored according to phenotype. A narrower definition of ACOS is needed for the performance of future clinical trials.