We have shown here that longer asthma duration and the absence of rhinosinusitis, in addition to cigarette smoking, are independent factors associated with the development of irreversible FAO in Korean patients with severe asthma. Although effective methods to improve the management of patients with severe asthma remain a challenge for physicians, the results presented here provide further evidence of the importance of quitting smoking in preventing irreversible airway obstruction, especially in patients with severe asthma . These results also indicate that patients with a certain subtype of severe asthma, without upper airway pathology such as rhinosinusitis, are more likely to develop irreversible airway obstruction. Moreover, our findings highlight the significance of understanding the heterogeneity of severe asthma and suggest that the pathogenesis of severe asthma without rhinosinusitis might differ from that of severe asthma with rhinosinusitis. Clarification of the mechanisms underlying certain subtypes of severe asthma may provide clues to therapeutic strategies for overcoming this condition.
Although only a small proportion of patients with asthma have severe asthma, this subtype of asthma is associated with most asthma-related morbidities and asthma-associated costs . Severe asthma is characterized by frequent asthma attacks, resistance to high-dose ICS treatment and fixed irreversible airway obstruction . As many studies have suggested that the clinical manifestations of severe asthma are heterogeneous [4, 5], progressive decline in lung function leading to FAO has been reported in about 50% of patients with severe asthma, which is in agreement with our and other results . FAO is thought to be closely related to the development of airway remodeling, as well as with poorer prognosis [21, 22]. Identification of risk factors related to the occurrence of FAO in severe asthma may therefore be critical because it may provide a foundation for clarifying the pathogenesis of the disease and may ultimately lead to effective therapeutic approaches. Although several studies had assessed the factors causing irreversible airway obstruction in asthmatic patients of other ethnic groups, the characteristic features of severe asthma with FAO and the factors associated with its pathogenesis had not previously been clarified in Korean patients with severe asthma.
Various clinical characteristics have been proposed as risk factors for the development of FAO in patients with severe asthma . Several studies have found that smoking is one of the most important risk factors for FAO [15, 23]. Other suggested risk factors for FAO include adult-onset asthma, airway hyperresponsiveness and, most importantly, sputum eosinophilia . Low lung function at a young age has been reported to be a risk factor for FAO, suggesting that structural changes already occur during the early course of the disease . Other possible risk factors for FAO include recurrent severe asthma exacerbation, higher degree of asthma severity, male sex [8, 25–27], longer disease duration , advanced age and aspirin sensitivity . In agreement with these findings, we found that longer disease duration and smoking history were closely associated with FAO in Koreans with severe asthma.
In the current study, we also found that an absence of rhinosinusitis was closely associated with FAO in our patient population. Interestingly, the factor of absence of rhinosinusitis had not been previously described as a risk factor for FAO. Rather, patients with severe asthma were reported to have more severe rhinosinusitis than were those with mild asthma . Furthermore, uncontrolled rhinosinusitis is a well known compounding factor which is involved with poorly controlled asthma . Meanwhile, there is a report that the prevalence of rhinosinusitis has been found to decrease, and asthma severity to increase, with age . Our finding, of a reduced prevalence of rhinosinusitis in patients with more severe asthma, may be due to the spontaneous regression of rhinosinusitis during the course of asthma. The relationship between FAO and the absence of rhinosinusitis in patients with severe asthma, however, is not yet clear, although it may represent a unique feature of Korean patients with severe asthma.
In the present study, asthmatic patients with FAO tended to be more non-atopic, although the difference was not statistically significant. Non-atopic asthma without rhinosinusitis may be a pre-requisite factor for the development of FAO in our patient cohort, because atopic asthma is usually milder, has an earlier onset and is more commonly accompanied by other allergic disease such as allergic rhinosinusitis [1, 31, 32]. Classification of severe asthma into several groups through cluster analysis also found that one cluster was characterized by childhood onset, more atopic and presence of RAO, while the other cluster consisted of patients with later-onset disease, less atopic and FAO. Thus, FAO in severe asthma may be related to the absence of rhinosinusitis due to the non-atopic conditions of the subjects.
Many studies have reported that longer duration of asthma may lead to irreversible airway obstruction [28, 33, 34]. Prolonged airway inflammation may be related to increased remodeling of the airway walls and a greater reduction in the airway lumen over time. We also observed significant correlations between asthma duration and FAO in multivariate analysis.
In previous reports, advanced age was associated with the development of FAO [33, 35]. Elderly asthma patients tend to show reduced immediate bronchodilator responses and decreased reversibility of airway obstruction after treatment. These results may be caused by the occurrence of irreversible airway remodeling in elderly asthma patients, who presumably have longer disease duration. However, in our study, older age was not an independent risk factor for FAO.
Sputum eosinophilia is thought to be an important marker of FAO, suggesting that eosinophilic airway inflammation may contribute to persistent airflow limitation in patients with severe asthma[36, 37]. Eosinophils can secrete a variety of chemical mediators which may induce airway remodeling [36, 37]. We found, however, no significant differences between the FAO and RAO groups in numbers of sputum or blood eosinophils, although the numbers tended to be higher in the patients with FAO.
This study had several limitations. First, as it was observational study in design, the clinical situations of the patients may have been diverse regarding types of medications, adherence to medications, familiarity with a certain inhaler device, and environmental control of workplaces or home. These might have affected the clinical course and the proportion of FAO, although all enrolled patients were optimally treated by experts and with correct medications and were also believed to be compliant with their prescribed medications. In addition, FAO was defined one year after enrollment, a relatively short follow-up period. FAO may have been a consequence of long lasting inflammatory processes in the asthmatic airways. Thus, a longer-term follow-up study is required to determine the risk factors for FAO in patients with severe asthma.
Another limitation of our study is that the presence or absence of rhinosinusitis was basically identified by history-taking and according to patients' symptoms. As not all study patients underwent objective measures to confirm their diagnosis, such as rhinoscopy, paranasal sinus radiography or ostiomeatal unit computed tomography, patients with asymptomatic rhinosinusitis may have been misclassified in this study. Future studies should include objective tests to exclude patients with asymptomatic rhinosinusitis.
As it is not always possible to completely exclude smoking-related COPD, this may be another important limitation of this study. Although patients whose major diagnosis could be COPD were not included in this study, some of the participants may have belonged to the asthma and COPD overlap syndrome population . Moreover, not only the patients with RAO but also those with FAO may be heterogeneous in terms of the reversibility according to the level of airway obstruction. Although in the current study FAO was defined as existing only when all three pulmonary function tests, when performed under stable conditions, showed an FEV1/FVC ratio < 0.7, considerable heterogeneity in the patients clinical features is still present even in severe asthma. Thus, there is an urgent need to clarify the heterogeneity of asthma, and further studies should be conducted.
Finally, our population of patients with severe asthma might not be representative of all Korean patients with severe asthma enrolled in the COREA since some clinical features differed between the groups of included and non-included patients. Hence, further studies with larger study populations are also needed to confirm our findings.
In conclusion, this study is the first to report factors that may be related to persistent airflow limitation in Koreans with severe asthma. We found that long-standing asthma and the absence of rhinosinusitis were more likely to lead to persistent irreversible airway obstruction. In addition, our findings further demonstrated that smoking is an important cause of irreversible airway damages. Further studies are required to clarify the mechanisms underlying the development of FAO in Korean subjects with severe asthma.