Discussion
This is the first study that employed EB-OCT measurement to unravel the objective evidence of luminal narrowing and airway wall thickening in medium-sized and small airways that correlate with asthma severity. Airway remodeling in mild asthma was characterized by airway wall thickening from the 3rd to 9thgeneration, without notable luminal narrowing. The duration of symptoms, but not sputum eosinophil count, correlated with airway remodeling. After salbutamol inhalation, medium-sized and small airways elicited the most prominent changes in moderate-to-severe asthma, and the increase of medium-sized airway inner area correlated significantly with that of FEV1 and FVC.
Remodeling of the asthmatic airways has been attributable to mucus gland hypertrophy, smooth muscle hyperplasia, increased fibroblasts and collagen deposition18-25. High-resolution CT showed that asthmatic patients had significantly greater Aw and smaller airway Ai compared with control subjects26. Our study has extended these findings with EB-OCT measurement which provided high-resolution images and had a high consistency to histological findings 8, 9. Furthermore, EB-OCT could measure airway architectures as distal as to the 9thgeneration of bronchi. Consistent with CT studies which probed the airways up to the 6th generation bronchi27, both Ai and Aw% of the medium-sized and small airways correlated significantly with asthma severity. The Ai tapered and Aw% increased more considerably in patients with greater asthma severity (particularly the 5th-9th generation). The concomitant decrease in Ai/BSA and increase in Aw% indicated the myriad of smooth muscle and mucus gland hypertrophy, increased collagen deposition and mucus plugging in moderate-to-severe asthma28-30. Importantly, patients with mild asthma have already developed airway remodeling, evidenced by the significantly greater Aw% in the 3rd-9th generation of bronchi compared with control subjects, which was in accordance with the results of previous studies that airways of patients with mild asthma yielded greater collagen and matrix production from fibroblasts compared with control subjects31-33. However, thickened airway wall with a relative nomal inner airway luminal area in mild asthma indicated different remodeling patterns as compared with that of early-stage COPD, characterized by airway narrowing with airway wall thickening in medium-sized and small airways (see Table E8 in Online Supplment)34. Endobronchial biopsies from COPD patients with features of asthma and the asthmatic patients who have smoked showed an overlap of the histological features of inflammatory cell infiltration and thickening of the basement membrane35. Findings of the present study coupled with the published evidence suggested that OCT measurements would provide a complementary evidence of the airway wall structural characteristics, particularly in small airways. This will help illuminate the discrepancies between asthma and COPD, or asthma-COPD overlap. However, asthma remained suboptimally controlled in a considerable proportion of patients with mild asthma. Notably, the airway structural changes in patients with mild asthma may be explained by the chronic inflammatory that predisposed to airway wall thickening and remodeling. Our results have offered indirect support to the findings of the recent clinical trials – as-needed inhaled corticosteroids effectively improved syptom control and prevented from excebations in patients with mild asthma36, 37. Hence, the airway remodeling of the medium-sized and small airways might the rationale for targeted anti-inflammatory therapies for asthma.
The morphological changes in response to bronchodilators has been related to the variable airflow limitation in asthma. Multiple-breath nitrogen washout technique revealed that both conductive airways and acinar airways were partly reversible after salbutamol inhalation in asthma38. Furthermore, xenon-enhanced CT showed that the changes in Ai correlated significantly with improvements of FEV139. Here, we have further extended the morphological assessment directly with EB-OCT to small airways in a real-time fashion. Notably, the airway caliber significantly increased in both medium-sized and small airways after bronchodilator inhalation. Furthermore, the improvement in FEV1 correlated with the increase in Ai/BSA of medium-sized, but not small, airways. FEV1 primarily reflects the airflow in central airways and reportedly correlated with wheezing in asthma40-42. Because bronchoconstriction in medium-sized airways mainly contributed to the increase of airway resistance41, the dilatation of medium-sized airways might lead to re-opening of the occluded small airways and improvement in ventilatory heterogeneity43. A study with technetium-99m-labeled albuterol aerosols showed that large particles had a more proximal deposition, and achieved greater short-term lung function improvement than smaller particles44, 45. The proximal deposition might be responsible for the dilatation of medium-sized airways, which significantly correlated with the improvement of FEV1. Hence, proximal (the 3rd-6th generation) airways responded most prominently to salbutamol inhalation. Our observations also indicated the modes of action of bronchial thermoplasty, the effects of which were confined to a small number of large and medium-sized airways (the 3rd-5thgeneration) that contributed to symptom control in severe refractory asthma46. From morphological and physiological perspectives, these findings added to our understanding of the mechanisms on how and when bronchodilators improve lung function and alleviate asthmatic symptoms.
Persistent chronic inflammation is related to airway remodeling (e.g. inflammatory cells infiltration, collagen deposition, connective tissue and smooth muscle proliferation) in asthma.28-30Patients with severe asthma and airflow limitation usually had a longer disease duration47, which significantly correlated with more prominent airway wall thickening28, 48. Consistently, Ai and Aw% of medium-sized bronchus (the 3rd-6th generation), but not small airways (the 7th-9th generation), markedly correlated with the disease duration. Hence, prolonged courses of asthma might aggravate medium-sized airways remodeling and smooth muscle contraction, and lung function decline. However, we did not observe a significant correlation between sputum or blood eosinophil count and airway remodeling.
EB-OCT measurement has its unique advantage over CT assessment, including the avoidance of radiation exposure, the ability to continuously measure the airway morphology in vivo , and the ability to detect dynamic airway morphologic changes in terms of bronchodilator responses. Nonetheless, some caveats should be considered. This study is limited by the lack of direct bronchoscopic biopsies from the asthmatic airways to compare the OCT images and histological findings. However, the consistency between OCT and histological measurements had been well acknowledged 9, 15. We therefore believed that OCT measurements might better reflect the asthmatic airway morphological changes (particularly the caliber)in vivo . Second, our study was limited by its cross-sectional design. A longitudinal study with a longer follow-up duration (i.e. 12 months) or different medication categories (i.e. long-acting beta-receptor agonists or muscarinic receptor antagonists) would be needed. To secure the comparability of EB-OCT measurement in an identical bronchial segment during scanning, we have only detected the bronchodilator responses at a single segment (RB9), because it would not be ethical and practical to detect the whole airway structure before and after salbutamol inhalation.
In conclusion, we have unraveled airway remodeling (luminal narrowing and airway wall thickening) that correlated with asthma severity. Patients with mild asthma have already developed airway remodeling, lending support to the use of anti-imflammatory intervention in mild asthma. The understanding of the principal anatomical site of bronchodilator responses might shed light on the development of inhaled bronchodilators to more effectively improve lung function and ameliorate symptoms in asthma.
Author contributions: Z. Q. S., Z. Q. Z. and W. J. G. performed the literature search and drafted the manuscript; Z. Q. S., Z. Q. Z., Y. C., X. B. C., C. H. Z. and C. L. T. were responsible for subject recruitment; Z. Q. S., Z. Q. Z., and W. J. G. contributed to the data collection, data analysis and data interpretation; Z. Q. S., Z. Q. Z., W. J. G., S. Y. L. and N. S. Z. contributed to study conception; S. Y. L. and N. S. Z. provided critical review of the manuscript and approved the final submission.