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.