Interventional Pulmonology

Respiration Received: August 13, 2018

Accepted after revision: November 9, 2018
DOI: 10.1159/000495298 Published online: March 22, 2019

Management of Persistent Air Leaks Using

Endobronchial Autologous Blood Patch and
Spigot Occlusion: A Multicentre Randomized
Controlled Trial in China
Hai-tao Zhang a Yong-hong Xie a Xing Gu a Wang-ping Li a Yi-ming Zeng b Shi-yue Li c
Zhi-guang Liu d Hong-wu Wang e Chong Bai f Fa-guang Jin a
a Department of Respiration, Tangdu Hospital, Air Force Military Medical University, Xi’an, China; b Department

of Pulmonary and Critical Care Medicine, Second Affiliated Hospital of Fujian Medical University, Quanzhou,
China; c Department of Respiratory, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China;
d Department of Respiratory Medicine, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan

Normal University, Changsha, China; e Department of Medical Oncology, Meitan General Hospital, Beijing, China;
f Department of Respiratory Medicine, Changhai Hospital, Navy Military Medical University, Shanghai, China

Keywords tube-attached water-seal drainage (CTD), ABP, and BOS that

Secondary spontaneous pneumothorax · Persistent air
leaks · Alveolar-pleural fistula · Bronchoscopic management
Abstract
Background: Optimal management of persistent air leaks
(PALs) in patients with secondary spontaneous pneumotho-
rax (SSP) remains controversial. Objective: To evaluate the
efficacy and safety of endobronchial autologous blood plus
thrombin patch (ABP) and bronchial occlusion using silicone
spigots (BOS) in patients with SSP accompanied by alveolar-
pleural fistula (APF) and PALs. Methods: This prospective
multicentre randomized controlled trial compared chest
were performed between February 2015 and June 2017 in
one of six tertiary care hospitals in China. Patients diagnosed
with APF experiencing PALs (despite 7 days of CTD) and in-
operable patients were included. Outcome measures includ-
ed success rate of pneumothorax resolution at the end of the
observation period (further 14 days), duration of air leak stop,
lung expansion, hospital stay, and complications. Results: In
total, 150 subjects were analysed in three groups (CTD, ABP,
BOS) of 50 each. At 14 days, 60, 82, and 84% of CTD, ABP, and
BOS subjects, respectively, experienced full resolution of
pneumothorax (p = 0.008). All duration outcome measures
were significantly better in the ABP and BOS groups than in
the CTD group (p < 0.016 for all). The incidence of adverse
events, including chest pain, cough, and fever, was not sig-

Hai-tao Zhang, Yong-hong Xie, and Xing Gu contributed equally to Prof. Fa-guang Jin
Department of Pulmonary Diseases, Tangdu Hospital
the study. Air Force Medical University
569 Xinsi Road, Xi’an, Shaanxi 710038 (China)
129.215.17.190 - 3/26/2019 2:24:09 AM

E-Mail jinfag @ fmmu.edu.cn

© 2019 S. Karger AG, Basel Prof. Chong Bai

Department of Respiratory Medicine, Changhai Hospital
Navy Military Medical University
University of Edinburgh

E-Mail karger@karger.com
168 Changhai Road, Shanghai 200433 (China)
www.karger.com/res
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E-Mail bc7878 @ sohu.com

nificantly different. All subjects in the ABP and BOS groups
experienced temporary haemoptysis. Spigot displacement
occurred in 8% of BOS subjects. Conclusion: ABP and BOS
resulted in clinically meaningful outcomes, including higher
success rate, duration of air leak stop, lung expansion, and
hospital stay, with an acceptable safety profile.
© 2019 S. Karger AG, Basel
Introduction
Secondary spontaneous pneumothorax (SSP) is com-
monly encountered in hospital practice [1, 2]. Air leaks can
be caused by either an alveolar-pleural fistula (APF) or
bronchopleural fistula, of which APF is the most common.
APF is a communication between the alveoli and pleura,
whereas bronchopleural fistula is defined as a communica-
tion between the bronchus and pleura [3, 4]. Patients with
SSP can be initially managed with chest tube-attached wa-
ter-seal drainage (CTD) [5, 6]. However, despite 5–7 days
of CTD, many patients may still develop persistent air leaks
(PALs) [3, 5, 7]. The presence of PALs is associated with
significant morbidity, prolonged hospital stay, and in-
creased health care costs [8, 9]. Nevertheless, the optimal
management of PALs remains controversial.
Numerous therapeutic options are available for treating
PALs. The American College of Chest Physicians recom-
mends continued observation with CTD for 4 days [6], al-
though many cases resolve spontaneously if managed
conservatively for as long as 14 days [10]. If the previous
treatment fails, surgical intervention, whether open
thoracotomy or video-assisted thoracoscopic surgery, is
currently recommended for PALs [6, 11]. However, sur-
gery is not without hazards, especially in older patients
with underlying lung disease, poor cardiopulmonary re-
serve, and/or concomitant medical problems [12]. Medical
pleurodesis is recommended for inoperable patients [6, 11]
as it indirectly affects air leaks by creating pleural symphy-
sis and a localized inflammatory response [13]. Neverthe-
less, pleurodesis should not be used without considering
possible complications such as hypoxaemia, hypotension,
and adult respiratory distress syndrome [14].
With the development of endobronchial intervention
techniques, there has been active interest in the explora-
tion of effective bronchoscopic management options for
treating PALs [7]. Two of the most representative and
easy approaches are autologous blood patch (ABP) [15,
16] and bronchial occlusion using silicone spigots (BOS)
[17, 18]. ABP helps to seal air leaks with blood compo-
nents that can initiate and support a fibrinous and inflam-
2 Respiration
DOI: 10.1159/000495298
matory response [16]. Thrombin could be applied simul-
taneously to promote blood clotting to enhance the seal-
ing effect [19]. BOS has been reported to be highly effective
in managing intractable pneumothorax [17]. These ap-
proaches have been reported only in several case or case
series reports to be successful in resolving PALs.
Given the lack of prospective and comparative evi-
dence of prolonged observation with CTD, ABP, and
BOS in routine practice, we report the outcomes of these
treatments and discuss the effectiveness and problems as-
sociated with these procedures to determine and compare
management strategy and outcomes in treating PALs us-
ing endobronchial intervention techniques.
Methods
Study Population
The present study was a prospective, randomized, unblinded,
comparative analysis of bronchoscopic procedures performed in
SSP patients with APF experiencing PAL, who were hospitalized
at one of six tertiary care hospitals across six large cities in China.
Data capture spanned from December 2014 to December 2017.
Research ethics boards at each institution approved the study, as
well as the Institutional Review Board (IRB) at Tangdu Hospital,
Xi’an, China (IRB number: 2013027). Written informed consent
was obtained from the patients or their immediate relatives. All
procedures were performed in accordance with the tenets of the
Declaration of Helsinki.
All included patients were diagnosed with SSP and initially
treated with a 16- to 22-Fr standard chest tube. They all experi-
enced PALs despite >7 days of water-sealing intercostal drainage.
Exclusion criteria included severe gas exchange abnormalities,
other major diseases that would limit patient evaluation during the
study, acute exacerbations of chronic obstructive pulmonary dis-
ease, active treatment of disease that failed to stabilize, and female
patients positive for urine human chorionic gonadotropin. Using
a random number table, the patients were allocated to one of the
three therapeutic intervention groups receiving only prolonged
observation with CTD, ABP, or BOS.
Bronchoscopic Procedures
Before the bronchoscopic procedures, all patients underwent
chest computed tomography (CT) or chest X-ray to detect the side
of pneumothorax. The size of pneumothorax was estimated using
an automatic calculation program [20] or Rhea’s method manu-
ally [21]. After administration of local pharyngeal anaesthesia, all
patients were lightly sedated with individually calculated doses of
intravenous midazolam. Routine bronchoscopy was conducted to
exclude patients with bronchopleural fistula.
Identification of the Responsible Bronchus
If the patients were assigned to the ABP or BOS group, the re-
sponsible bronchi were identified using a transbronchoscopic bal-
loon with a balloon catheter (Disposable balloon catheter B-
V232P-A, Olympus Medical Systems, Tokyo, Japan) (Fig. 1a). The
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balloon catheter was introduced through the working channel of a

Color version available online

flexible bronchoscope (BF-260, Olympus Medical Systems). Re-
sponsible bronchi leading to air leakage were defined as those
demonstrating a reduction or cessation of air leakage (bubbling in
water-sealing drainage) when the balloon occluded the appropri-
ate bronchus. The occlusion time for each bronchus was 3–5 min.
If the transbronchoscopic balloon detection failed (i.e., bubbles
from the chest tube were not reduced), the patients were excluded
from the study.

Selective Bronchial ABP a b

The bronchial sealant consisted of two components: autolo-
gous blood (20–30 mL) and thrombin solution (3 mL) containing
2,000–3,000 IU of thrombin for each segment of lung. When the
leading bronchus had been identified, the balloon was kept inflat-
ed and bronchial sealants were instilled into the bronchial tree
through another lumen of the balloon catheter (Fig. 1b). The bal-
loon was then maintained for an additional 5 min. This procedure
could be repeated, as necessary, during the treatment period at the
discretion of the physician.

BOS
Silicone bronchial spigots used in this study were fabricated from
chin implants (Kangning Medical Device, Shanghai, China). The
chin silicone implants were trimmed into two sizes of dumbbell-
shaped silicone plugs (5–7 mm in diameter and 15–20 mm in
length). If the size of bronchial plug was inappropriate, they were
trimmed accordingly. The middle of the silicone plug was tied using
#0 surgical suture with a knot to adjust orientation (Fig. 1c). Bron-
choscopes with a 2.8-mm diameter working channel (BF-260,
Olympus Medical Systems) and grasping forceps (FG-26C-1, Olym-
pus Medical Systems) were used for insertion of the silicone plugs
into the targeted bronchi. After reaching the target bronchus, the
plug was inserted into the bronchus by adjusting the angle and direc-
tion of the spigot (Fig. 1d). Multiple spigots could be placed at the
same time, and this procedure could be repeated during the treat-
ment period when the doctor deemed it to be necessary.
Outcome Measures
All patients were continuously observed for up to 14 days after
enrollment. When there is no bubbling in the water-seal drainage,
the intercostal drainage tube was then clamped for at least 1 day.
Chest X-ray or chest CT was then dynamically performed to con-
firm lung re-expansion. Complete re-expansion was defined as up
to 10% residual pneumothorax. Patient symptoms during treat-
ment, such as chest pain, cough, temperature, haemoptysis, among
others, were documented. A visual analogue scale was used for
scoring the criteria of chest pain and cough. Patients could receive
necessary treatment at the discretion of the physician (including
antibiotics, non-steroidal anti-inflammatory drugs, bronchodila-
tors, etc.). Patients were discharged in stable clinical condition for
a minimum of 12 h after CTD removal.
Statistical Analysis
A priori, sample size calculation was based on the estimated
successful pneumothorax resolution rate in observation before the
study. The effective rate of CTD was approximately 50%, and ap-
proximately 80% for ABP and BOS. Each group required at least
47 patients to attain a power of 80% to detect a difference, with a
two-sided significance level of 5%. Continuous data are expressed
c d
Fig. 1. Bronchoscopic management of persistent air leaks. a Iden-
tification of the responsible bronchus by balloon detection. b Au-
tologous blood and thrombin solution were instilled into the bron-
chial tree. c Silicone bronchial spigots were fabricated from chin
implants. d Silicone spigots were inserted into the targeted bronchi.
as mean ± standard deviation. Categorical data are expressed as
proportions. Statistical analysis was performed using one-way
ANOVA, Pearson’s χ2 test, and Kruskal-Wallis test. If the test
yielded significant effects, Bonferroni correction was used (post
hoc) to identify the specific significant differences between indi-
vidual groups. Statistical analysis was performed using SPSS ver-
sion 24.0 (IBM Corporation, Armonk, NY, USA). A two-sided p ≤
0.05 was considered to be statistically significant.
Results
Patient Characteristics
Of 197 patients with PAL who were screened, 17 with
confirmed bronchopleural fistula in a previous bronchos-
copy test, 18 with failed transbronchoscopic balloon de-
tection, and 12 who were deleted from the database due
to early withdrawal were excluded, leaving 150 subjects
for analysis in this study; a flow diagram is shown in Fig-
ure 2. The mean age of the 150 subjects (139 male) was
55.7 ± 14.9 years, 107 patients (71.3%) had a history of
smoking, and the average size of pneumothorax was 54.53
± 13.25%. All patients were diagnosed with SSP based on
the British Thoracic Society guideline definition. These
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Bronchoscopic Management of Persistent Respiration 3

Air Leaks: RCT DOI: 10.1159/000495298
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 Assessed for eligibility n = 197

Enrollment
Excluded n = 17
Patients with BPF n = 17

Randomly assigned n = 180

Allocation

Allocated to CTD n = 59 Allocated to ABP n = 61 Allocated to BOS n = 60

Received CTD n = 59 Balloon test failed n = 10 Balloon test failed n=8
(balloon test not performed) Received ABP n = 51 Received BOS n = 52
Observation

Withdrew consent n=9 Withdrew consent n=1 Withdrew consent n=2

Analysis

Analyzed n = 50 Analyzed n = 50 Analyzed n = 50

Excluded from analysis n = 0 Excluded from analysis n = 0 Excluded from analysis n = 0

Fig. 2. CONSORT diagram for the trial. BPF, bronchopleural fistula; CTD, chest tube drainage; ABP, autologous
blood patch; BOS, bronchial occlusion using silicone spigots.

patients had at least one of the following conditions: Table 1. Patient characteristics (n = 150)
chronic obstructive pulmonary disease (n = 65), pulmo-
nary bullae (n = 47), pneumonia (n = 24), pulmonary can- Characteristic Value
cer (n = 20), bronchiectasis (n = 11), asthma (n = 9), and Age, years 55.7±14.9
pulmonary fibrosis (n = 6). Characteristics of the study Male sex 139 (92.7)
participants are summarized in Table 1. Smokers 107 (71.3)
Each of the three groups (i.e., CTD, ABP, and BOS), Size of pneumothorax, % 54.53±13.25
comprising 50 patients each, had comparable baseline Underlying lung disease
Chronic obstructive pulmonary disease 65 (43.3)
characteristics in terms of age, sex, and pneumothorax
Pulmonary bullae 47 (31.3)
size (Table 2). The location of pneumothorax was also Pneumonia 24 (16)
similar among the groups, although the responsible bron- Pulmonary cancer 20 (13.3)
chus was not detected in patients in the CTD group. Bronchiectasis 11 (7.3)
Asthma 9 (6)
Pulmonary fibrosis 6 (4)
Outcomes
At the study endpoint, successfully resolved pneumo- Data presented as mean ± standard deviation or n (%).
thorax was found in 30 (60%), 41 (82%), and 42 (84%) of
patients in the CTD, ABP, and BOS groups, respectively.
Both ABP and BOS resulted in significant improvement
compared with CTD (p < 0.016, for all). Furthermore,
there was a significant difference in duration of air leak Complications
stop, lung re-expansion, and hospital stay in favour of The three patient groups exhibited similar rates of
ABP and BOS when compared with CTD (p < 0.016, for chest pain (>30 mm on visual analogue scale), cough (>30
all). However, parameters between ABP and BOS were mm on visual analogue scale), and fever (>38 ° C). It should
not statistically different (p > 0.016, for all) (Table 3). be noted that all patients in the ABP and BOS groups ex-
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4 Respiration Zhang/Xie/Gu/Li/Zeng/Li/Liu/Wang/Bai/
DOI: 10.1159/000495298 Jin
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 Table 2. Characteristics of the different groups

Characteristic Group p
CTD (n = 50) ABP (n = 50) BOS (n = 50)

Age, years 53.24±16.02 56.42±14.88 57.44±13.72 0.342

Male sex 47 (94) 47 (94) 45 (90) 0.675
Size of pneumothorax, % 52.82±2.08 54.72±1.84 56.06±1.69 0.592
Location of pneumothorax
Right side 27 (54) 25 (50) 24 (48) 0.830
Left upper lobe NA 17 (34) 14 (28) 0.517
Left middle lobe NA 3 (6) 4 (8) 0.695
Left lower lobe NA 5 (10) 8 (16) 0.372
Right upper lobe NA 12 (24) 14 (28) 0.648
Right middle lobe NA 4 (8) 3 (6) 0.930
Right lower lobe NA 9 (18) 7 (14) 0.585

Data presented as mean ± standard deviation or n (%). p values were calculated using one-way ANOVA, χ2
test, or Kruskal-Wallis non-parametric test. ABP, autologous blood patch; BOS, bronchial occlusion using
silicone spigots; CTD, chest tube drainage; NA, not applicable.

Table 3. Outcomes

Outcome Group p
CTD (n = 50) ABP (n = 50) BOS (n = 50)

Successful pneumothorax resolution 30 (60) 41 (82)* 42 (84)* 0.008

Duration of air leak stop, days 8.39±2.16 6.02±1.42* 5.21±1.66* <0.001
Duration of lung re-expansion, days 9.48±1.98 6.59±1.45* 6.31±1.55* <0.001
Hospital stay, days 10.06±2.00 8.12±1.60* 7.31±1.62* <0.001

Data presented as n (%) or mean ± SD. p values were calculated using one-way ANOVA, χ2 test, or Kruskal-
Wallis non-parametric test. * p < 0.016 compared with chest tube drainage (CTD) using post hoc Bonferroni test.
ABP, autologous blood patch; BOS, bronchial occlusion using silicone spigots.

perienced temporary haemoptysis (<10 mL), the vast ma-
jority of them appeared within the first 24 h after broncho-
scopic treatment; however, only 6 participants in the CTD
group experienced haemoptysis. Four patients in the BOS
group experienced spigot displacement, including one
case with final treatment failure (the plug was expecto-
rated) and three with final treatment success (at the time
of removal of bronchial plug) (Table 4).
Discussion
Our investigation was the first prospective, random-
ized multicentre study in China comparing CTD, ABP,
and BOS as alternative treatments for SSP patients pre-
senting with APF and PALs. Finally, 150 patients with
PALs (despite 7 days of CTD) admitted to five large hos-
pitals were analysed during the period 2014–2017. We
found that patients who received either ABP or BOS ex-
hibited higher pneumothorax resolution rates than those
in the CTD group in a further 14-day observation. Addi-
tionally, ABP and BOS significantly decreased the dura-
tion of air leak stop, lung re-expansion, and hospital stay.
PAL is a challenging clinical problem in SSP patients
with APF. Evacuation of intrathoracic air using CTD is
recommended as an initial treatment for APF [6, 11, 22].
However, in some patients with particularly severe dis-
ease (similar to patients in our study), resolution of an air
leak using CTD alone may take weeks or even months
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Bronchoscopic Management of Persistent Respiration 5

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 Table 4. Complications
Complication
Chest pain (>30 mm VAS)
Cough (>30 mm VAS)
Temporary haemoptysis (<10 mL)
Fever (>38° C)
Spigot displacement
Data presented as n (%). p values were calculated using χ2 test. * p < 0.016 compared with CTD using post hoc
Bonferroni test. ABP, autologous blood patch; BOS, bronchial occlusion using silicone spigots; CTD, chest tube
drainage; NA, not applicable; VAS, visual analogue scale.
until the chest tube can be removed [4]. Previous research
has shown that there is a 50% chance of air leak resolving
between days 7 and 14 with prolonged observation with
CTD [10]. Our data demonstrated that 30 of 50 patients
in the CTD group experienced cessation of air leak be-
tween days 7 and 28. This suggests that CTD is an effec-
tive and basic treatment for SSP.
Surgical intervention of PALs has been the definitive
approach in patients in whom air leaks do not resolve us-
ing conservative means [6, 11, 23]; however, many SSP
patients are not fit for surgery by virtue of the severity of
their underlying diseases, or are unwilling to proceed
with surgery. Under these circumstances, bronchoscopic
techniques have been among the therapeutic options for
decades [3, 7]. The endoscopic approach is particularly
attractive because of its relatively low invasiveness, which
is of great value especially for PAL patients who are at
high surgical risk.
There are two main strategies for the treatment of
PAL in bronchoscopy – sealants or implants. Among
the sealants reported are autologous blood [15, 16], fi-
brin glue [24], cyanoacrylate glue [25, 26], oxidized cel-
lulose [27], albumin-glutaraldehyde glue [28], and hy-
drogel [29]. Autologous blood was used as the injection
material to treat pneumothorax and PAL, not only be-
cause of its favourable bioadhesive properties, but also
because it is relatively safe and is easily archived [15].
The instillation of autologous blood through a chest
tube for the successful management of PAL was first
documented by Robinson in 1987, with a success rate of
85% in 25 patients with difficult, chronic, or recurrent
pneumothoraces [30]. Endoscopic catheter-guided de-
livery of autologous blood was described by Wiaterek et
al. [16]. Simultaneously, thrombin could be applied to
6 Respiration
DOI: 10.1159/000495298
Group p
CTD (n = 50) ABP (n = 50) BOS (n = 50)
21 (42) 13 (24) 18 (36) 0.236
18 (36) 14 (28) 22 (44) 0.176
6 (12) 50 (100)* 50 (100)* 0.003
9 (18) 5 (10) 8 (16) 0.593
NA NA 4 (8) NA
promote blood clotting in the lung to enhance the seal
effect [19]. Reported endobronchial implants include
silicone spigot [17, 31], one-way valves [32], metallic
stents [33], and septal defect closure devices [34]. Bron-
chial occlusion therapy using silicone-based spigot as a
treatment for PAL was originally developed by Wata-
nabe et al. in 1991 [31]. This group also developed en-
dobronchial Watanabe Spigots (EWS, Novatech,
France) to treat 60 patients with PAL of various aetiolo-
gies. In nearly 80% of cases, they were able to eliminate
or reduce air leaks [17].
In the present prospective, randomized, controlled
study, patients who underwent ABP and BOS treatment
experienced success rates of 82 and 84%, respectively.
Our results are somewhat higher than those published in
previous studies (nearly 80%). This may be due to the dif-
ferent composition of included subjects. For example, we
excluded patients with failed transbronchoscopic balloon
detection, while previous studies included patients with
various aetiologies such as bronchopleural fistula. Fur-
thermore, ABP and BOS treatment also shorten the dura-
tion of air leak stop, lung re-expansion, and hospital stay,
compared with CTD.
There were no severe complications recorded in our
study. Patients in the different groups experienced sim-
ilar rates of chest pain, cough, and fever. All patients
experienced haemoptysis (< 10 mL) as a result of bron-
choscopic intervention; however, the incidence was
10% in the CTD group. This is due to the fact that the
patients received bronchial injection of autologous
blood or the silicone plugs rubbed against the bronchi-
al wall. We noted that four patients experienced plug
displacement, but only one case was defined as a treat-
ment failure.
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 Some limitations should also be acknowledged. First,
the size of pneumothorax is generally considered as a
reliable indicator of pneumothorax severity at present,
and there is no difference in the average size of pneumo-
thorax among the three treatment groups after random-
ization. However, due to the routine operating proce-
dures and ethical requirements, the patients in the CTD
group after randomization did not undergo balloon test,
which may cause selection bias in the composition of
patients in the bronchoscopy group and the chest drain-
age group. In future research, it is necessary to make a
more rigorous distinction between patients with or
without multiple air leak areas. Second, although the
subjects and the data collectors were not informed of the
assigned treatment groups, double-blinding is difficult
to achieve in a study like this. Third, a possible limita-
tion of the present study was that no bronchial silicon
plugs similar to the EWS® are yet listed in China. The
plugs used in our study were trimmed from chin silicone
implants. Improper plug size may induce the displace-
ment of plugs and affect the success of BOS. However,
this situation is not very common (4 of 50) in the hands
of the skilled operators in our study.
In conclusion, in our study involving SSP patients with
APF accompanied by PALs, we demonstrated that com-
bined intervention with both ABP and BOS lead to high-
er success rates, a shorter duration of air leaks, faster lung
re-expansion, and shorter hospital stay than treatment
with CTD alone. Bronchoscopic intervention did not in-
crease the rate of severe complications. We believe that
both ABP and BOS are safe and effective procedures for
treating PALs.
Acknowledgements
We would like to thank and acknowledge the study investiga-
tor, coordinator team, and participants for their support of this
study.
Statement of Ethics
Research ethics boards at each institution approved the study,
as well as the Institutional Review Board (IRB) at Tangdu Hospital,
Xi’an, China (IRB number: 2013027). Written informed consent
was obtained from the patients or their immediate relatives. All
procedures were performed in accordance with the tenets of the
Declaration of Helsinki.
Disclosure Statement
The authors declare no conflicts of interest.
Funding Sources
This study was sponsored and funded by grants from Health
Public Welfare Industry Research Projects of China (201402024).
Author Contributions
H.Z., Y.X., and X.G. performed the analysis and manuscript
writing. W.L., Y.Z., S.L., Z.L., H.W., and C.B. conducted the data
collection. C.B. was crucial to the data collection and analysis of
the study. F.J. had full access to all the data in the study and takes
responsibility for the integrity of the data and the accuracy of the
data analysis.

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