1164541

review-article20232023
TAR0010.1177/17534666231164541Therapeutic Advances in Respiratory DiseaseL Jin and Y Li

Therapeutic Advances in
Respiratory Disease Review

Bronchoscopic interventions for

Ther Adv Respir Dis

2023, Vol. 17: 1–10

bronchopleural fistulas DOI: 10.1177/

https://doi.org/10.1177/17534666231164541
https://doi.org/10.1177/17534666231164541
17534666231164541

© The Author(s), 2023.

Article reuse guidelines:

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Abstract: Bronchopleural fistula is a potentially fatal disease most often caused after
pneumonectomy. Concomitant problems such as pulmonary infection and respiratory failure
are typically the main contributors to patient mortality because of the improper contact
between the bronchial and pleural cavity. Therefore, bronchopleural fistulas need immediate
treatment, which requires the accurate location and timely closure of the fistula. Currently,
bronchoscopic interventions, because of their flexibility and versatility, are reliable alternative
therapies in patients for whom surgical intervention is unsuitable. Possible interventions
include bronchoscopic placement of blocking agents, atrial septal defect (ASD)/ventricular
septal defect (VSD) occluders, airway stents, endobronchial valves (EBVs) and endobronchial
Watanabe spigots (EWSs). Recent developments in mesenchymal stem cells (MSCs)
transplantation technology and three-dimensional (3D) printed stents have also contributed to
the treatment of bronchopleural fistula, but more research is needed to investigate the long-
term benefits. This review focuses on the effectiveness of various bronchoscopic measures for
the treatment of bronchopleural fistula and the directions for future development.

Keywords: airway stent, bronchopleural fistula, bronchoscopy, endobronchial valve,

Correspondence to:
endobronchial Watanabe spigot, septal defect occluder Yaqing Li
Department of Internal
Medicine, Cancer Hospital
Received: 10 December 2022; revised manuscript accepted: 3 March 2023. of the University of
Chinese Academy of
Sciences (Zhejiang Cancer
Hospital), Hangzhou
310022, China.
Institute of Cancer and
Introduction bacterial invasion, resulting in the development of Basic Medicine (ICBM),
Bronchopleural fistula (BPF) is defined as a com- infections such as thoracic abscesses and medias- Chinese Academy of
Sciences, Hangzhou
munication between the bronchial trunk or seg- tinitis. In addition, as air partially enters the pleu- 310022, China.
mental bronchus and the pleura due to various ral cavity, the amount of air that can be effectively Department of Pulmonary
causes. The most common cause is post-pneu- exchanged is reduced, leading to inadequate ven- and Critical Care Medicine,
Hainan General Hospital
monectomy, with the frequency of occurrence tilation/blood perfusion and inevitable hypoxia or (Hainan Affiliated Hospital
estimated to be 4.5–20% after total pneumonec- even respiratory failure. of Hainan Medical
University), Haikou 570100,
tomy and 0.5–1% after lobectomy,1 but the mor- China.
tality rate for BPF after pneumonectomy is as Based on the time of onset, BPF after pneumo- lidoctor03@126.com

high as 18–50%.2 Patients who underwent right nectomy can be classified according to the modi-
Lingli Jin
pneumonectomy and a right lower lobectomy had fied Le Brigand classification6 as follows: (1) The Second Clinical
the highest incidence.3 Other causes include early: 1–7 days after surgery; (2) intermediate: Medical College,
Zhejiang Chinese Medical
necrotising infections such as pulmonary tuber- 8–30 days after surgery; and (3) late: more than University, Hangzhou,
culosis, pneumonia, empyema, chemotherapy or 30 days after surgery. In general, fistulas most China

radiation therapy, and thoracic trauma.4,5 commonly occur within 8–12 days after surgery.1 Department of Internal
Medicine, Cancer Hospital
Early-stage patients are usually caused by failure of the University of
The pleural cavity is a closed latent space con- of surgical stump suturing or acute ischemic Chinese Academy of
Sciences (Zhejiang Cancer
taining a small amount of body fluid that acts as a necrosis of the bronchial stump. These patients Hospital), Hangzhou, China
lubricant during respiratory movement. When it present with sudden onset of dyspnoea, decreased Institute of Cancer and
Basic Medicine (ICBM),
comes into contact with the outside environment, oxygen saturation and blood pressure, subcutane- Chinese Academy of
prolonged fluid and air retention allow for ous or mediastinal emphysema, cough, purulent Sciences, Hangzhou, China

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Therapeutic Advances in
Respiratory Disease
sputum and possibly even life-threatening tension
pneumothorax, which often requires urgent sur-
gical repair. Patients with intermediate or
advanced stages of the disease usually have fistu-
las due to infiltration of the tumour growth in the
stump or chronic ischaemia.6 At this time, patients
often experience pneumothorax, often accompa-
nied by severe infection, decreased immune func-
tion and malnutrition. A small number of patients
have insidious manifestations, with weight loss,
chronic cough and fever as the first symptoms. As
such, this is often difficult to diagnose and can
prevent the condition from being controlled in
time.
Before the advent and development of broncho-
scopic intervention, surgical intervention was the
only effective treatment for BPF.7 Accordingly,
fistulas were treated through fistula repair, thora-
coplasty and other means. However, patients with
malignant BPF are usually undergoing antitumor
therapy such as radiotherapy and chemotherapy
and are not tolerant to surgery due to poor health.
Even if surgery is performed, the rate of postop-
erative complications and the risk of death are
greater.8 In such cases, using bronchoscopic
interventional procedures to treat BPF has great
benefits. This review focuses on the broncho-
scopic interventions for BPF and the prospects
for development.
Fistula localisation
Early and accurate identification and localisation
are important for the management of BPF.
Imaging findings such as increased air in the pleu-
ral cavity, the appearance of new air-fluid planes,
changes in pre-existing air-fluid planes, the devel-
opment of tension pneumothorax and air-fluid
planes exceeding ⩾2 cm are strong indicators of
BPF.1 In some patients, abnormal channels
between the bronchi or lung parenchyma and
pleural cavity can even be directly observed by
computed tomography (CT).9 In addition, bron-
choscopy can detect most bronchial fistulas
located in the main bronchus or the postpneumo-
nectomy stump, while bronchial fistulas located
distally or peripherally often require serial balloon
occlusion to locate.10 To observe the air leak, bal-
loon occlusion is first recommended using a flex-
ible bronchoscope at each bronchial opening on
the affected side. If the leak does not stop, the
entire access from the chest tube opening to the
closed drain needs to be tested. This method is
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Volume 17
cumbersome, time-consuming, and requires a
chest drainage bottle.
Injecting methylene blue into a thoracic drainage
tube or directly into the trachea is another reliable
method for locating bronchial fistulas. Under
direct bronchoscopic view, methylene blue is
instilled through the surgical stump or suspected
target bronchial opening, and the diagnosis is
aided by observing the change in fluid level and
the presence of blue fluid spillage from the chest
drainage device. Alternatively, retrograde instilla-
tion of methylene blue through the chest drain
while under bronchoscopy observation has also
proven to be a viable approach.11 The diagnosis is
confirmed when the dye is observed to enter the
tracheobronchial tree from the diseased airway.
This procedure is easy and inexpensive, making it
a feasible alternative to serial balloon occlusion.
However, as the dye will exit through the least
resistant channel, this method may miss the diag-
nosis of multiple fistulas. Nevertheless, this draw-
back can then be overcome by sealing the initial
diseased airway with a balloon and then repeating
this technique in other airways. Yet, when the
patient requires surgery, the presence of dye will
compromise the ability to discriminate between
mediastinal and thoracic tissues.11
Treatment
Conservative treatment of BPF is simple, safe and
non-invasive. Thoracic drainage is usually the
first step of intervention. The placement of a
chest tube not only drains excess gas and fluid but
also serves as a delivery channel for sclerosing
agents to facilitate the performance of pleural fix-
ation.4 In addition, prophylactic use of adequate
antibiotics and mechanical ventilation are also
essential parts of the process. However, one
study12 has been published claiming that mechan-
ical ventilation is a risk factor for BPF in patients
after pneumonectomy. Therefore, when mechan-
ical ventilation is necessary for patients with BPF,
mean airway pressure should be reduced as much
as possible, and an intermittent command venti-
lation mode with low tidal volume, reduced res-
piratory rate and shortened inspiratory time is
appropriate.1 Although conservative treatment
does not directly heal BPF, it allows for partial
closure of small fistulae (>3 mm in diameter) by
removing pus and maintaining fluid balance or by
bronchoscopic assistance.13 In recent years, a ret-
rospective study found that the success rate of the
 L Jin and Y Li

bronchoscopic technique was 71–92% when the
fistula was distal and small (<6 mm).14 In addi-
tion, bronchoscopic treatment may serve not only
as the first treatment but may also provide a
bridge to subsequent related treatments, offering
new treatment pathways for patients with BPF.
The advantages and disadvantages of the various
treatment methods and the scope of their applica-
tion are shown in Table 1. The success and com-
plication rates of their BPF treated by each device
in relevant literature are also shown in Table 1.
Some of the values can range widely and may
depend on the patient’s conditions and the proce-
dures used in the study. In summary, the treat-
ment of BPF is individualised and adaptive.
Blocking agent
A variety of blocking agents have been used in
BPF through bronchoscopy, which works mainly
by inducing or stimulating granulation tissue for-
mation, leading to cell proliferation, scarring and

Table 1. The advantages, disadvantages, success rate, complication rate and applications of different devices.

Treatments Advantages Disadvantages Success rate Complication rate Applications

Blocking agent Rich in variety; Not suitable for large – – Small peripheral fistulas
convenient; fistulas; low overall (3–5 mm)
affordable success rate

ASD/VSD Size can be personalised; Risks such as 77–96% 8–23%13,15–18 Fistulas that cannot be
occluders good biocompatibility; displacement are treated surgically; bronchial
super elasticity; good common; not suitable for fistulas above grade 1–3
airtightness peripheral fistulas bronchial segments

Silicone stent Good biocompatibility Limited type; poor 77% 29%19 Fistulas that take longer
and tolerance; can be adaptability; difficult to recover or are caused
processed on-site; not to place under flexible by malignant diseases;
easy to form granulation bronchoscope surgery is inappropriate or
contraindicated.

Covered metal Good support; Prone to granulation 67–100% 3–4320–24 Suitable for different fistula
stent unbreakable; tissue formation; locations; bronchial fistula
good airtightness; membrane or metal due to malignancy
variable in shape destruction

EBVs One-way valve structure More complications such 67–93% 15–22%25–28 Peripheral fistulas; the
that allows air and fluids as infection, migration surgical stump was long
out but keeps them from and granulation tissue enough, and the diameter
getting into the diseased formation; costly of the fistula was ⩾3 and
part of the lung ⩽8 mm28

EWS Available in three sizes; Poor stability; difficult to 40–86% 17–50%29–31 Intractable BPF; peripheral
rapid occlusion of target place fistulas
bronchus

ASD, atrial septal detect; BPF, bronchopleural fistula; EBVs, endobronchial valves; EWS, endobronchial Watanabe spigot; VSD, ventricular septal
detect.

finally fistula closure. As early as 1977, two arti-
cles32,33 reported the successful treatment of BPF
using glue and lead shots for the first time, respec-
tively. Since then, ethanol, fibrin glue, albumin-
glutaraldehyde tissue adhesive, oxidised
regenerated cellulose, ethyl-2-cyanoacrylate and
silver nitrate have been reported successively.34–39
Although not commonly used, argon plasma
coagulation can be an alternative treatment for
small and uncomplicated BPF cases.40 Recently,
Alcaraz et al.41 explored the surgical treatment of
bronchial fistulas with ethanolamine oleate and
showed complete closure in 75% (6/8) of patients.
However, no randomised controlled studies have
been conducted that compare the advantages,
disadvantages and safety of various occlusion
agents. Furthermore, most successful cases
involve fistulas of the peripheral type; therefore,
this technique may not be widely used for BPF
closure. The choice of occlusion material still

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Therapeutic Advances in
Respiratory Disease
depends on the size of the fistula and the patient’s
underlying condition.
Atrial septal defect/ventricular septal defect
occluders
Atrial septal defect (ASD)/ventricular septal
defect (VSD) occluders were first used to treat
ASD/VSD of the heart. Kramer et al.42 described
the effective treatment of two patients with BPF
after pneumonectomy using Amplatzer ASD
devices for the first time, heralding a broad
increase in prospects for the treatment of BPF
with ASD/VSD occluders. The device has a
double-disc mesh structure made of woven
nickel-titanium alloy wire with self-expanding
properties. It can contract within the catheter
and be delivered via catheter into the fistula site
for subsequent release to seal the fistula by the
waist, with the double discs located on each side
of the fistula. The waist size varies from 4 to
40 mm, so the device can be matched to the size
of the fistula and is equally suitable for patients
with fistula diameters ⩾8 mm. While there is no
standard for the selection of the waist diameter
of the occluders, Motus et al.43 recommended
that the waist should be 30% wider than the
diameter of the fistula. In congenital heart dis-
eases, the size of occluders chosen should be
comparable to or slightly more than the diame-
ter of the fistula (within 2 mm).44 In a study of
31 patients with BPF, Fruchter et al.16 found
that 96% of patients had immediate sympto-
matic relief after treatment with Amplatzer
occluders (19 cases of ASD occluders and 12
cases of vascular plugs) and performed well at
subsequent follow-up times. The device induced
local granulation tissue formation, which
enhanced their fistula occlusion without affect-
ing airway patency. Zhang et al.18 also invented
a ‘sheath-free method’ for the placement of the
ASD occluder, making the placement more
convenient and efficient in clinical use. However,
there are some reports that the device carries the
risk of displacement and infection.13,17 At pre-
sent, the treatment of BPF with cardiac occlud-
ers is still ‘off-label’ and is contingent on the
specifics of the condition and the wishes of the
patient and their family. Thus, there is a need
for continuous improvement of the device in the
future, to make it more adaptable to the envi-
ronment of the airway to provide treatment pro-
tection for otherwise inoperable patients.
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Volume 17
Airway stent
Airway stenting is more widely used in malignant
BPF. It provides immediate symptomatic relief
and significantly improves the patient’s quality of
life. Airway stents include metal and silicone vari-
ants. There are advantages and disadvantages to
various stents, but the needs of the individual
patient, as well as the condition of the fistula,
must be taken into account when deciding which
stent to use.
Silicone stent
The Dumon silicone stent is the most commonly
used stent invented by Dumon and was first used
in patients with external compressional stenosis
of the main airway.45 Silicone stents can be classi-
fied as straight stents or Y-stents. Straight stents
are mainly used for lesions involving the upper or
middle trachea or mainstem bronchi, while
Y-stents are most suitable for lesions involving
the lower trachea, tracheal carina, mainstem
bronchi and secondary carina.46 In BPF treat-
ment, silicone stents are rarely used because of
their limited type and poor adaptability. However,
silicone stents can overcome this disadvantage
through manual modifications on-site, such as
cutting, suturing and snapping. Moreover, sili-
cone stents have the advantages of durability, ease
of removal and low cost compared with metal
stents. Zeng et al.19 retrospectively analysed the
clinical data of 17 patients with BPF who under-
went bronchoscopic placement of a modified
Y-shaped silicone stent, and 16 patients were suc-
cessfully stented (initial success rate: 94.1%). All
patients had improved respiratory symptoms,
with a clinical success rate of 76.5%. For refrac-
tory BPF, placement of the modified silicone
stent could be an effective and safe option.
However, the stent needs to be completed under
a rigid bronchoscope, which is more demanding
for the operator. In addition, silicone stents have
been used in conjunction with covered metal
stents in patients with serious malignant airway
stenosis and fistulas.47 This hybrid stent approach
involves a Y-shaped silicone stent to maintain
central airway ventilation and a metal-covered
stent placed distal to the Y-shaped silicone stent
to reconstruct the airway from the main ramus to
the distal main bronchus and to seal the fistula.
The results of that study showed immediate relief
of dyspnoea and improvement in various scores
after placement of the hybrid stent. Furthermore,

there were no serious complications associated
with the hybrid stent within 6 months of place-
ment. However, that study lacked control for
single-stent placement, and the sample size was
small. Thus, extensive studies exploring the pro-
longed benefits and safety of hybrid stents are
warranted.
Metal stent
In 1989, Simonds et al.48 first placed a self-
expanding metal stent into the trachea for bron-
chial obstruction. Subsequently, metal stents
have gained widespread use in various respiratory
diseases. Yet the use of tracheal stents to treat
benign tracheal diseases has been warned against
by the US Food and Drug Administration (FDA)
because of the risk of stent-related complications
and difficulties associated with their removal.49
In BPF, metal stents are not routinely used, but
in a few carefully selected patients, self-expand-
ing covered stents may be used with caution.
Furthermore, the stent is not left in the body for
too long, to reduce complications if the condition
permits. The metal mesh provides good support
and is resistant to fracture, while the laminate
surface is effective in sealing the fistula. Menna
et al.20 evaluated the efficacy of conical covered
stents in the treatment of postoperative BPF and
found that permanent closure of bronchial dehis-
cence was achieved in all patients without recur-
rence. In almost all patients (91.7%), the stent
was successfully removed and not replaced due
to the patient recovering from the fistula. Covered
bullet stents, which have an occlusive bullet at
one end, also have been shown to be a feasible
and safe option for treating BPFs in several stud-
ies.50,51 Han et al.21 described their experience
with 148 patients undergoing postoperative BPF
using customised, covered metallic stents. The
stent shape can be adjusted according to the
position and length of the bronchial stump. They
achieved a success rate of 96.6% in patients with
BPF who underwent first time airway occlusion
stent implantation. This still underscores the
importance of individualised treatment for BPF.
However, stent placement in this article was
done under fluoroscopy, which, if assisted by
bronchoscope, may improve the success rate of
sealing the bronchial fistula and reduce the risk
of incorrect placement. The customisation of
metal supports often takes time, and how to pro-
cess them in the field is still the subject of con-
stant investigation.
journals.sagepub.com/home/tar
L Jin and Y Li
Stent management
Tracheal stents are correlated with improved
overall survival and reduced mortality in several
studies.52 However, both metal and silicone stents
are foreign bodies, and complications such as
infection, granulation tissue formation, stent
migration and mucus plugging are inevitable.
Currently, some studies comparing silicone and
metal stents in malignant airway disease showed
no significant differences in symptom relief,
safety, complication rates or survival between the
two types of stents.53,54 In addition, stent place-
ment into the trachea is not a one-time event and
requires regular management and maintenance.
Bronchoscopy is recommended 48–72 h after
successful stent placement to confirm whether
the stent is in place.55 Then, bronchoscopy
should be followed weekly to determine stent sta-
tus and clear airway secretions. The follow-up
time can be extended to once a month after the
patient’s condition improves. The data suggest
that bronchoscopy within 4–6 weeks after stent
placement may help in the early detection of
complications and their subsequent manage-
ment.56 This hints that patients should be actively
followed up and reviewed to lower the probability
of complications.
Endobronchial valves
The endobronchial valve (EBV) is a novel device
for the management of BPF, further categorised
as Zephyr endobronchial valve (ZEBV, Pulmonx
Inc., Neuchatel, Switzerland) and intrabronchial
valve (IBV, Spiration Inc., Redmond, WA, USA),
originally designed for bronchoscopic lung
decompression procedures. Following approval
of the IBV by the FDA in 2008 under the
Humanitarian Device Exemption Program for
patients with persistent air leaks after parenchy-
mal lung resection, the bronchial valve has been
successfully used for postoperative persistent BPF
occlusion.25,57,58 The ZEBV was also approved by
the FDA in 2018 to treat breathing difficulties
associated with severe emphysema. The device is
a one-way valve structure that allows air and flu-
ids out but keeps them from getting into the dis-
eased part of the lung, thereby reducing air leaks
and the incidence of obstructive pneumonia. It
can also be placed through a flexible broncho-
scope under general or local anaesthesia. A
recent study27 observed that EBVs therapy was
effective in more than 70% of patients with BPF
and prolonged air leaks, with no intraoperative or
5
Therapeutic Advances in
Respiratory Disease
postoperative complications. An interesting find-
ing is that a higher comorbidity burden appears to
be a risk factor for delayed recovery, regardless of
the EBVs implantation status.59 To reduce the
risk of infection, migration and granulation tissue
formation, it is now recommended that the valve
be removed 4–6 weeks after placement or upon
resolution of the air leak.60 Furthermore, the cost
of these valves is a drawback that prevents their
widespread use in clinical practice.
Endobronchial Watanabe spigot
The endobronchial Watanabe spigot (EWS),
first invented by Watanabe and his team in
1991,61 is a silicone bronchial plug in the form
of a socket with a studded surface and gripping
ends. It is available in three sizes: small,
medium and large, which are 5, 6 and 7 mm in
diameter, respectively, allowing adaptation to
different bronchial diameters. EWS can be
simply placed into the target bronchus, usually
the peripheral bronchus, by the ‘forceps
grasp’30 method, the ‘curette’ method31 or the
‘traction’ method62 under bronchoscopy,
thereby preventing air from entering the dis-
eased bronchus. Bronchial obstruction with
the EWS is an appropriate treatment for BPF
when the target bronchus is well-defined.
Himeji et al.29 found in a retrospective study
that the application of the EWS had an 85.7%
success rate for cases of pneumothorax, pyo-
thorax with bronchial fistula and postoperative
air leakage. The biggest drawback of the EWS
is migration. To prevent migration, it is recom-
mended that EWS should be inserted as far as
possible, and appropriate medications should
be used to reduce cough.30 The specific timing
and indications for their placement still require
considerable research.
Outlook
Currently, mesenchymal stem cells (MSCs) are
starting to be used for the treatment of BPF due
to their strong differentiation capacity and weak
immunogenicity. MSCs can be delivered surgi-
cally or bronchoscopically to the lesion site and
left to divide and differentiate into specific cells
to achieve fistula closure. In 2015, Petrella
et al.63 successfully treated a patient with BPF
for the first time with bone marrow MSCs. In
addition, the use of umbilical cord MSCs for
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Volume 17
BPF closure after pneumonectomy has also
been reported.64 Bottoni et al.65 performed a
study on the treatment of post-pneumonectomy
BPF with bronchoscopic autologous fat fillers
and observed a 100% success rate without
rejection, with positive efficacy observed even
in fistulas >8 mm in diameter. MSCs trans-
plantation technology may be a new option for
treating severe lung diseases with a broad devel-
opmental perspective. It is currently used only
in cases where other interventions have failed,
and large-scale clinical trials are still needed to
investigate the effectiveness of MSCs in such
settings.
The advent of three-dimensional (3D) printed
stents has opened a new era of stent placement.
Almost all stents are held in place by the fric-
tion created by the pressure applied to the air-
way wall. Hence, the stent must fit perfectly
into airway wall to seal the fistula. As a result, it
is important to perform stent placement with-
out stretching the fistula to maximise the ben-
efit. In large part, this can be done by cutting,
suturing or ordering special forms of stents to
simulate the human airway structure as closely
as possible, which is usually time-consuming
and subject to error.52 3D-printed stents can be
designed to fit an individual in a matter of
weeks or even hours by deriving the appropriate
model from CT or bronchoscopic images.66
The 3D printing technology is widely used,
except for metal stents67 and silicone stents,68
biodegradable stents69 and drug-eluting stents70
that have been reported for airway stenosis. In
the future, these are expected to be used in the
treatment of BPF. With the rapid advances in
bronchoscopic treatment technology, treatment
options for large fistulas can now be explored
more thoroughly.
Conclusion
The treatment of BPFs often requires a multi-
disciplinary approach, including thoracic sur-
gery and respiratory intervention. There are no
uniform guidelines recommending standard-
ised treatment of BPF, and bronchoscopic
treatment is usually recommended for fistulas
⩽8 mm in diameter, but the closure of large fis-
tulas remains a challenge. It is worth acknowl-
edging that bronchoscopic treatment plays an
integral role in BPF, and treatments should be

tailored according to the patient’s individual
condition.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Author contributions
Lingli Jin: Conceptualization; Data curation;
Writing – original draft; Writing – review & and
editing.
Yaqing Li: Conceptualization; Supervision;
Validation; Writing – review & editing.
Acknowledgements
None.
Funding
The authors disclosed receipt of the following
financial support for the research, authorship and
publication, or both, of this article: This work was
supported by grants from the Key Research and
Development Project of Hainan Province (grant
no. ZDYF2022SHFZ281) and the National
Natural Science Foundation of China (grant no.
81870028).
Competing interests
The authors declared no potential conflicts of
interest with respect to the research, authorship
and publication, or both, of this article.
Availability of data and materials
Not applicable.
ORCID iD
Lingli Jin https://orcid.org/0000-0001-9256-
7271
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