Keywords
congenital lung abnormalities - bronchopulmonary sequestration - surgery - surgical
resection - embolization - survey
Introduction
Congenital lung abnormalities (CLAs) include a variety of developmental disorders
of the respiratory tract and pulmonary vascularization.[1] The incidence is approximately 4 in 10,000 births. A number of diagnosed cases have
increased over the past decades, presumably due to the implementation of standard-of-care
prenatal ultrasound imaging with better image quality.[2]
[3] Comprising approximately 23% of all prenatally detected CLAs, bronchopulmonary sequestration
(BPS) is the second most frequent subtype.[4] A BPS consists of lung tissue that is not connected to the tracheobronchial tree
and derives its blood supply from the systemic circulation instead of the pulmonary
arteries.[5]
[6] The majority of neonates with BPS are asymptomatic at birth and the prognosis is
usually good.[6]
[7] In case symptoms do occur, most often they consist of recurrent pneumonia, respiratory
distress, or high output congestive heart failure due to right-to-left shunt.[8]
[9]
Two separate types of BPS can be distinguished: intralobar sequestration (ILS) and
extralobar sequestration (ELS).[6] An ILS shares the visceral pleura with the adjacent lobe and accounts for 75% of
cases, whereas an ELS is encompassed by its own pleura, separating it from the rest
of the lung and accounts for the remaining 25% of cases.[6]
[8] A hybrid lesion is either an ILS or an ELS which shows the characteristics of both
a BPS and a congenital pulmonary airway malformation (CPAM), another type of CLA in
which overgrowth of respiratory tract tissue leads to the formation of cysts.[6]
[10]
[11]
BPS can be diagnosed prenatally by routine ultrasonography, when it resembles a hyper
echogenic solid mass, commonly appearing like a wedge.[12]
[13] Doppler ultrasound is frequently used to identify the systemic feeding artery, which
is pathognomonic for a BPS.[14]
[15] In two-thirds of cases, the lesion regresses during gestation, in some cases even
becoming undetectable on consecutive ultrasonography or postnatal chest X-ray.[14]
[16]
[17] After birth, a BPS is usually confirmed by visualizing the systemic feeding artery
on chest computed tomography scan (CT scan) with intravenous contrast, angiography,
or magnetic resonance imaging (MRI). Occasionally, the feeding artery can be visualized
on Doppler ultrasound. The optimal management of a newborn with BPS who remains asymptomatic
is still under debate, whereas it is generally accepted that an intervention is indicated
when symptoms occur.[5]
[6]
[7]
Treatment options for symptomatic cases are surgery, endovascular embolization, or
combination of both. Complete surgical resection of the lesion is considered curative
and is associated with relatively low morbidity, especially in an elective setting.[5]
[6]
[7]
[8]
[18]
[19]
[20] An alternative treatment option is endovascular embolization of the systemic arterial
supply to the lesion through percutaneous endovascular access, to block the blood
flow to the lesion and induce necrosis and involution.[8]
[21]
[22]
[23] Embolization is considered a viable, less invasive alternative to surgical intervention
but has not yet been properly evaluated in prospective, comparative trials.[8] Moreover, embolization can serve as treatment prior to surgical resection, by shrinking
the lesion and possibly reducing the risk of intraoperative hemorrhage.[8]
To date, no studies have compared the abovementioned treatment modalities and only
a few follow-up studies on BPS patients are available, limiting the understanding
of outcome in this patient group.[5]
[24] In addition, the current standard of care in BPS patients is unknown due to the
absence of large cohort data and international guidelines.[25] As a first step, we conducted a survey to identify the management preferences for
BPS among a European group of specialized caregivers.
Methods
Survey Design and Distribution
An online survey was designed in Google Forms (Google LLC, Mountain View, CA, United
States), consisting of 44 questions in total, which addressed the following areas:
general management, prenatal management, postnatal management, follow-up, and future
research. The full survey can be found in [Supplementary Materials] (available in the online version). The survey was sent to all members of the Collaborative
Neonatal Network for the first European CPAM Trial (CONNECT) consortium, an international
collaboration of specialist caregivers aimed at improving the care for patients with
congenital lung disease.[26] Moreover, the survey was dispersed in the Association for European Pediatric and
Congenital Cardiology (AEPC) working group database.[27] Apart from being a member of (at least) one of these two networks, no further criteria
had to be met to be able to partake in the survey.
Considering this survey did not involve the inclusion of patients or the collection
of patient-related data, no ethical approval was required for this study.
Data Management and Analysis
All responses were included for analysis. Anonymized data were stored on a secure
online server and managed according to the European General Data Protection Regulation.[28] Responses to each question are shown in numbers (percentages). Analyses were performed
in SPSS (version 25, IBM Corporation, Armonk, NY, United States), and significance
was tested using Fisher's exact test. Significance was set at p < 0.05.
Results
The survey was completed by 63 participants, divided over 46 individual hospitals,
from 17 countries, and consisted of 33 pediatric surgeons (52%), 14 pediatric pulmonologists
(22%), and 12 pediatric cardiologists (19%), see [Fig. 1]. In three cases, a maximum of three participants were associated with the same center.
Most centers treated five or less BPS cases each year (65%) and performed 0 to 5 resections
(79%) and between 0 and 1 embolization (67%). Pediatric surgeons and pediatric pulmonologists
were available in nearly all centers (95 and 92%), followed by pediatric interventional
cardiologists in 75% and interventional radiologists in 54%. There were no missing
data from the survey.
Fig. 1 Participant characteristics.
Prenatal Management
Most participants (57%) estimated that the majority of BPS cases are diagnosed prenatally,
usually through ultrasonography or fetal MRI, see [Fig. 2]. Parents who are expecting a child with a BPS are standardly referred to a specialized
center for delivery, although up to 30% of participants stated to refer parents only
occasionally or never (8%). Parental counseling is offered as a standard of care in
87%. Pregnancy termination, however, is offered only incidentally (5%). Parental preference
is taken into consideration when deciding on the best treatment in 66%, and half of
the participants (52%) confirmed that management strategy is always discussed in a
multidisciplinary team.
Fig. 2 Diagnostic workup of BPS patients.
Postnatal Management
Neonates in good clinical condition without symptoms are generally observed one to
several days after birth (75%), while some are discharged immediately (5%) or observed
a week or longer (5%). Postnatal imaging is usually performed as the standard of care
(86%) and most often consists of chest X-ray and chest CT imaging, see [Fig. 2].
Half of the participants (52%) base their management strategy on the presence of symptoms,
while one-third (32%) take into account the intralobar or extralobar location of the
BPS. As for hybrid lesions, the majority of participants (71%) treat these like regular
BPS lesions. Please see [Fig. 3] for an overview of management preferences.
Fig. 3 Management of BPS patients.
Most centers have access to both surgical and interventional cardiac/radiological
facilities (85%). Among these centers, surgery was the preferred treatment over embolization
in symptomatic cases (62 vs. 15% of participants), and a combination of surgery and
embolization was chosen in 17%, see [Table 1]. A significant difference was observed in these preferences between surgeons and
nonsurgeons, showing a greater preference for surgery among surgeons as opposed to
a greater preference for embolization or combined treatment amongst nonsurgeons (p = 0.006). For asymptomatic cases, too, surgery was generally the preferred management
to embolization (38 vs. 9% of participants), while 32% preferred noninterventional
treatment, see [Table 1]. Again, a significant difference was observed between surgeons and nonsurgeons due
to a greater preference for surgery among surgeons, although the preference for noninterventional
treatment was roughly comparable between these two specialist groups (p = 0.04). The above-mentioned management preferences do not significantly differ between
centers with both surgical and interventional facilities and centers with only surgical
treatment options. Unfortunately, the sample size of the latter group was limited
(n = 7), see [Table 2].
Table 1
Management preferences among surgeons and nonsurgeons, in centers with both surgical
and interventional capacities
|
What is the preferred management of symptomatic BPS patients?
|
|
Nonsurgeons
|
Surgeons
|
Total
|
|
|
n (%)
|
n (%)
|
n (%)
|
|
|
Surgical resection
|
10 (40)
|
23 (84)
|
33 (62)
|
|
|
Embolization
|
7 (28)
|
1 (4)
|
8 (15)
|
|
|
Combination of above
|
5 (20)
|
4 (14)
|
9 (17)
|
|
|
Variable
|
2 (8)
|
0
|
2 (4)
|
|
|
Unknown
|
1 (4)
|
0
|
1 (2)
|
|
|
Total
|
25
|
28
|
53
|
p = 0.006
|
|
What is the preferred management of asymptomatic BPS patients?
|
|
Nonsurgeons
|
Surgeons
|
Total
|
|
|
n
(%)
|
n
(%)
|
n
(%)
|
|
|
Surgical resection
|
6 (24)
|
14 (50)
|
20 (38)
|
|
|
Embolization
|
5 (20)
|
0
|
5 (9)
|
|
|
Noninterventional treatment
|
7 (28)
|
10 (35)
|
17 (32)
|
|
|
Variable
|
3 (12)
|
3 (11)
|
6 (11)
|
|
|
Combination of above
|
3 (12)
|
1 (4)
|
4 (7)
|
|
|
Unknown
|
1 (4)
|
0
|
1 (2)
|
|
|
Total
|
25
|
28
|
53
|
p = 0.04
|
Table 2
Preferred treatment of centers with only surgical capacities versus centers with both
surgical and interventional capacities (i.e., cardiology and/or radiology)
|
What is the preferred management of symptomatic BPS patients?
|
|
Surgery
|
Surgery + interventional
|
p-Value
|
|
Surgical resection
|
7 (100%)
|
33 (62%)
|
|
|
Embolization
|
0 (0%)
|
8 (15%)
|
|
|
Combination of above
|
0 (0%)
|
9 (17%)
|
|
|
Other
|
0 (0%)
|
3 (6%)
|
|
|
Total
|
7
|
53
|
p = 0.47
|
|
What is the preferred management of asymptomatic BPS patients?
|
|
Surgery
|
Surgery + interventional
|
p
-Value
|
|
Surgical resection
|
4 (57%)
|
19 (36%)
|
|
|
Noninterventional treatment
|
1 (14%)
|
17 (32%)
|
|
|
Other
|
2 (29%)
|
8 (15%)
|
|
|
Embolization
|
0 (0%)
|
5 (9%)
|
|
|
Combination of above
|
0 (0%)
|
4 (8%)
|
|
|
Total
|
7
|
53
|
p = 0.64
|
The timing of surgery was considered optimal either at 6 to 12 months of age (38%),
upon the onset of symptoms (22%) or after the age of 1 year (14%), see [Fig. 4]. Regarding embolization, more than one-third of the participants (38%) had no preference
regarding the optimal timing of intervention. In addition, 37% of all participants
estimated that surgical resection would be necessary after primary embolization in
some cases though another 42% stated not to know this rate, see [Fig. 4].
Fig. 4 Preferred timing of intervention in BPS patients.
Follow-up
An overview of follow-up details is shown in [Fig. 5]. A structured follow-up program is offered in 75% of the centers, involving predominantly
pediatric pulmonologists (89%), pediatric surgeons (78%), and pediatric cardiologists
(41%). In general, the follow-up consists of physical examination (88%), imaging (80%),
growth assessment (61%), and lung function tests (55%). Follow-up imaging generally
includes chest X-ray (71%), CT-scan imaging (41%), and in some cases MRI (13%). The
follow-up duration varies widely from one postoperative visit to monitoring up to
the age of 18 years, or even indefinitely. Half of the centers (54%) apply different
follow-up schemes for surgically managed children and children assigned to noninterventional
treatment.
Fig. 5 Follow-up of BPS patients.
Discussion
This survey, completed by 63 participants from 17 countries, shows the general lack
of standardization in Europe toward the diagnostics, management, and follow-up of
children with BPS ([Fig. 6]). A possible reason for this might be the diversity of the caregivers for this orphan
disease—predominantly pediatric surgeons (52%), pediatric pulmonologists (22%), and
pediatric cardiologists (19%)—combined with the different available facilities within
one center. The results of this study have to be interpreted with caution but some
careful conclusions may be drawn. In centers with access to both surgical and interventional
treatment options, there was a preference for surgical resection, both in children
with and without symptoms, as previously shown in the literature.[5]
[6]
[7]
[8]
[18]
[19]
[20]
[29] Regarding symptomatic children, the majority of participants considered embolization
as the second best management, while opinions on the management of asymptomatic children
differed—a watchful waiting approach appeared to be the main alternative to surgery
for these children. Significant differences were found in the management preferences
of surgical and nonsurgical participants, irrespective of the presence of symptoms.
This variation in management preferences is in line with the ongoing discussion surrounding
the optimal management of CLA in general, as reflected in several surveys in Europe,
the United Kingdom, and Canada.[30]
[31]
[32] Consensus on the optimal management for asymptomatic children with CLA is still
lacking—including children with asymptomatic BPS.[33]
Fig. 6 Graphical abstract.
In general, surgical resection of BPS and other CLA is considered effective with close
to zero mortality.[33] Postsurgical complications occur in 5 to 30% of cases, with risk factors being described
as younger age, emergency as opposed to elective setting, and open versus thoracoscopic
surgery.[20]
[34]
[35] Long-term morbidity is estimated to be low, primarily consisting of recurrent infection,
symptomatic residual disease due to nonradical resection and pulmonary hyperreactivity.[20]
[36] Furthermore, mixed results have been reported concerning long-term functional outcomes
in children who underwent surgery for CLA.[37]
[38]
[39]
[40]
In our survey, consensus on the optimal timing of surgery was not evident: 38% of
the participants deemed an age of 6 to 12 months optimal, while 22% found the onset
of symptoms the ideal moment and 14% preferred to wait until the age of 1 year. Several
studies support surgery before the age of 12 months because of the higher risk of
perioperative complications due to possible infectious alteration in the lesion past
this age.[29]
[41]
[42]
[43] In addition, younger age has a possible advantageous effect on postoperative compensatory
lung growth, which is assumed to occur up to the age of 2 years.[44]
[45]
[46] However, lung function measurements later in the life of children who underwent
early surgery do not support this assumption.[47]
[48] From an anesthetic view, surgery after the first year of life is often preferred,
considering the elevated risk of adverse neurodevelopmental outcomes that is described
following exposure to anesthesia and/or surgery during early childhood.[49]
[50]
Embolization has several possible advantages over surgical resection. The percutaneous
access is less invasive, and it does not require direct access to the thoracic cavity.
This could probably result in decreased short- and long-term morbidity but data are
sparse and comparative studies are lacking.[21]
[51] One major disadvantage of embolization is the risk of symptomatic residual disease,
as shown in several small cohort studies where up to one in three children required
a secondary treatment.[21]
[51]
[52] In our survey, 37% of participants estimated that surgical resection could be necessary
after primary embolization but even more participants (42%) did not know the extent
of this risk.
Another argument against embolization of BPS is the risk of malignant deterioration
in the residual lesion. Although malignancy in the context of BPSs has not been extensively
investigated, certain genes such as KRAS and DICER-1 have been suggested to be associated with mucinous proliferation of lung tissue in
congenital lung malformations, which in turn is considered a risk for malignancy development.[20]
[53]
[54] However, it is important to underscore that the overall risk of malignant degeneration
in these lesions, although difficult to estimate, is believed to be low, and therefore,
clinicians may consider not to resect all identified lesions.[55]
[56]
[57] Moreover, it is worth mentioning that the presence of malignancy in CLAs with a
systemic arterial branch, like BPS and hybrid lesions, is believed to be even less
frequent than in other CLAs.[58] Additional research is still needed to establish definitive associations.[59]
Regarding the management of asymptomatic lesions, the risk of a lesion becoming symptomatic
should be weighed against the risk of posttherapeutic complications. This risk may
well differ between ILS and ELS lesions. An ILS lesion is thought to be more prone
to infections since it is connected to the adjacent lung tissue by the pores of Kohn,
which permit bacteria to enter the sequestration.[6]
[24] It has been reported that by the age of 20, 60% of ILS cases have become symptomatic
with recurrent infections, and the risk of infection could therefore potentially outweigh
the risk of interventional complications.[24]
[60] An ELS, on the other hand, is surrounded by its own visceral pleura and therefore
is not directly connected to the adjacent lung tissue. An ELS will often remain asymptomatic
during childhood, and some authors think it is likely to remain asymptomatic throughout
life.[61] Hence, a conservative approach for ELS seems a decent option, though large-scale
studies or registries are needed to confirm this.[24]
[60] Interestingly, in our survey, the majority (57%) of participants noted that they
treat children with ILS and children with ELS in the same manner, suggesting that
only few treating specialists are aware of the potential differences in natural history
between the BPS subtypes. It is currently unclear with what degree of accuracy ILS
and ELS can be distinguished from each other preoperatively.[8]
[62]
[63] This could explain the similar treatment of both subtypes that was observed in this
survey.
To the best of our knowledge, no studies or guidelines are available concerning the
best follow-up strategy of children with BPS. Nonetheless, 75% of the participants
stated that a local standardized follow-up scheme is in place. Even so, clear variability
was observed in the duration of follow-up, ranging from 1 year to observation up to
adulthood or even indefinitely. Chest X-ray and CT-scan imaging during follow-up is
standard of care in 80% of the centers, corresponding with available literature.[6] The value of regular follow-up imaging can be questioned and must be weighed against
the potential harmful effects of ionizing radiation unless MRI is used as a radiation-free
method.[64]
[65]
[66] In our opinion, imaging should be reserved for selected cases but is mandatory in
patients that develop symptoms during follow-up. Furthermore, MRI imaging has recently
been posed as a viable, radiation-free alternative.[66]
[67]
This study has several limitations. First, the total number of participants in this
survey (63) was relatively low, despite the fact that we approached specialized caregivers
through two considerable international networks. Especially within the AEPC, the response
rate was low at approximately 10%. The results from this survey therefore do not necessarily
reflect the opinions of the complete network. Second, due to the higher response rate
within the CONNECT consortium, the majority of participants were pediatric surgeons,
introducing a possible bias in the results that reflects certain specialist expertise.
Management preferences significantly differed between surgical participants and their
nonsurgical colleagues, in accordance with earlier studies.[26] These findings stress the need for a multidisciplinary approach toward children
with BPS, but this appeared to be the standard of care in only half of the participating
centers in this survey. Third, the number of survey questions was limited, and the
majority were multiple-choice questions, with little room for personal remarks or
considerations. Through this design, we aimed to maximize the participation of clinicians
and aimed to collect objective data suitable for direct analysis. Possibly this survey
is a first step toward international discussions and collaboration to work toward
a standardized treatment for this rare congenital abnormality.
In conclusion, this survey demonstrates a wide variation in management strategies
for BPS, probably in part due to specialist expertise. The majority of centers treat
five or less BPS cases per year, and there are no generally accepted follow-up standards.
Discussing the management of patients with BPS in a multidisciplinary team consisting
of all potentially concerned with the care of these patients should become standard.
Finally, recording patient data in an international registry are desirable to gain
insight into and compare management strategies and outcomes, which could probably
support the development of future guidelines.
Abbreviations
AEPC:
Association for European Pediatric and Congenital Cardiology
BPS:
bronchopulmonary sequestration
CLA:
congenital lung abnormality
CONNECT:
Collaborative Neonatal Network for the first European CPAM Trial
CPAM:
congenital pulmonary airway malformation
CT-scan:
computed tomography scan
ELS:
extralobar sequestration
ILS:
intralobar sequestration
MRI:
magnetic resonance imaging
