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\begin{document}

\title{Care Recommendations for the Respiratory Complications of Esophageal
Atresia-Tracheoesophageal Fistula: The International Network of
Esophageal Atresia, Respiratory Complications Working Group}



\author[1]{Anastassios Koumbourlis}%
\author[2]{Yvonne Belessis}%
\author[3]{Mary Cataletto}%
\author[4]{Renato Cutrera}%
\author[5]{Emily DeBoer}%
\author[6]{Mikhail Kazachkov}%
\author[7]{Sophie Laberge}%
\author[8]{Jonathan Popler}%
\author[9]{Federica Porcaro}%
\author[10]{Tom Kovesi}%
\affil[1]{Children's National Medical Center}%
\affil[2]{Sydney Children's Hospital Randwick}%
\affil[3]{New York University Medical Center}%
\affil[4]{Bambino Gesù  Childrens’ Hospital, IRCCS}%
\affil[5]{University of Colorado Anschutz Medical Campus}%
\affil[6]{NYU Langone Medical Center}%
\affil[7]{CHU Sainte-Justine}%
\affil[8]{Children's Physician Group Pulmonology}%
\affil[9]{Bambino Gesù Children's Hospital}%
\affil[10]{CHEO,Ottawa}%


\vspace{-1em}



  
  \date{June 12, 2024}


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\selectlanguage{english}
\begin{abstract}
Tracheoesophageal fistula (TEF) with esophageal atresia (EA) is a common
congenital anomaly that is associated with significant respiratory
morbidity throughout life. The objective of this document is to provide
a framework for the diagnosis and management of the respiratory
complications that are associated with the condition. As there are no
randomized controlled studies on the subject, a group of experts used a
modification of the Rand Appropriateness Method to describe the various
aspects of the condition in terms of their relative importance, and to
rate the available diagnostic methods and therapeutic interventions on
the basis of their appropriateness and necessity. Specific
recommendations were formulated and reported as Level A, B, C based on
whether they were based on ``strong'', ``moderate'' or ``weak''
agreement. The tracheomalacia that exists in the site of the fistula was
considered the main abnormality that predisposes to all other
respiratory complications due to airway collapse and impaired clearance
of secretions. Aspiration due to impaired airway protection reflexes is
the main underlying contributing mechanism. Flexible bronchoscopy is the
main diagnostic modality, aided by imaging modalities, especially CT
scans of the chest. Non-invasive positive airway pressure support,
surgical techniques such as tracheopexy and rarely tracheostomy are
required for the management of severe tracheomalacia. Regular long-term
follow-up by a multidisciplinary team was considered imperative.
Specific templates outlining the elements of the clinical respiratory
evaluation according to the patients' age were also developed.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Congenital tracheoesophageal fistula (TEF) is almost always (92\% of
cases) associated with esophageal atresia (EA) (commonly referred to as
EA-TEF)\textsuperscript{1} with an estimated incidence of approximately
1 in 3500-4500 live births \textsuperscript{2,3}.

The trachea and the esophagus share a common embryologic origin from an
outgrowth of the foregut, the ``lung bud'', that appears around the
fourth week of gestation. By the end of the fifth week a septum divides
it in two parts and it separates from the foregut \textsuperscript{4}.
The TEF is caused by a defect in the septum that preserves the
communication between the esophagus and the lower trachea. Rare variants
include a communication between the esophagus and the right main stem
bronchus or the connection of the trachea and esophagus at proximal and
distal sites by two or even three fistulae\textsuperscript{5}.

Repair of the TEF consists of the separation of the esophagus from the
trachea and closure of the defect of the tracheal wall. There is usually
a visible ``ridge'' at the site of the repair and often a blind pouch
that can be intermittently open (Image 1A). The repair of the esophagus
is far more complex, particularly if there is a long gap between the two
atretic segments\textsuperscript{6}. Despite the repair of the defect,
the condition carries a very high morbidity primarily associated with
the presence of severe tracheomalacia (TM) or tracheobronchomalacia
(TBM). The complications of TEF are most prevalent and severe during the
first few years of life but may last in varying degrees throughout
life\textsuperscript{7--18}.

Improvement in the survival of infants born with EA-TEF has highlighted
the need to optimally manage their symptoms, reduce morbidity, and
improve quality of life. The International Network on Esophageal Atresia
(INoEA), comprised of health professionals involved in the care of
children with EA-TEF, published guidelines for the evaluation and
treatment of gastrointestinal and nutritional complications in EA-TEF
and on the surgical management of long-gap EA\textsuperscript{6,19,20}.
The Respiratory Complications Working Group (RCWG) was formed at the
invitation of the INoEA Steering Committee, to develop a similar
framework for the management of the respiratory complications of TEF.
The RCWG consists of 10 academic Pediatric Pulmonologists from Canada,
Italy, Australia, and the USA, with experience in the diagnosis and
management of infants and children with EA-TEF.

The document is intended for all health care professionals who are
involved in the care of patients with EA-TEF in or outside the hospital
setting. It may also be useful for the families of patients with EA-TEF
in understanding the rationale behind the multiple diagnostic and
therapeutic interventions that may be necessary throughout childhood and
adolescence.

\textbf{METHODS}

The literature on the respiratory complications of TEF is based on
small, single institution, retrospective case series and case reports.
There are no systematic reviews or randomized controlled trials to
formulate evidence-based guidelines on diagnosis and treatment. To
address this deficiency the RCWG chose a modification of the RAND
Appropriateness Method (RAM)\textsuperscript{21} developed by the RAND
Corporation--University of California Los Angeles, that helps synthesize
the available empirical evidence using the collective experience of a
panel of experts. The RAM approach has been widely used in the
development of clinical practice guidelines, including in adult
respiratory care\textsuperscript{22}, in primary pediatric
care\textsuperscript{23} and in rare pediatric conditions such as
Duchenne Muscular Dystrophy\textsuperscript{24--26}.

The RAM rates diagnostic and therapeutic interventions on the basis of
their ``appropriateness'' and ``necessity''. The appropriateness of an
intervention is based on its known or expected medical benefit without
consideration of any logistical or financial obstacles. Appropriateness
does not automatically imply necessity (e.g. bronchoalveolar lavage is
an appropriate diagnostic modality for the evaluation of pneumonia, but
it is not necessary for every case of pneumonia). The ``necessity'' is
based on whether a) the specific intervention has been deemed
appropriate; b) there is reasonable expectation it will benefit the
patient in a substantial way; c) according to prevailing standards of
care, it would be inappropriate not to offer this intervention to the
patient. The RAM enables individual expert opinion to be independently
and anonymously expressed and identifies areas of agreement as well as
of disagreement or uncertainty that are in need of further study.

The development of the recommendations consisted of the following steps
(Figure 1):

\textbf{Step 1} . \textbf{Review of the literature andformulation of
statements} . Questions relating to the domains of\emph{Respiratory
Physiology} \emph{(RP), Diagnostic Methods (DM)} and\emph{Therapeutic
Interventions (TI)} for the management of respiratory complications in
EA-TEF were generated by literature reviews limited to the English
language. Each question was subsequently discussed and reformulated into
specific statements during a face-to-face meeting. The agreed upon
statements were entered into matrices containing clinical scenarios with
a list of potential interventions in 3 areas: Respiratory
Pathophysiology (RP) Diagnostic Methods (DM) and Therapeutic
Interventions (TI).

\textbf{Step 2. Rating of statements for ``appropriateness''} . All
statements were individually rated for appropriateness on an ordinal
scale of 1-9 as follows: INAPPROPRIATE: ratings 1-3; UNCERTAIN: ratings
4-6; and APPROPRIATE: ratings 7-9. Pathophysiologic mechanisms were
rated as ``appropriate'' according to the degree to which the statement
was supported by generally acknowledged pulmonary physiology, currently
available literature, and/or by the clinical experience of the
responders. Statements in which all responses were in agreement i.e.
within the same category were set aside whilst the remaining statements
underwent a second and third round of rating. The results of each round
were shared within the RCWG without identifying the responders.

\textbf{Step 3.} \textbf{Rating of statements for ``necessity''} .
Necessity ratings were applied only to statements pertaining to
Diagnostic Methods and Therapeutic Interventions and were rated on an
ordinal scale 1-9 as follows: UNNECESSARY: 1-3; UNCERTAIN: 4-6;
NECESSARY: 7-9. The median, range and the mean (\selectlanguage{ngerman}±SD) were calculated. In
the final collation, the responses were classified as follows:

\begin{itemize}
\tightlist
\item
  \textbf{``Strong'' agreement} : both the median and the mean values of
  the responses for a given item were within the highest category (7-9)
\item
  \textbf{``Moderate'' agreement} : both the median and the mean values
  of the responses for a given item were within the middle category
  (4-6)
\item
  \textbf{``Weak'' agreement} : The median value was in the lowest
  category (1-3) and/or the difference between the highest and lowest
  value was \selectlanguage{english}[?] 3.
\end{itemize}

\textbf{Step 4} . \textbf{Formulation of the recommendations.} The
recommendations were classified as Level A (based on strong agreement),
B (moderate agreement) and C (weak agreement). The ratings on Necessity
were formulated into specific recommendations presented in 10 sections
(6 for Diagnostic Methods and 4 for Therapeutic Interventions) with
their supportive evidence.

\textbf{RESULTS}

\emph{RESPIRATORY PATHOPHYSIOLOGY}

Respiratory complications in TEF are the result of several interacting
anatomic and functional abnormalities (Figure 2), and they can be
summarized as follows:

1. \textbf{Tracheomalacia:} Tracheomalacia in EA-TEF was identified as
the main pathology that causes or predisposes to almost all other
respiratory complications.\textsuperscript{27} Tracheomalacia is caused
by the anteroposterior collapse of the cartilaginous wall and especially
by the intrusion of the posterior trachealis muscle into the lumen. This
changes its appearance from the typical ``Horseshoe arch'' shape, to a
flattened ``crescent'' shape (Images 1B \& 1C). Bronchomalacia is often
present as well (Image 1D).

Factors implicated in the development of TM include deficient tracheal
cartilage at the level of the fistula, intrinsic cartilage weakness over
longer tracheal segments due to \emph{in-utero} compression from the
dilated proximal esophageal pouch\textsuperscript{14} and/or aberrant
myoelastic development of the posterior
membrane.\textsuperscript{27--29}. The lower (intrathoracic) trachea
collapses mostly during exhalation, whereas the extrathoracic trachea
collapses during inspiration. Further deterioration of the TM may ensue
post-repair, from recurrent tracheal inflammation due to aspiration and
infection, or due to tracheal wall weakness secondary to prolonged
intubation and long-term mechanical
ventilation.\textsuperscript{27,28,30--33} Intermittent dilatation of
the esophagus due to bolus obstruction can easily overcome the
resistance of the weakened tracheal wall and cause its further
collapse\textsuperscript{34,35}. Complications attributed to TM are:

\textbf{- Cyanotic spells} : Early in infancy, patients can develop
severe or even life-threatening airway obstruction associated with
profound drops in oxyhemoglobin saturation and bradycardia (colloquially
referred to as the TEF ``death spells''). \textsuperscript{34,36,37} The
episodes tend to occur when there are increases in intrathoracic
pressure (e.g. during crying or straining) that cause almost complete
collapse of the tracheal lumen\textsuperscript{37,38}The desaturation is
more dramatic when there are anatomical communications (e.g. PDA, ASD,
VSD) causing right-to-left shunt.

- \textbf{Chronic cough} : A dry barking cough (also described as
``honking'' or ``brassy'') is the trademark symptom of TM especially in
infancy and childhood; this cough tends to decrease somewhat with
age\textsuperscript{8,18,39}. A chronic wet cough (often described as
``smoker's cough'') may develop in early childhood and can remain across
the lifespan\textsuperscript{40,41}.

\textbf{- Recurrent lower respiratory tract infections} : Multiple
episodes of pneumonia--especially during the first few years of
life--are reported in as many as 50\% of the children whereas
intermittent or chronic bronchitis is reported by almost 2/3 of adults
with EA-TEF.\textsuperscript{9,11,13,15--18,41--46} Recurrent lower
respiratory tract infections can lead to bronchiectasis, poor lung
function, and lower quality of life in
adulthood.\textsuperscript{40,43,47}

\textbf{- Chronic or recurrent ``wheezing''} : Infants and young
children with EA-TEF often produce a wheeze-like persistent harsh
expiratory noise that is often misdiagnosed as ``bronchiolitis'' or
``asthma'', or in older patients as exercise induced asthma. The
``wheeze'' is produced by the collapse of the tracheal lumen and not by
bronchospasm and therefore does not respond to
bronchodilators.\textsuperscript{11}

\textbf{2. Impaired airway clearance:} The narrowing of the tracheal
lumen leads to retention of airway secretions whose clearance is further
impaired by the loss of cilia on the respiratory epithelial cells at the
fistula site\textsuperscript{28,33,48}. The retention of secretions
predisposes to colonization with bacterial organisms and progressive
airway inflammation that may lead to irreversible lung damage, including
bronchiectasis. Affected patients are likely to have recurrent or
chronic wet cough often termed protracted bacterial
bronchitis\textsuperscript{49--51}.

3. \textbf{Aspiration} : Recurrent aspiration is the result of
anatomical and/or functional abnormalities and it is recognized as a
cause or contributing factor of acute and chronic respiratory morbidity
in various conditions\textsuperscript{52--56}. The anatomical
abnormalities consist of direct communications of the tracheobronchial
tree and the alimentary tract (such as laryngeal clefts,
tracheoesophageal or bronchoesophageal fistulae) and result in direct
aspiration\textsuperscript{12,52,53}. Direct aspiration can also result
when one or both vocal cords are paralyzed in
abduction.\textsuperscript{57} The functional causes are due to
predisposing conditions that allow liquids or solids near the larynx.
Such factors include dysphagia and swallowing impairment (e.g. inability
to or delayed bolus formation, pooling of secretions in the pyriform
sinuses etc.), GER, and regurgitation of foodstuff that is stuck in the
esophagus\textsuperscript{58--61}. All of these factors can result in
aspiration if the patient is also unable to protect the airways with
laryngospasm and/or clear the trachea after laryngeal penetration using
cough.

Regardless of the underlying mechanism, aspiration can exacerbate
chronic airway inflammation, facilitate the colonization of the airways
with bacteria, and expose the infants to allergens at an early age,
potentially leading to atopy\textsuperscript{62}. The ensuing chronic
inflammation and recurrent infections may lead to the development of
bronchiectasis and severe impairment of the lung function consisting of
lower airway obstruction with air-trapping as well as actual loss of
lung volume\textsuperscript{53,55,63,64}.

\textbf{3. Bronchiectasis:} Bronchiectasis is one of the more serious
pulmonary complications in patients with
EA-TEF\textsuperscript{9,11,43,65--70}. Although it is the end-result of
other complications (especially recurrent LRTIs and aspiration), it
becomes a specific entity by itself, becoming the source of even more
infections and causing irreversible damage to the airways. Clinically,
it is characterized by daily productive cough (even in the absence of an
acute infection). Exacerbations are associated with increased purulent
sputum production, frequently fever, dyspnea, and in advanced cases
hemoptysis.\textsuperscript{49,50} Because young children cannot
expectorate, changes in the quality of the cough from dry to ``wet''
have been proposed as an alternative to changes in sputum production and
appearance\textsuperscript{47,49,50} .

4. \textbf{Gastroesophageal dysmotility:} EA-TEF is characterized by
multiple functional and anatomical gastroesophageal abnormalities that
have been discussed in detail elsewhere.\textsuperscript{19,59} In
general, these abnormalities tend to be contributing or predisposing
factors to the development of respiratory complications from the upper
and/or lower airways.\textsuperscript{58--61} Gastroesophageal reflux
and/or esophageal regurgitation can cause chronic laryngeal irritation
that may manifest itself as recurrent stridor and/or chronic
hoarseness.\textsuperscript{9,53,58,71} However, chronic stridor,
especially if it is not accompanied by difficulty in breathing, should
raise suspicions of vocal cord paralysis due to trauma of the recurrent
laryngeal nerve during the repair\textsuperscript{57,72}. Effects in the
lower airways include tracheal compression from a dilated esophagus, and
conditions that increase the risk of aspiration such as regurgitation,
impaired swallow, and GER.

\textbf{5. Associated congenital abnormalities} . Although EA-TEF can be
an isolated abnormality, in about 50\% of patients it is part of
syndromes involving multiple other organ-systems\textsuperscript{3,73}.
The most common include the VACTERL association~(vertebral defects, anal
atresia, cardiac defects, TEF, renal anomalies, and limb abnormalities),
the CHARGE syndrome~(coloboma, heart defects, atresia choanae, growth
retardation, genital abnormalities, and ear abnormalities) and
chromosomal abnormalities (including Down syndrome). Of special interest
are associated abnormalities of the upper
airways\textsuperscript{74--77} as well as various cardiovascular
anomalies\textsuperscript{78--84}. All of these conditions increase the
morbidity and, in the case of congenital heart disease, the mortality as
well\textsuperscript{85}.

\textbf{B. RECOMMENDATIONS ON DIAGNOSTIC METHODS}\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{Evaluation of Tracheobronchomalacia}\tabularnewline
\midrule
\endhead
\textbf{Level A Recommendations} \textbf{Recommendation 1:} Flexible
bronchoscopy is the gold standard for the evaluation of TBM
\textbf{Recommendation 2:} Flexible bronchoscopy is recommended for
unexplained wheezing or exercise intolerance \textbf{Recommendation 3:}
Flexible bronchoscopy is indicated for all patients with a tracheostomy
\textbf{Recommendation 4}: Rigid bronchoscopy is not a sensitive method
for the evaluation of the severity of TBM\tabularnewline
\textbf{Level B Recommendations} \textbf{Recommendation 5}:
Multi-detector CT scan is an accurate method of assessing TBM
\textbf{Recommendation 6}: Spirometry is a reliable way of assessing the
severity of TBM in older children\tabularnewline
\textbf{Level C Recommendations} \textbf{Recommendation 7}: Tidal
flow-volume loops are a reliable way of assessing the severity of TBM in
infants and toddlers\tabularnewline
\bottomrule
\end{longtable}

Flexible bronchoscopy is considered the gold standard for the evaluation
of the presence and severity of TBM. Rigid bronchoscopy tends to
underestimate the degree of the tracheal collapse because it ``stents''
the airway\textsuperscript{51,86--88}.

There was moderate agreement regarding the use of standard chest CT
because it may not capture the dynamic changes of the tracheobronchial
lumen that occur during the respiratory cycle (especially with cough).
Inspiratory and expiratory dynamic multi-detector chest CT scans were
considered superior because they are fast, relatively inexpensive, and
provide additional and detailed information about the airways, the lung
parenchyma, and the thoracic vasculature\textsuperscript{51,87,89,90}.
However, at the moment they may not be available in every hospital.

Maximal expiratory flow-volume curves (MEFVCs) can be often diagnostic
of tracheomalacia\textsuperscript{91}, showing a characteristic
flattening of the initial portion of the MEFVC (Figure 3A). Its
disadvantage is that it can only be performed in children over 4-5 years
of age, and it becomes less sensitive in older children and
adolescents\textsuperscript{44,92}. Infants can be evaluated with the
raised-volume rapid thoracoabdominal compression (RVRTC) technique,
which allows the performance of MEFVCs without the patient's cooperation
but is labor intensive and usually requires
sedation\textsuperscript{93}. An alternative easy, non-invasive
technique to evaluate flow-limitation is with tidal flow volume
loops\textsuperscript{94} (Figure 3B). However, it is not well
standardized, and it may miss mild/moderate TBM.\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{Evaluation of a Recurrent Tracheoesophageal
Fistula}\tabularnewline
\midrule
\endhead
\textbf{Level A Recommendations} \textbf{Recommendation 8:} Combined
endoscopy and bronchoscopy are the gold standard for the diagnosis of
recurrent TEF\tabularnewline
\textbf{Level C Recommendations} \textbf{Recommendation 9}: Barium
swallow in prone/semi-prone position is the preferred radiographic
method for the detection of recurrent TEF \emph{Recommendation}
\textbf{10}: Pressure esophagogram is the preferred method for the
detection of a small TEF\tabularnewline
\bottomrule
\end{longtable}

Recurrent TEFs occur in 5-10\% of cases after primary repair, as a
result of esophageal anastomotic leak, trauma from esophageal
dilatations and/or airway infections\textsuperscript{95--102}. The
manifestations of recurrent TEF are potentially severe and include
cough, choking and cyanosis during feeds, and recurrent pneumonias.
Diagnosis is challenging and often delayed despite multiple
investigations. There was strong agreement that recurrent TEFs are best
diagnosed with simultaneous esophageal endoscopy and bronchoscopy, aided
by the infusion of methylene blue on the tracheal or esophageal side and
observing its appearance on the other side\textsuperscript{98,103}. An
esophagogram in prone or semi-prone position with contrast administered
under pressure can be diagnostic and has the fewest false negative
results (compared with upper GI in supine or erect positions), but it
may miss a TEF in the presence of an esophageal
stricture\textsuperscript{95,97,104,105}. Moreover, it is not a standard
technique among radiologists, and therefore did not receive strong
recommendation. This multidisciplinary approach is increasingly used to
optimise outcomes in children with recurrent
TEF\textsuperscript{106,107}.\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{Evaluation of Bronchitis and Pneumonia}\tabularnewline
\midrule
\endhead
\textbf{Level A Recommendations} \textbf{Recommendation 11}: The
presence of a chronic wet cough requires further evaluation
\textbf{Recommendation 12}: Children with more than one episode of lobar
pneumonia should be evaluated for aspiration or underlying anatomical
abnormalities \textbf{Recommendation 13}: Bronchoalveolar lavage is
indicated for recurrent or persistent cough to rule out colonization of
the airways by pathogens \textbf{Recommendation 14}: CT scan of the
chest should be considered in cases of frequent respiratory infections
\textbf{Recommendation 15}: CT scan of the chest is more useful as a
baseline but not during an acute lower respiratory tract
infection\tabularnewline
\textbf{Level B Recommendations} \textbf{Recommendation 16}: Pneumonia
in patients with EA/TEF should be confirmed by CXR\tabularnewline
\textbf{Level C Recommendations} \textbf{Recommendation 17}: The
threshold for obtaining CXR should be low because pneumonia in children
with TEF may not be associated with fever \textbf{Recommendation 18}:
CXR should be obtained in each episode of suspected pneumonia
\textbf{Recommendation 19}: Chest CT should be considered in case of
suspected pneumonia \textbf{Recommendation \emph{20}}: BAL should be
considered in cases of suspected pneumonia \textbf{Recommendation 21}:
Cultures from BAL should be obtained before starting antibiotics for
suspected pneumonia \textbf{Recommendation22}: CBC with differential
should be done only in cases of suspected pneumonia associated with
fever\tabularnewline
\bottomrule
\end{longtable}

Based on the high risk for recurrent episodes of bronchitis and/or
pneumonia in EA-TEF, the RCWG strongly recommended that chronic wet
cough should be evaluated for underlying undiagnosed anatomic and/or
functional abnormalities. The main evaluation includes a CT scan to
determine the presence of chronic changes such as
bronchiectasis\textsuperscript{47,50}, and a BAL to determine presence
of colonization with bacterial and other pathogens as well as for
evidence of aspiration(see also section V for the evaluation of
aspiration). The threshold for repeating the investigations should be
low because there is evidence that airway inflammation, bacterial
bronchitis, and bronchiectasis may be present in young children with
EA/TEF even when they are asymptomatic\textsuperscript{9,45,65,107,108}.
However, for patients with an established pattern it is not necessary to
repeat the work-up for every exacerbation unless there is suspicion of
new pathology. A CXR with each suspected episode of pneumonia may be
useful to document how often a patient is having lobar pneumonia, which
may, in turn, determine the necessity for further investigations.\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{Evaluation of Bronchiectasis}\tabularnewline
\midrule
\endhead
\textbf{Level A Recommendations} \textbf{Recommendation 23}: A negative
CXR does not rule out the presence of bronchiectasis
\textbf{Recommendation 24}: The presence of bronchiectasis can be best
evaluated by low radiation chest CT without contrast
\textbf{Recommendation 25}: Chest CT should be considered in cases of
chronic irreversible changes on CXR\tabularnewline
\textbf{Level C Recommendations} \textbf{Recommendation26}: CXR should
be obtained annually in all children with TEF regardless of their
clinical status \textbf{Recommendation27}: Chest CT should be obtained
annually in all children with TEF regardless of their clinical
status\tabularnewline
Bronchiectasis is defined as an abnormal dilatation of the bronchial
tree and it is one of the more serious pulmonary complications in
patients with EA-TEF\textsuperscript{65,66,109}. A ratio
\textgreater{}0.8 of the bronchial \& arterial lumens in a chest CT is
considered diagnostic\textsuperscript{50}. The finding of ``tramlines''
and/or of ``signet ring'' sign opacities in plain radiographs are
typical of bronchiectasis but their absence does not rule out the
diagnosis\textsuperscript{110,111}. Monitoring of disease progression is
best achieved with a low-dose high resolution chest CT because it may
reveal airway changes that can be prevented from progressing if treated
early and aggressively\textsuperscript{9,50,65,107}. Radiation exposure
from chest CT evaluations remains a concern, especially for young
children. High-resolution ultrashort echo time (UTE) magnetic resonance
imaging (MRI) completely eliminates radiation
exposure\textsuperscript{112}, whereas modifications in the technique of
the dual multidetector CT (MDCT) allow scanning of the pediatric lungs
in less than 1 sec and with markedly lower dose of radiation than a
regular CT scan\textsuperscript{113}. Neither technique requires
sedation. However, the techniques are not readily available in every
hospital and therefore they are not recommended at this
point.\tabularnewline
\textbf{Evaluation of Possible Aspiration}\tabularnewline
\textbf{Level A Recommendations} \textbf{Recommendation 29}: Multiple
episodes of lobar pneumonia should be evaluated for aspiration or
possible underlying anatomical abnormalities \textbf{Recommendation 29}:
Rigid bronchoscopy is indicated for the evaluation of a possible
laryngeal cleft\tabularnewline
\textbf{Level B Recommendations} \textbf{Recommendation 30}: BAL is
indicated in cases of suspected aspiration\tabularnewline
\textbf{Level C Recommendations} \textbf{Recommendation 31}:
Asymptomatic children with EA/TEF who have positive cultures in BAL
should be evaluated for possible aspiration \textbf{Recommendation 32}:
In infants with TEF, the CXR may show characteristic changes consistent
with aspiration \textbf{Recommendation 33}: Chest CT should be
considered in cases of known or highly suspected chronic aspiration
\textbf{Recommendation 34}: Presence of lipid laden macrophages in BAL
of children without acute or chronic lung disease is suggestive of
aspiration \textbf{Recommendation 35}: Modified Barium Swallow should be
performed in all patients prior to initiating oral
feedings\tabularnewline
Patients with EA-TEF are predisposed to aspiration and the possibility
should be investigated in cases of recurrent pneumonia. Conditions to be
ruled out include undiagnosed occult communications (e.g. laryngeal
cleft and/or undiagnosed fistulae)\textsuperscript{18,59--61,74--76,114}
or functional abnormalities such as impaired swallowing, vocal cord
dysfunction and esophageal dysmotility that predispose to aspiration.
Laryngeal clefts in particular can be found in almost 20\% of the cases
of EA-TEF, and rigid airway endoscopy with probing of the posterior
glottis is the gold standard for its diagnosis\textsuperscript{115,116}.
Presence of contrast material in the tracheobronchial tree after a
contrast study (e.g. upper GI series) or foodstuff seen in the trachea
of a patient with tracheostomy are definitive of the diagnosis but
rather ``accidental'' findings. Direct visualization of the swallowing
with videofluoroscopy or flexible laryngoscopy are the most commonly
used clinical modalities that can provide a definitive diagnosis when
positive but do not rule out the diagnosis when
negative\textsuperscript{52,117,118}. Chest radiographs and especially
CT scans of the chest are useful in documenting the presence and extent
of the lung damage but they are not pathognomonic of aspiration.
Bronchoalveolar lavage is widely used for the diagnosis of aspiration on
the basis of the presence of lipid laden macrophages (LLM) in the
BAL\textsuperscript{119}. The assumption is that normally there are no
lipid molecules in the BAL, therefore their presence is evidence of
aspiration of exogenous lipids\textsuperscript{119,120}. However, lipid
molecules are also released as part of cell death. Therefore lipid-laden
macrophages can be found in conditions causing acute or chronic damage
to the airways independent of aspiration (e.g. pneumonia, Cystic
Fibrosis)\textsuperscript{121,122}. Of other potential biologic markers,
the most promising is pepsin, but its use has not yet been
standardized\textsuperscript{123,124}. A detailed approach to the
investigation of gastroesophageal abnormalities predisposing EA-TEF
patients is provided in the INoEA gastroesophageal guidelines
statement\textsuperscript{19}.\tabularnewline
\textbf{VI. Evaluation of Cyanosis}\tabularnewline
\textbf{Level A Recommendations} \textbf{Recommendation 36}: An
echocardiogram should be performed in infants with EA-TEF who develop
episodes of severe cyanosis in order to rule out anatomical
shunts\tabularnewline
\textbf{Level B Recommendations} \textbf{Recommendation 37}: Chest CT
with contrast should be performed when a vascular anomaly is
suspected.\tabularnewline
\bottomrule
\end{longtable}

Intermittent acute profound cyanosis in patients with EA-TEF is usually
due to near complete collapse of the trachea. However, the possibility
of an anatomical shunt has to be ruled out because congenital heart
malformations associated with right-to-left shunts (such as valve
atresia, Tetralogy of Fallot, anomalous pulmonary venous return, and
septal defects or patent ductus arteriosus) are present in more than one
quarter of the patients\textsuperscript{80,84} and they are independent
predictors of survival\textsuperscript{125}. For children with no
history of congenital heart disease an echocardiogram is useful in order
to investigate for presence of vascular abnormalities such as
right-sided or double aortic arch, and aberrant right or left subclavian
arteries that may complicate the clinical presentation by causing or
exacerbating the degree of
tracheomalacia\textsuperscript{37,78,80,81,126}. Definitive confirmation
will require a CT-angiogram or an MRI/MRA or cardiac catheterization.

\textbf{RECOMMENDATIONS ON THERAPEUTIC INTERVENTIONS}\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{VII. Management of Tracheobronchomalacia}\tabularnewline
\midrule
\endhead
\textbf{Level A Recommendations} \textbf{Recommendation 1}: Non-invasive
Positive Pressure Ventilation is useful in children with severe TBM
\textbf{Recommendation 2}: Tracheostomy may be necessary for TBM
associated with severe cyanotic episodes and/or respiratory failure
\textbf{Recommendation 3}: Custom-made long tracheostomy tube and
positive pressure support may be necessary for severe TBM\tabularnewline
\textbf{Level B Recommendations} \textbf{Recommendation 4}: Aortopexy is
a safe \& effective way to treat severe TBM \textbf{Recommendation 5}:
Posterior tracheopexy than aortopexy is preferable for severe TBM
\textbf{Recommendation 6}: Bethanecol could be considered in cases of
severe TBM\tabularnewline
\bottomrule
\end{longtable}

Infants with mild TM can be successfully extubated after the repair of
the EA-TEF and do not require any ventilatory or other support. They
often remain symptomatic with recurrent or persistent symptoms (such as
``barking'' cough and coarse wheeze), which tend to be amplified during
episodes of upper and/or lower respiratory tract infections.
Tracheomalacia tends to improve over time due to the increase in
diameter of the tracheal lumen and a reduction in airway collapsibility
that minimize the degree of obstruction relative to lumen size. However,
it is a slow process that even under the best circumstances continues
for years.

Patients with severe (especially extensive) tracheomalacia (with or
without bronchomalacia) may have severe, potentially life-threatening
symptoms due to the almost complete tracheal collapse, and they are
likely to require some type of ventilatory
support\textsuperscript{127--130}. Such support is usually needed
immediately after extubation following the surgical repair of the
EA-TEF, but may be needed for weeks or months afterwards. Patients
without lung disease and/or respiratory muscle weakness respond well to
non-invasive positive airway pressure (continuous positive airway
pressure (CPAP) or Bi-Level Positive Airway Pressure (PAP)) that
prevents the complete collapse of the tracheal lumen. High flow nasal
cannula (HFNC) is a newer modality that has been shown to be effective
and safe\textsuperscript{71,131--133}.

There is concern that non-invasive PAP in the immediate post-repair
period increases the risk of air leak in the area of the repaired TEF,
or damage to the esophageal anastomosis\textsuperscript{134}. However,
in practice the various forms of PAP/HFNC have been used
safely\textsuperscript{135} and the RCWG felt that the risk of
respiratory decompensation in the immediate post-operative period,
outweighs the theoretical risks of non-invasive PAP. The situation is
more problematic for infants who may need prolonged continuous support
because in many countries (including the US) the non-invasive types of
ventilation are not approved for continuous use in the home environment.

Aortopexy has been used successfully for TM due to compression of the
anterior tracheal wall (e.g. compression by the innominate
artery)\textsuperscript{136}. However, in EA-TEF the tracheal occlusion
is caused mostly by the intrusion of the posterior tracheal wall into
the tracheal lumen. Thus a posterior tracheopexy (pulling of the
posterior tracheal membrane with sutures that are secured onto the
anterior longitudinal spinal ligament) has been suggested as a more
definitive treatment. The technique has been modified to include
aortopexy of the descending aorta that is often causing severe
compression of the posterior wall of the left main stem
bronchus\textsuperscript{36,71,100,127,136--140}. These techniques are
still very much dependent on specific surgical and institutional
expertise and the evidence about their long-term effectiveness is still
scant. Even the timing of the procedure varies, with some centers
performing these procedures at the time of the initial repair of the
EA-TEF, while other consider them only for severe persisting malacia not
responding to non-invasive PAP. Thus, they did not receive a strong
recommendation by the RCWG. However, it was recognized that they could
become the standard of care in the future.

For patients who have repeated, life threatening cyanotic episodes
despite non-invasive PAP, and are not candidates for surgical repair, a
tracheostomy provides a secure airway that can be used with or without
positive pressure support\textsuperscript{141}. Because most TEFs are
located near the carina, a regular tracheostomy tube that extends only
to the middle trachea may not prevent the collapse of the lower trachea.
Therefore a custom made tube that extends to the lower trachea may be
necessary (these tubes may also provide enough stenting of the main stem
bronchii)\textsuperscript{142}.

The use of tracheal (and/or bronchial) stents for the management of
severe TBM was recently reviewed by the European Respiratory
Society\textsuperscript{143}. Theoretically, stents would be the
``ideal'' solution to the problem of severe TBM. However, they are
rarely used in infants because of lack of size-appropriate stents, stent
migration, difficulty of removal, and most importantly, because of the
need to replace them with a bigger stent as the trachea grows.

Bethanecol is a synthetic muscarinic stimulant that has been used in
certain cases of tracheomalacia. Stimulation of the muscarinic receptors
in the airways should normally produce bronchospasm, but it seems to
actually ``open'' an airway that is floppy due to malacia by increasing
the trachealis muscle tone. There are no RCTs on its use but in a small
series it appeared to be safe \textsuperscript{144}.\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{VIII. Antibiotic Therapy}\tabularnewline
\midrule
\endhead
\textbf{Level A Recommendations} \textbf{Recommendation 7}: The
threshold for considering antibiotics should be lower in children with
EA-TEF \textbf{Recommendation 8}: Azithromycin may be useful in children
with recurrent respiratory infections and presence of
bronchiectasis\tabularnewline
\textbf{Level B Recommendations} \textbf{Recommendation 9:} Antibiotic
therapy is indicated for asymptomatic children with positive cultures
for bacteria in BAL \textbf{Recommendation 10:} Antibiotics should be
given only in patients who have respiratory symptoms and radiographic
changes\tabularnewline
\textbf{Level C Recommendations} \textbf{Recommendation 11}. Antibiotics
should be given only in patients who are febrile and have elevated white
blood count\tabularnewline
\bottomrule
\end{longtable}

The retention of secretions due to poor airway clearance, and the high
prevalence of recurrent, aspiration that promotes the colonization of
the lower airways with organisms from the oropharynx, predispose
children with EA-TEF to recurrent LTRIs\textsuperscript{9,12,17,145}.
There was strong agreement that these factors justify the lower
threshold for initiating antibiotics with the development of symptoms
such as increased ``wet'' cough (even without fever) or when cultures
from BAL are positive for bacterial pathogens even in the absence of
symptoms.

Borrowing primarily from the experience in patients with Cystic
Fibrosis\textsuperscript{146--148}, there was strong agreement on the
use of prophylactic azithromycin due to its antimicrobial and
anti-inflammatory properties for patients with chronic symptoms,
especially those with documented
bronchiectasis\textsuperscript{149,150}. However, there was only
moderate agreement on using antibiotics in asymptomatic children who
have positive BAL cultures especially with organisms are considered to
be ``normal'' oral flora.

There are no systematic studies on the exact organisms that may colonize
the airways of patients with EA-TEF, but it is reasonable to assume that
they are colonized by the same organisms found in children without
EA-TEF who have chronic wet cough (such as \emph{Haemophilus influenzae,
Staphylococcus aureus and Streptococcus pneumoniae, Moraxella
Catarrhalis)} \textsuperscript{50,70,111}, \emph{as well as} anaerobic
organisms due to possible aspiration. Most of these organisms are
usually sensitive to amoxicillin/clavulanic acid that is recommended for
the treatment of chronic cough\textsuperscript{151}.\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{IX. Health Maintenance and Prevention}\tabularnewline
\midrule
\endhead
\textbf{Level A Recommendations} \textbf{Recommendation 12}: Children
with EA-TEF should be followed by a specialized interdisciplinary team
\textbf{Recommendation 13}: Children with EA-TEF should be evaluated at
least annually \textbf{Recommendation 14}: Routine evaluation should
continue throughout childhood and adulthood \textbf{Recommendation 15} :
Annual Influenza vaccination is indicated for children with
EA-TEF\tabularnewline
\textbf{Level B Recommendations} \textbf{Recommendation 16}: Anti-RSV
prophylaxis is indicated for infants with EA/TEF under 12 months of age
\textbf{Recommendation 17}: Airway clearance techniques should be
instituted in asymptomatic children with positive cultures in
BAL.\tabularnewline
\bottomrule
\end{longtable}

Historically, patients with EA-TEF had little follow-up by specialists
once they recovered from the initial repair. However, longitudinal
studies in adult survivors of EA-TEF highlighted the high prevalence of
respiratory complications across the lifespan\textsuperscript{44,46}.
Early detection and management of respiratory complications may prevent
irreversible structural lung disease and loss of lung
function\textsuperscript{11,16,18,152}.

The RCWG strongly recommends systematic follow-up by multidisciplinary
teams that include pulmonologists, gastroenterologists,
otolaryngologists, pediatricians and thoracic surgeons, as well as
dieticians, physiotherapists, speech-language pathologists or
occupational therapists, and social
workers\textsuperscript{2,19,20,107,124,153--155}. Some centres have
also included diagnostic and interventional radiologists and an
intensivist\textsuperscript{156}. Special emphasis is given to have
regular evaluation and follow-up by psychologists because of growing
concern about the long-term effect of EA-TEF on the quality of life of
the patients and their families \textsuperscript{157--160}.

This approach allows the timely identification of multisystem treatable
abnormalities, better care coordination and increase safety by reducing
the number of exposure to general anesthesia\textsuperscript{152}. For
the family, it decreases the number of visits to the hospital and the
associated facility charges. This results into higher family
satisfaction, while it remains cost effective for the
hospitals\textsuperscript{106,161,162} .

The RCWG strongly agreed that patients with EA-TEF should receive all
recommended mandatory vaccinations as well as the annual influenza
vaccine. There was only moderate agreement on the need for RSV
prophylaxis possibly reflecting different policies that exist in each
country regarding this intervention.

How often the patients need to be evaluated by the entire team depends
on the special needs of the patients and the feasibility of assembling
such a large team in each institution\textsuperscript{158}.
Acknowledging that such a team may not be feasible in smaller
institutions, let alone in clinics or doctors' offices, the RCWG
developed a list of the essential elements for the follow-up of patients
with EA-TEF (Tables 1A, 1B \& 2)\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{X. Adjunct Therapies}\tabularnewline
\midrule
\endhead
\textbf{Level A Recommendations} \textbf{Recommendation 18}: Airway
clearance techniques should be instituted in asymptomatic children with
positive cultures in BAL.\tabularnewline
\textbf{Level B Recommendations} \textbf{Recommendation 19}: A trial of
medical anti-GER therapy is useful in children with persistent
respiratory symptoms \textbf{Recommendation 20\emph{:}} Bronchodilators
should not be used because they may worsen the airway
collapse\tabularnewline
\textbf{Level C Recommendations} \textbf{Recommendation 21}: Mucolytics
should be used routinely to facilitate airway clearance
\textbf{Recommendation 22}: Inhaled steroids should be used routinely
due to presence of chronic airway inflammation \textbf{Recommendation
23}: Inhaled steroids should be used in cases of suspected pneumonia
\textbf{Recommendation 24}: Systemic steroids should be used in cases of
suspected pneumonia \textbf{Recommendation 25}: Fundoplication may be
required for chronic respiratory symptoms and poorly controlled
GER\tabularnewline
\bottomrule
\end{longtable}

Virtually all therapies used in patients with EA-TEF are directed to
specific problems/symptoms and are based on empiric evidence. The RCWG
rated the following:\emph{Airway Clearance}: There was strong agreement
that age appropriate airway clearance techniques (e.g. manual chest
physiotherapy, High Frequency Chest Wall Oscillation, Positive
Expiratory Pressure valve) should be used routinely to aid the clearance
of secretions. There are no studies comparing these techniques in the
EA-TEF population (or in tracheomalacia in general). Therefore, the
selection relies on the availability of the various devices, and on
institutional practices\textsuperscript{163--165}. The Positive
Expiratory Pressure valve technique may be particularly helpful in
patients with tracheomalacia and/or bronchiectasis, by stenting
collapsible airways open and aid airway
clearance\textsuperscript{166}.\emph{Anti-GE Reflux therapy}: The
association of GER with respiratory morbidity and the effectiveness of
empiric anti-GER treatment remain highly
controversial\textsuperscript{58,61,167}. This is in part, due to the
fact that respiratory symptoms from the upper and/or from the lower
airways can be caused by miniscule amounts of refluxate and as a result
the usual diagnostic studies for GERD may likely be within the normal
range. The RCWG did not address in detail the management of GER, GERD
and aspiration because they have been recently reviewed in detail in the
INoEA Consensus Guidelines on Gastrointestinal Complications of
EA-TEF\textsuperscript{19,167}. However, a moderate agreement was
reached on trying empirically anti-GER therapy for patients with
persistent respiratory symptoms based primarily on the fact that the
prevalence of GER is very high in EA-TEF\textsuperscript{52,168}.

\emph{Bronchodilators} : The use of bronchodilators in EA-TEF remains
controversial. On one hand there is evidence of increased airway
hyperreactivity among patients with EA-TEF that warrants the use of
bronchodilators\textsuperscript{15,68}. Albuterol is also being used to
improve mucociliary clearance\textsuperscript{169}. On the other hand,
chronic ``wheezing'' in patients with EA-TEF is often caused by the
collapse of the tracheal lumen that cannot be prevented or reversed with
bronchodilators. Moreover, the overrelaxation of the tracheobronchial
smooth muscle may actually worsen the obstruction (Figure
3A)\textsuperscript{170}. Thus, although, a trial with bronchodilators
for symptomatic children is warranted, the RCWG does not recommend
\selectlanguage{greek}β\selectlanguage{english}\textsubscript{2}-agonists as standard therapy for EA-TEF. However,
ipratropium bromide (an anticholinergic agent) has been shown to be
associated with improved symptoms in children with TM (possibly due to
decreased effect on the tracheobronchial muscle tone and/or by reducing
the amount of secretions) and it may be considered as an alternative of
albuterol\textsuperscript{171}..

\emph{Inhaled corticosteroids (ICS)} : The role of steroids in TBM is
rather controversial and there was weak agreement on their routine use
because the inflammation in EA-TEF tends to be neutrophilic and
therefore less likely to respond to steroids\textsuperscript{63}.
Furthermore, there is some evidence that chronic use of high doses of
ICS may actually cause or exacerbate existing
tracheomalacia\textsuperscript{172} . Thus of the routine use of ICS
should be reserved for documented or highly suspected airway
hyperreactivity.

\textbf{Mucolytics} : Mucolytic agents (Dornase alpha, hypertonic
saline, N-Acetylcysteine) are often used in patients with tracheomalacia
on the assumption that the impaired airway clearance probably results in
the accumulation and possibly thickening of secretions. Dornase alpha
and hypertonic saline are commonly used in the management of cystic
fibrosis-related chronic bronchiectasis, but their effect in non-CF
bronchiectasis is not as well defined\textsuperscript{173}. Thus, the
RCWG did not support its routine use.

\textbf{DISCUSSION}

Guidelines are intended to review systematically the available evidence,
rate its validity, and distill the findings into easy to understand
recommendations that practitioners can follow. Many different
methodologies have been developed for this
purpose\textsuperscript{21,174,175} The GRADE method (Grading of
Recommendations Assessment, Development and
Evaluation)\textsuperscript{175}, has been recently adopted by a number
of professional organizations for the development of guidelines, but we
did not choose it because it relies heavily on RCTs and systematic
observational studies that are not available in the literature on
EA-TEF.

We developed our recommendations on the basis of the Rand
Appropriateness Method\textsuperscript{24--26}, offered certain
important advantages for the type of evidence we had available such as:
a) the responders do not have to accept positions they do not agree
with, in order to reach a consensus; b) disagreements are not
suppressed, thus reflecting more accurately the uncertainties and
variability that exist in the actual clinical practice; c) each item is
rated by all responders, and their responses carry the same weight (thus
preventing a single issue (or a single person) from dominating the
process; d) the anonymity of the responses allows the participants to
express their opinions more freely; and e) it provides timely feedback
by communicating the results of each round to the responders, allowing
them to compare their responses to others and potentially adjust them.

Our recommendations were based on the strength of the agreement among
the RCWG members. Thus, Level A recommendations refer to unanimous
adoption of specific interventions and care practices. Level B \& C
recommendations reflect both the lack of evidence and actual
controversies on a specific topic, as well as the different areas of
expertise, skill mix, resource availability and hospital culture among
the RCWG's representative institutions. This differs from other
consensus based methods that assign different weight on the evidence
depending on the design of the study, its size, the type of analysis
etc.)\textsuperscript{176}.

As diagnostic methods improve and therapeutic interventions become more
precise, it is likely that many of the current recommendations will have
to be revised. In the meantime, the document provides a common approach
for the evaluation and management of these complex patients at levels
that can be provided by most practitioners and institutions. It may also
serve as the basis for multicenter collaborations that will eventually
provide a higher level of evidence.

ACKNOWLEDGMENTS

The authors would like to acknowledge the contribution of Dr. Michael
Rutter and Dr. Marlene Soma for their input in the development of the
original statements. We would also like to thank Drs. Frederic Gottrand,
Christophe Faure, Luigi dall' Oglio, and Usha Krishnan for their
critical review of the manuscript.

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LEGENDS - FIGURES

\textbf{Figure 1} . Schematic presentation of the methodology for the
development of the recommendations on the diagnosis \& management of the
respiratory complications of EA-TEF.

\textbf{Figure 2.} Schematic diagram of the pathophysiology of the
respiratory complications of TEF.

\textbf{Figure 3A.} MEFVCs in a child with EA-TEF and
tracheomalacia.\textbf{Red line (Baseline )} . The flow-volume curve is
concave consistent with significant lower airway obstruction. The
partial collapse of the trachea affects the initial portion of the MEFVC
causing greater decrease in the FEFmax and the FEF\textsubscript{25}
than on the FEV\textsubscript{1}. . The inspiratory flow-volume loop is
normal.\textbf{Green line (post-bronchodilator ):} There is more
extensive flattening of the MEFVC reflecting increased collapse of the
trachea and major bronchii due to overrelaxation of the airway smooth
muscle. The inspiratory flow-volume loop remains normal.

\textbf{3B.} Tidal flow-volume loop in an infant with significant
tracheomalacia. The flattening of the expiratory tidal loop is due to
the collapse of the trachea on expiration, while the inspiratory
flow-volume loop is normal. The ratio of the maximal expiratory to the
maximal inspiratory flow (ME/MI) that is normally approximately 1, is
only 0.3. The tidal inspiratory and expiratory volumes are not affected.

\textbf{LEGENTS - IMAGES}

\textbf{Image. Tracheoesophageal fistula \& Tracheobronchomalacia:
(A)}TEF post repair. Note the ridge on the posterior tracheal wall above
the carina as well a visible pouch (the pouch is often closed);
\textbf{(B)}At rest, the mid-trachea maintains its characteristic
``horseshoe'' shape; \textbf{(C):} Severe obstruction of the trachea
lumen and change in its shape due to the intrusion of the posterior
membranous wall into the lumen during cough; \textbf{(D):} Almost
complete occlusion of the Right Main Stem Bronchus during cough\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

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\includegraphics[width=0.70\columnwidth]{figures/Image-1A-1D/Image-1A-1D}

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