RESULTS
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. Tracheomalacia: Tracheomalacia in EA-TEF was identified as
the main pathology that causes or predisposes to almost all other
respiratory complications.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 in-utero compression from the
dilated proximal esophageal pouch14 and/or aberrant
myoelastic development of the posterior
membrane.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.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 collapse34,35. Complications attributed to TM are:
- 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”). 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 lumen37,38The desaturation is
more dramatic when there are anatomical communications (e.g. PDA, ASD,
VSD) causing right-to-left shunt.
- 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 age8,18,39. A chronic wet cough (often described as
“smoker’s cough”) may develop in early childhood and can remain across
the lifespan40,41.
- 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.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.40,43,47
- 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.11
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 site28,33,48. 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
bronchitis49–51.
3. 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 conditions52–56. 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 aspiration12,52,53. Direct aspiration can also result when one
or both vocal cords are paralyzed in abduction.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 esophagus58–61. 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 atopy62. 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 volume53,55,63,64.
3. Bronchiectasis: Bronchiectasis is one of the more serious
pulmonary complications in patients with
EA-TEF9,11,43,65–70. 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.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
appearance47,49,50 .
4. Gastroesophageal dysmotility: EA-TEF is characterized by
multiple functional and anatomical gastroesophageal abnormalities that
have been discussed in detail elsewhere.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.58–61 Gastroesophageal reflux
and/or esophageal regurgitation can cause chronic laryngeal irritation
that may manifest itself as recurrent stridor and/or chronic
hoarseness.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 repair57,72. 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.
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-systems3,73.
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 airways74–77 as
well as various cardiovascular anomalies78–84. All of
these conditions increase the morbidity and, in the case of congenital
heart disease, the mortality as well85.