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.