Respiratory morbidity is still highly prevalent in EA and TEF survivors despite the improvement of perinatal and surgical care, the greater awareness and more aggressive therapeutic strategies concerning associated morbidity. We must consider that many factors contributing to the clinical complexity of patients play a pivotal role for the respiratory morbidity of EA and TEF patients.
Firstly, the associated congenital malformations frequently described in male patients [24]. Heart abnormalities and VACTERL association are equally distributed in our sample between male and female patients; they are mostly described in our study population if compared with data of the international literature, in which the rate of malformations and defects of VACTERL association is respectively about 31.6% and 9.6% and heart abnormalities interest about 29.4% of children [2]. Considered alone, isolated malformations, abnormalities related to VACTERL association and heart defects are not significantly related to respiratory complaints. This observation is consistent with that reported by Legrand and coworkers [25].
Secondly, airway anomalies such as tracheomalacia that is reported in more than half of our sample, tracheobronchial malformations and lung hypoplasia [6, 9] contribute to recurrent respiratory exacerbations through the impairment of the mucociliary transport.
In addition, esophageal dismotility due to esophageal stenosis and GER may cause and/or worsen respiratory function. Even if the relationship between gastrointestinal disturbances and respiratory symptoms is not always clear [25], in our patients the rate of esophageal strictures and GER is in line with that reported by Allin [26] and Acher [27].
Although several articles on the main long term respiratory complications in EA children have been published [1, 6, 8, 9, 12, 25, 28,29,30,31], a shared management design has never been developed. Only a recent paper has proposed a simplified management algorithm of pulmonary complications resulting from the review of 26 original articles that exclusively investigated respiratory disease in EA survivors [32].
In order to understand better the need of this group of children and improve their care, we have described a large case series that reinforces some of what other smaller studies have shown about respiratory symptoms and bronchoscopic findings [9].
We want to point out that the present study is a retrospective study carried out in a real life situation, so we decided the diagnostic approach in reason of clinical symptoms reported by patients and their parents. Consistent with the international literature [10], the EA with distal TEF (Gross type C) was the most detected in our sample.
Data about the rate of leak of anastomosis in EA patients are not available in scientific literature. In our sample this short term digestive complication is present in patients treated at our institution twice more than children initially treated in other hospitals. This observation is probably an overestimation due to the poor received information about the post-operative complications interesting the second group of children. Anyway, the described minor leak of anastomosis – that was always conservatively treated – appears not related to respiratory symptoms.
Limited to the long term digestive complications, the rate of esophageal stricture and GER is consistent with that reported by other studies describing these complications in 18% to 60% of patients with EA [25, 33–35].
Children with symptoms of nausea, vomiting, dysphagia or failure to thrive were examined in order to exclude GER that was detected with pH ± impedance in the major number of cases. According to recent ESPGHAN-NASPGHAN Guidelines for the Evaluation and Treatment of Gastrointestinal and Nutritional Complications in Children With Esophageal Atresia-Tracheoesophageal Fistula, all children (including asymptomatic patients) should undergo monitoring of GER through impedance/pH-metry and/or endoscopy at time of discontinuation of anti-acid treatment and during long-term follow-up [36]. Even if esophagogastroduodenoscopy with biopsy remains the primary surveillance tool of GER disease, less-invasive modalities can also be evaluated. In particular, the multichannel intraluminal impedance and pH monitoring appear to correlate strongly with esophageal histology and may provide sufficient information to guide treatment in patients with GER [37]. In our sample, the rate of Nissen fundoplication treatment is greater in children initially surgically treated at other hospitals. This observation is probably influenced by the selection bias represented by the complexity of this group of children that was referred at our institution just because of the greater clinical complexity developed in the postoperative period.
About the rate of atopy, it is lower in our paper than usually reported in scientific literature [38] and, as expected, it seems to be independently associated with higher risk of lower respiratory disturbances as also previously found by Sistonen et al. [38].
Even if symptoms occur in the first 3 years of life, their onset is precocious in children with heart disease. It is likely that cardiac disease [39, 40] and atopy [41] promote the onset of symptoms through the reduction of the threshold of the bronchial reactivity that is intrinsically linked to the congenital malformative picture, thus contributing to the respiratory morbidity.
Except for cases with aspiration pneumonia in the immediately post-operative period, the most frequent respiratory symptoms occurring in the first 3 years of life are recurrent pneumonia and wheezing, the rate of which is in line with that reported by other authors [9].
In our study, the delay in referral of children with respiratory symptoms to pneumologist is particularly interesting.
The delay is probably due to the attribution of respiratory complaints to gastroesophageal reflux for which some patients performed medical and then surgical therapy. Only after the verification of failure of the above therapeutic options, children were sent to a pediatric respiratory specialist.
The described tracheomalacia, residual tracheal diverticulum and recurrent TEF have surely contributed to the lower respiratory exacerbations as reported by other studies [42–44].
The rate of detected tracheomalacia is in line with that described in scientific literature [9, 16]. Because of only few case series describe the presence of residual tracheal diverticulum in children underwent to correction of EA and TEF [42, 43], it’s not possible to estimate the real frequency of this complication. Only the frequency of recurrent TEF in our study population is higher than previously described [44] and also this finding is greater in children surgically corrected at other centers: this observation is probably influenced by the same selection bias previously discussed for children undergoing Nissen fundoplicatio.
In our study population, chest CT scan with contrast enhancement is useful in the search of vascular anomalies, tracheal compression or esophageal diverticulum not otherwise detectable with flexible bronchoscopy. Furthermore, it is able to show atelectasis that we interpreted as the effect of disventilation due to mucus plugging and the pulmonary damage due to recurrent respiratory exacerbations. In the latter case, the greater frequency of bronchiectasis is most likely influenced by the higher mean age of the enrolled patients that could justify the establishment of lung damage. Abnormal pulmonary function is well described in patients with EA and TEF and the restrictive ventilatory impairment prevails over the obstructive and the mixed ones [30]. Also in our sample we observed a higher frequency of restrictive defects (58%) with obstructive, mixed and normal ventilatory pattern respectively in 8%, 4% and 31% of patients. Restriction may result from surgical trauma, repeated aspiration, or recurrent chest infections, as well as from associated thoracic musculoskeletal defects such as postoperative rib fusions, scoliosis or other chest deformities.
In interpreting the provided data, the limitations of retrospective analysis must be considered.
The limitations include primarily patients selection bias: examined patients were surgically treated not only at our institution and children coming from other centers often showed a greater clinical complexity due to postoperative complications.
Moreover, because not all participants had bronchoscopy, thorax CT, impedance testing and spirometry we cannot be certain that those not tested had normal findings, so our estimated prevalence of abnormality is likely underestimated.
Nevertheless, even though we are aware of the difficult to generalize the proposed data because describing the experience of a single center, our study confirms that respiratory symptoms are frequent in a large group of pediatric patients with EA and TEF and mostly develop in the first 3 years of life and that residual anatomical and dysfunctional airway anomalies contribute to their presentation. As showed by Fig. 2 describing the rate of medical evaluation in the study period, the respiratory burden among children with EA and TEF is high, so the need of strict respiratory assessment in symptomatic children becomes imperative.
In our opinion, our findings add weight to the need of routine surveillance protocols and close monitoring of these patients from the neonatal period onwards.
To date, although the need for careful multidisciplinary follow-up is highlighted, no recommendations on the respiratory management of infants and children with EA and TEF are available. The only available algorithm [32] suggests the stratification of disease severity on the basis of recurrence of respiratory symptoms and functional and instrumental abnormalities, providing a regular tertiary care follow up only for patients having moderate to severe airway disease.
Conversely, on the basis of our direct experience and the results provided by our study, we believe that all children, after the first 12 months of life, should be monitored at least every 6 months up to 36 months in a multidisciplinary pediatric setting for the evaluation of clinical history, growth and relevant symptoms.
Other professional figures, such as gastroenterologist, dietitian, cardiologist, otorhinolaryngologist, neuropsychiatrist, orthopedist and physioterapist could be variously involved in relation to the presence of gastrointestinal symptoms, poor growth, heart or airway abnormalities, neuromotor delay, congenital or acquired skeletal malformations. Respiratory evaluation should be performed when recurrent pneumonia (>2 episode/years), recurrent bronchitis or unexplained wheezing, persistent wet cough, nocturnal apnea and exercise intolerance occur. Also children with abnormalities on thorax X-ray, moderate to severe tracheomalacia and tracheostomy should be evaluated by a pulmonologist. The respiratory assessment should provide for chest X-ray at the first visit in order to define the lung baseline condition and whenever there is a suspicion of pneumonia. Nocturnal pulse oximetry and forced oscillation technique (FOT) could be performed once a year. The first one would detect desaturations deserving of other insights to exclude heart problems, central or obstructive respiratory events. Because it is provided that FOT yields concordant information of lung function with other conventional methods [45], this technique could be used for monitoring pulmonary function in the pre-school children.The purpose of the above suggested clinical assessment is to manage respiratory symptoms through medical treatment and chest physiotherapy, prevent lower respiratory exacerbation with precocious antibiotic therapy and gather information enabling the clinician to suspect an underlyng condition responsible of persistence of symptoms and requiring additional investigations such us bronchoscopy and CT scan. Because of the detection of associated vascular abnormalities determining airway compression in 21% of patients, we believe that thorax CT scan study should be completed with angiography.
Children with more than one radiographically confirmed episode of lobar pneumonia, chronic wet cough and suspected bronchiectasis must also be evaluated for aspiration with assessment for lipid laden macrophages on bronchoalveolar lavage (BAL). The last one should also be useful to rule out colonization of the airway by bacterial and other respiratory pathogens. The suggested follow-up program could avoid the underestimation of respiratory morbidity in this group of patients allowing the precocious and better management of the respiratory long term complications.