Our series of 36 cases of TO is one of the largest reported series [1, 4,5,6, 11]. Our results identified a typical clinical and bronchoscopic presentation of TO and suggested that no treatment might be required in most cases.
The causes of TO are largely unknown. The diagnosis is usually made during the 5th or 6th decade [1, 4, 11,12,13], 65 years in our study. TO has been described in children [14, 15], suggesting that TO might occur early in life with a very slow and silent evolution. In our study and others [1, 4, 11], TO occurred in men and women in the same proportion. Compared to other series [1, 4,5,6, 11], our patients were more frequently smokers (56% vs 18–42%). Occupational exposure to inhaled irritants or pollutants was described in 60% of the cases. Previous studies suggested the role of long-term occupational exposure to dust or irritant gases [1]. The potential link between TO and environmental exposure remains to be elucidated.
In our study, 3 cases were associated with symptomatic GERD, corresponding to the prevalence of GERD in the general population [16]. One patient suffered from atrophic rhinitis, also known as ozena. Atrophic rhinitis is a chronic nasal disease that was suspected to be associated with TO in previous studies [11]. This association has been questioned in more recent studies [4], suggesting a recruitment bias. We did not find any clear link between TO and other respiratory inflammatory diseases (COPD, asthma, chronic rhinitis) or tuberculosis. One case of family history of TO has been previously described [17]. We did not find any familial history of TO in our study.
In our series, a mild to severe airflow obstruction was described in 55% of the cases. The evolution of airflow obstruction is not determined [4, 18]. Long-term follow-up PFT results were not available in our study.
We showed that radiological abnormalities are present in 97% of the cases (82–87% in previous studies [1, 5]) and typically included tracheal and/or bronchial calcifications in chest X-ray and CT-scan submucosal nodules with or without calcifications located in the tracheal and proximal bronchi. CT scan is currently considered the most reliable imaging exam to screen TO [1, 4, 19].
The diagnosis of TO relies on bronchoscopy, which is frequently performed for another medical indication or non-specific symptoms. In our study, 19% of the subjects did not describe any respiratory symptom (5–52% in other series [1, 4, 6],). Our results and others [20,21,22,23] identified TO-related symptoms like chronic cough, dyspnea on exertion, hemoptysis, and dysphonia. One patient in our study underwent bronchoscopy to explore difficult intubation occurring during abdominal surgery. Similar cases have been previously published [24,25,26]. TO should be considered in case of difficult intubation and attention should be paid to the CT scan regarding tracheal abnormalities.
The bronchoscopic aspect of TO is characterized by the presence of numerous cartilaginous and/or bony nodules on the submucosa of the tracheobronchial tree, protruding in the lumen and typically sparing the posterior membranous wall [5]. Several descriptions have been made regarding the typical aspect of TO on bronchoscopy, depending on the severity of obstruction: cobblestone, stalactitic cave, mountainscape, or rock garden [5]. Biopsies of these lesions can be difficult, mainly because of the hard consistency of nodules, and usually do not induce important bleeding [27]. Another characteristic is the grinding of the bronchoscope under the lesions [28]. In our study, lesions were predominantly scattered, involving the trachea and proximal bronchi in most of the cases, and spared the posterior wall in all cases.
TO can induce tracheal stenosis (10–27% [1, 4, 5, 11], 17% in our study), sometimes important [29, 30], and then require specific endoscopic management (4–5% in the previous series, 8% in our study). Another complication of TO is bronchopulmonary infections [31], probably linked to mucociliary system failure. Klebsiella ozaenae is a Gram-negative organism colonizing the oral and nasopharyngeal mucosa. K. ozaenea has been thought to be involved in TO physiopathology through the alteration of the mucociliary system and induction of squamous metaplasia [32]. We did not identify any K. ozaenae in bronchial aspiration samples in our study.
The need for histopathologic proof of TO is controversial; some authors consider that typical findings on bronchoscopy are sufficient to diagnose TO [33]; others consider it necessary to exclude differential diagnoses such as tracheal amyloidosis, polychondritis, or papillomatosis [1, 34]. In our study, biopsies were performed in 42% of the patients, less than 64–70% described in other series. Typical histologic findings of TO, i.e. cartilaginous or bone formations in tracheal/bronchial submucosa can be frequently observed (63% in our study).
There are currently no guidelines for the management of TO. It usually depends on the severity of proximal airway obstruction. In our retrospective case series, TO therapeutic management was based on the physician’s experience and bronchoscopy habits. Different treatments have been described, including inhaled corticosteroids [3], bronchoscopic management or surgery [35] for the most severe cases with tracheal stenosis. In our study, bronchoscopic management was performed in 3 cases with tracheal stenosis. One subject has been treated with corticosteroids that have been described as improving symptoms, radiologic and bronchoscopic findings in some cases [1]. Two patients received bronchodilator treatment for either asthma, in combination with inhaled corticosteroids, or COPD with no purpose of any impact of bronchodilator treatment on TO. Further studies should analyze the interest of such long-term inhaled treatment in the evolution of TO.
TO usually has a benign course [36] but can sometimes be evolutive and life-threatening [37, 38]. In our study, 7 patients underwent a bronchoscopic reevaluation, that identified stability of TO in all cases.
The pathophysiology of TO remains unclear. Several assumptions have been made: one hypothesis suggested the role of ecchondrosis and exostosis from the lateral tracheal rings [39, 40]. Another hypothesis suggested metaplasia followed by ossification of the connective tissues [4]. The role of Bone Morphogenic Protein 2 (BMP-2) and Transforming Growth Factor beta-1 (TGF beta-1) in nodular formations has been suggested [41]. As described in other studies [1], a potential tracheal and bronchial chronic inflammation, associated with COPD, smoking, bronchopulmonary infections, or occupational exposure was described in most of our cases. Based on these elements, chronic inflammation could play a role in the development of TO. A very recent genome-wide study analyzing the whole genome expression and epigenetics of tracheal-bronchial basal cells obtained from TO and non-TO subjects identified a role of these cells in epithelial metaplasia and mesenchymal osteo-chondrogenesis, highlighting a malfunction of airway stem cells inducing neo-osteogenesis in TO [42].
Our study has some limitations, including its retrospective design, and the limited number of cases, although it is one of the largest reported to date. Given the lack of guidelines currently available for the diagnosis and therapeutic management of TO, we report here individual management based on the physician’s experience and bronchoscopy habits, especially regarding the indication for biopsies or bronchoscopic management. Despite those limitations, our study provides a clear picture of the clinical and bronchoscopic presentation of TO and reports the experience of TO management by bronchoscopy experts, which could be useful to less experimented physicians in such a rare condition.
