Objectives

1. Identify various disorders that primarily affect the airway cartilages.
2. Describe tracheobronchopathia osteochondroplastica.
3. Discuss relapsing polychondritis.
4. Define clinical aspects of tracheobronchomegaly.
5. Describe tracheomalacia and other disorders of airway cartilages.

Key words

airway cartilage; calcification; ossification; polychondritis; saber-sheath; tracheobronchomegaly; tracheobronchopathia

Abbreviations

RP = relapsing polychondritis; TGF = transforming growth factor; TO = tracheobronchopathia osteochondroplastica

Cartilage can be observed within the trachea as early as 7 weeks’ gestation, and further development continues into neonatal life. The simplified structural concept of the airway cartilage is that it provides skeletal support to the airways, thereby maintaining optimal luminal diameter to permit normal physiologic functions of the respiratory system. This is an important role for the cartilage because without it, the walls of the trachea and bronchi would collapse and limit airflow. Airway cartilages also have more complex role. An experimental study has shown that the tracheal cartilage modulates transforming growth factor-a (TGF-a) and TGF-b expression in respiratory epithelial cells, and may thus contribute to regulation of respiratory epithelial cell proliferation and differentiation.¹ The surfaces of tracheal cartilage matrix are collagen-rich and surround a proteoglycan-rich core. These hydrated proteoglycans in the central zone of the cartilage resist compression forces as the cartilage crescent bends.² The outermost layer of tracheal cartilage is the most stiff in all individuals, and the deeper layers are progressively less stiff. Water content and hydroxyproline and proteoglycan content decrease with increasing age.³ Average tensile modulus increases with age in human tracheal cartilage.⁴ These changes may be responsible for the changes observed in the airways of older persons.

Airway cartilages include those located in the nasal passages, laryngeal region, trachea, and bronchial tree. The tracheal cartilage plates consist of a series of 16 to 20 individual cartilages. The normal shape of cartilages in major airways resembles the letter C or U, with the open part of the shape representing the posterior membranous portion of the airway that is devoid of cartilage. The normal (C or U) shape of the cartilage is maintained in the trachea, main bronchi, and extrapulmonary bronchi, but the cartilaginous plates become irregular in shape in lobar and segmental bronchi. The bronchi and bronchioles with diameters <2.0 to 3.0 mm are devoid of cartilage. The shape of the cartilage determines the cross-sectional shape of the trachea. The most common tracheal shape is round or oval; other shapes include horseshoe with a flat posterior membrane, inverted pear shape, and square.⁵ In the normal trachea, the upper limits of the transverse and anteroposterior diameters in men aged 20 to 79 years are 25 mm and 27 mm, respectively (the average male tracheal diameter is 20 mm, with a cross-sectional area of 314 mm²).^6,7 These shapes and dimensions change with disease processes that primarily affect the tracheal cartilage, disorders that produce extrinsic compression of airways, and significant variations in the intrathoracic pressure. The following sections describe clinical entities that are caused by or associated with the disorders of airway cartilage.

Congenital Anomalies

The congenital tracheal cartilaginous sleeve is the result of vertical fusion of the tracheal cartilages. This uncommon malformation is usually associated with one of the craniosynostosis syndromes, such as Crouzon’s disease, Pfeiffer’s syndrome, or Goldenhar’s syndrome. A smooth trachea lacking the normal ridges of tracheal arches suggests the diagnosis of tracheal cartilaginous sleeve. This tracheal malformation is not incompatible with life.^8-10 In one report, 23 infants and children had severe tracheal stenosis due to congenital complete tracheal rings that produced a long-segment stenosis of the trachea. Nineteen patients (83%) survived this life-threatening airway obstruction after therapy consisting of pericardial patch tracheoplasty under cardiopulmonary bypass.¹¹

An “hourglass trachea” denotes a stenotic segment of the trachea. Congenital absence of the midtracheal pars membranacea is one of the mechanisms in the causation of such stenosis. Approximately a dozen cases of midtracheal stenosis, some with proven absence of the midtracheal pars membranacea, have been reported in children with Down’s syndrome. Respiratory difficulty and stridor were the reported clinical features in all but one of the patients.¹²

Short trachea, with a reduced number of cartilage rings, has been described in patients with DiGeorge syndrome. In a study of six patients with DiGeorge syndrome, the number of tracheal rings was significantly low (14.7±1.4). The authors of this study postulate that this finding is consistent with an effect of deficient blood supply to the fetal cervical region, a mechanism that also has been proposed to explain the defective development of thymus and parathyroid glands in DiGeorge syndrome.¹³

Williams-Campbell syndrome refers to severe deficiency of airway cartilages, particularly in the segmental and distal bronchi. Absence of cartilage can also occur. Larger airways are less commonly involved. Familial clustering and associated congenital anomalies have been observed. Children with this disorder develop severe tracheobronchomalacia and bronchiectasis. CT scans show cystic bronchiectasis limited to fourth- to sixth-generation bronchi and expiratory collapse of the bronchi and distal air trapping.

Cartilaginous Calcification and Ossification

Calcification of airway cartilage is common in subjects older than 65 years and should be considered part of the aging process. The calcification is more likely to affect the cartilage of the larger airways such as the trachea and mainstem bronchi. Cartilaginous calcification is best demonstrated by CT scan. The calcification is not uniform and tends to be patchy. Significant calcification produces varying degrees of stiffness of the airways. The latter is best seen during bronchoscopy: the normal inspiratory and expiratory variations are decreased and the airways appear larger than in younger patients. The calcified cartilage may appear whiter than normal cartilage and may bulge into the airway lumen. However, patients who have airway calcification associated with aging are usually asymptomatic. Calcification of airway cartilages can be seen in tracheopathia osteoplastica, hypercalcemia, “saber-sheath” trachea, and rarely in tracheobronchial amyloidosis.

Ossification of the airways is also normal in some individuals. One study examined the ossification process of the tracheal cartilage in 25 adults (mean age, 68 years) and discovered that 13 patients (52%) had ossification of the tracheal cartilage. The ossification was accompanied by the formation of lamellar bones with fatty bone marrow. Ossification was more pronounced at the lateral and peripheral aspects of the tracheal cartilages. Based on the immunolocalization study of different types of collagen, the study concluded that ossification of tracheal cartilage in older humans is a physiologic process promoted by aging itself.¹⁴

In contrast to normal calcification and ossification associated with aging, excessive calcification and ossification leading to nodular excrescences projecting into the airway lumen is considered abnormal. This process is termed tracheopathia osteoplastica (see below).

Saber-Sheath Trachea

“Saber-sheath” or “scabbard” trachea refers to a trachea that has a saber-sheath appearance. This appearance is caused by a markedly reduced coronal (lateral or transverse) diameter and either a normal or an increased sagittal (anteroposterior) diameter. One criterion used to define this disorder is to establish that the tracheal index (the ratio of coronal to sagittal diameter) is <0.5.⁶ Generally, this shape is present throughout the trachea, beginning just below the take-off of the intrathoracic trachea and extending to just above the main carina. In one small series of 13 patients with this disorder, all patients were men (age range, 52 to 75 years); the coronal diameter ranged from 7 to 13 mm (mean, 10.5 mm) and the tracheal index was 0.5 to 0.25 (mean, 0.4). Calcification of tracheal cartilages was present in 10 of these 13 patients and the tracheal walls were thickened.⁶ In another report on 60 men (age >50 years) with this disorder, 57 (90%) had COPD.¹⁵ It is unclear if the disorder is the cause or effect of COPD.¹⁶ The cause of saber-sheath trachea is unknown, but because it is seldom encountered in children, the abnormality is most likely acquired. It is thought to be caused by calcification, stiffening, and subsequent microfracture and destruction of the normally elastic tracheal rings.¹⁷ Many of the cases are incidentally diagnosed during bronchoscopy. Most patients with this disorder are asymptomatic. Saber-sheath trachea has caused unexpected difficulty and negative-pressure pulmonary edema during endotracheal intubation for anesthesia and ventilation.^17,18

Tracheomalacia and Bronchomalacia

Tracheomalacia, bronchomalacia, and tracheobronchomalacia are descriptive terms that refer to flaccidity of the airways caused by structural weakness of the airway walls. This causes significant narrowing of coronal diameter during forced expiration or cough. Circumferential collapse is less common. The primary process that is responsible for the easy collapsibility of the airways is the loss of cartilaginous integrity from various etiologies. The terms, namely tracheomalacia and bronchomalacia, are used loosely by some to describe excessive intraluminal bulging of posterior walls of airways in patients with COPD, airway stenoses, or strictures. It is better to limit these terms to describe airways that demonstrate easy and excessive collapsibility in any phase of breathing. Airway collapse seen in COPD does not represent true tracheobronchomalacia.

Tracheomalacia occurs as a primary condition to some degree in all infants and children with esophageal atresia. Anomalous great vessels may exacerbate the severity of tracheomalacia.2 Congenital or neonatal tracheobronchomalacia is associated with many structural congenital abnormalities. Among 115 laryngotracheal specimens collected during a 17-year period at a major medical center, 22 were found to have congenital tracheal anomalies. Six specimens were determined to have tracheomalacia, including one with primary tracheomalacia and five with secondary tracheomalacia: three were associated with tracheoesophageal fistula and two with aberrant innominate artery.¹⁹

In adults, tracheobronchomalacia can be caused by or associated with pressure necrosis of cartilage due to endotracheal intubation, thyroid lesions, vascular anomalies, trauma, chronic or recurrent infection of major airways (bronchiectasis), radiation therapy, relapsing polychondritis, tracheobronchomegaly, and collagen disorders including Ehlers- Danlos syndrome, cutis laxa, and Marfan’s syndrome.

Imaging procedures and pulmonary function tests may provide clues to the presence of excessive airway collapse. During bronchoscopy in conscious patients with tracheobronchomalacia, the coronal narrowing with coughing is >50%, vs <40% coronal narrowing in normal individuals.

Tracheobronchopathia Osteochondroplastica

Tracheobronchopathia osteochondroplastica (TO), also known as tracheopathia osteoplastica, is an uncommon benign disease of unknown etiology. TO is characterized by multiple cartilaginous or bony submucosal nodules that project into the tracheobronchial lumen and cause various respiratory symptoms.^20-22 The nodules almost always originate in airway cartilage and thus characteristically spare the posterior membranous wall. No other airway disorder demonstrates this characteristic feature. The bronchoscopic appearance alone is diagnostic of the disease and biopsy of the airway lesions is seldom, if ever, required.

Even though the disorder was observed in the necropsy specimens in the mid-1800s, only 245 cases of TO had been reported by 1974.²³ The incidence of TO has ranged from 1:400 to 3:1,000 in autopsies, and 1:125 to 1:6,000 by in vivo bronchoscopies. At the Mayo Clinic, the incidence of TO in patients undergoing bronchoscopy has been 1:772. An incidence of 15 cases of TO among 1,935 bronchoscopies over a 2-year period was been reported from Finland. In contrast, a relatively low incidence of TO (no instance of TO among approximately 25,000 bronchoscopies) was noted in Norway. One report from Spain observed TO in 9 of 7,584 patients who underwent bronchoscopy over a 9-year period, the overall prevalence being 0.12%.

The etiology of TO remains unknown. Only one reported instance of familial occurrence of TO has been reported.²⁴ The earlier literature described TO in association with various disorders such as chronic inflammation and infection, atrophic rhinitis, silicosis, amyloidosis, tracheal botryomycosis, and mycobacterioses. The more recent publications, however, have not observed these associations.²⁰ Association of TO with ozena, defined as an atrophic rhinitis marked by a thick mucopurulent discharge and mucosal crusting and fetor, has been described. There is no evidence of a relationship between TO and malignancy. Amyloidosis is another disorder that has been frequently described in association with TO. Many publications indicate that TO is the end result of amyloidosis. However, in a 1974 review of 245 cases of TO, there was not a single case of amyloidosis, and among the 30 cases of all other forms of amyloidosis involving the respiratory tract, there was no case of TO.²³ Most recent publications on TO have not reported an association between amyloidosis and TO.^20,21 There is no relationship to smoking or collagen-vascular disorders.

The pathogenesis of TO is not well defined. Theories of causation include formation of ecchondromas, which subsequently undergo calcification and ossification, metaplastic conversion of the elastic connective tissue to elastic cartilage, and the synergistic action of bone morphogenetic protein-2 and TGF-b1. Both bone morphogenetic protein-2 and TGF-b1 are potent inducers of new bone formation. The multiple benign cartilaginous or bony submucosal nodules on the tracheobronchial cartilages gradually increase in size and project into the airway lumen. This process usually takes several decades. As TO is a disorder of the cartilage, the nodules are located along the airway cartilages and thus characteristically spare the posterior membranous wall. The mucosa overlying the cartilaginous nodule may be thinned. Biopsy of the airway nodules has documented histologic confirmation of heterotopic bone formation in 60% of the patients.¹⁴

TO occurs more commonly than reported. It remains unrecognized because the disorder is frequently diagnosed as asthma, owing to the chronic cough and wheezing that are present. TO is more common in men and is usually diagnosed in adults in their sixth or seventh decades of life. Some studies have observed female predominance,²³ but other studies report no sex difference.^20,22 The clinical features at presentation in 41 patients with TO are shown in Table 1.²¹

There are no characteristic symptoms or signs to indicate the diagnosis of TO. Indeed, most patients with a mild degree of TO are asymptomatic. The severity of symptoms will depend on the size and number of intraluminal nodules that compromise the airway. Besides cough and wheezing, other symptoms include hoarseness, dyspnea, hemoptysis, and recurrent respiratory infections. In one series of 15 patients with TO, recurrent pulmonary infections were observed in 20%.²² Stridor and severe cases of TO are uncommon.

Results of routine blood tests are usually normal. Because there is no relationship between TO and calcium metabolism, metabolic tests to identify abnormal calcium metabolism are not indicated. Pulmonary function test findings depend on the location of the lesions and the degree of involvement. Symptomatic patients may exhibit an obstructive pattern. Flow-volume loops may demonstrate tracheal involvement. The chest radiograph findings are usually normal in TO. CT of the trachea and the main bronchi may reveal prominent cartilaginous nodules protruding into the airway lumen, particularly if they are calcified. The CT appearance of TO is that of multiple sessile submucosal nodules with or without calcification along the cartilaginous portion of the trachea. CT findings in 31 patients with TO are shown in Table 2.

Bronchoscopy is the most definitive technique to establish the diagnosis of TO. When the larynx and upper airway are affected, laryngoscopy may suffice to document the diagnosis. Bronchoscopy demonstrates characteristic multiple isolated or confluentappearing submucosal bony and cartilaginous nodules; the nodules measure 1 to 6 mm in diameter and project into the airway lumen at variable depths, leading to airway obstruction. The single most important bronchoscopic feature of TO is the noninvolvement of the membranous portion of the airways, where there is no cartilaginous tissue. The TO lesions occur more profusely in the distal two thirds of the trachea. The characteristic appearance has been compared to stalactite cave, a rock garden, and a cobblestone appearance. Involvement of the lobar and more peripheral bronchial tree is rare. When the luminal projection of cartilaginous nodules is significant, it can be difficult to advance the flexible bronchoscope into distal bronchial tree. Even rigid bronchoscopy can be difficult if the airway lumen is significantly narrowed. A pediatric flexible bronchoscope or an ultrathin flexible bronchoscope may be necessary to negotiate the distal passages.

Biopsy of the airway luminal nodules is not necessary to diagnose TO because the characteristic gross appearance itself is diagnostic. Occasionally, however, tracheobronchial amyloidosis, tracheal papillomata, or diffuse primary or metastatic malignancy can mimic TO. It is usually difficult or impossible to obtain biopsy specimens because of the hardness of the lesions.

There is no definitive therapy for TO and treatment is palliative. Bronchoscopic therapies attempted have included forceps removal of nodules, laser ablation, cryotherapy, external beam radiation, and tracheal or laryngeal resection. External beam radiation therapy has been reported to produce some temporary relief.

In summary, TO is an uncommon benign disease of unknown etiology, characterized by multiple cartilaginous or bony submucosal nodules that project into the tracheobronchial lumen. TO is not related to tracheobronchial amyloidosis, cancer, or smoking. Its etiology is unknown. It affects only the cartilaginous airways because it is fundamentally a disorder of the cartilages. TO can remain asymptomatic or cause nonspecific respiratory symptoms. Bronchoscopic appearance alone is sufficient to establish the diagnosis; imaging and biopsies are unnecessary. There is no specific therapy for TO.

Relapsing Polychondritis

Relapsing polychondritis (RP) is an uncommon disorder caused by recurrent inflammation and widespread destruction of cartilage and other connective tissues. RP is may have an immunologic basis because up to 25% of patients with RP have an associated autoimmune disorder or vasculitis.^25-27 The human leukocyte antigen DR4 allele has been identified in 56% of patients with RP, compared with 25% in control individuals.²⁸ Pathologic findings in RP include fragmentation of cartilage, loss of normal basophilic staining of the cartilage, perichondral inflammation, and eventual cartilage destruction with replacement by fibrosis. More than 600 cases have been reported in the literature.²⁹ In a series of 23 patients with RP, swelling and erythema of the ears and arthralgias were the most common features, observed in 88% and 81% of patients, respectively.²⁵ The common clinical features of RP are shown in Table 3. Among the 112 cases of RP seen at the Mayo Clinic, between 1.5 and 5 of the features noted in Table 3 were observed.³⁰ A relapsing course was seen in 86% of patients and continuous symptoms in 14%. In the Mayo series of 112 cases, the male-to-female ratio was equal and the age at diagnosis ranged from 13 to 84 years, with a mean of 51 years. Based on experience with 26 cases, one group of authors has described six criteria: (1) auricular chondritis, (2) polyarthritis, (3) nasal chondritis, (4) ocular inflammation, (5) audiovestibular damage, and (6) chondritis of the respiratory tract.²⁵ The diagnosis is established on the basis of recurrent inflammation of two or more cartilages, usually the cartilages of the nose or ears. Biopsy of cartilage is not necessary because no specific diagnostic features are present.

The respiratory system is affected in >50% of patients with RP, and pulmonary symptoms are the presenting features in up to 25%.^25,29 All sites of respiratory tract cartilage can be involved in the disease process, including those located in the external nares, nasal septal turbinates, eustachian tubes, epiglottis, larynx, thyroid, cricoid, arytenoid, the trachea, and bronchi. Laryngeal and tracheobronchial disease usually presents with a history of wheezing, stridor, dyspnea, cough, hoarseness or aphonia, and tenderness over the laryngotracheal cartilage. Obstructive symptoms are caused by airway narrowing from inflammation and strictures. In some patients, dynamic airway collapse occurs late and is caused by flaccidity of airways resulting from cartilaginous destruction. An association between RP and acute glomerulonephritis and alveolar hemorrhage has been reported.³¹

Chest radiograph findings may suggest tracheal stenosis. Short stenotic segments are more likely to occur than lengthy diffuse stenosis. The major bronchi are less commonly involved. CT may reveal thickening of the tracheobronchial wall. CT may also show collapse and calcification of the cartilages. Virtual images may provide better information than static CT images. The pulmonary parenchyma is uninvolved in RP. In late stages of the disease, bronchiectasis can be seen.

Pulmonary function tests can show flow limitation. Reductions in maximal voluntary ventilation can occur as a result of reductions in maximal expiratory flow. Diffusion and gas exchange properties are usually normal. Both fixed and variable extrathoracic or variable intrathoracic abnormalities can be seen when flow-volume loops are obtained.^29,32

Bronchoscopy is not always required in patients with RP. The bronchoscopic findings may include inflammation, collapse and stenosis of the larynx, trachea, and/or bronchi. Involvement of the airway can be localized, but is often more generalized. Obtaining biopsy of airway cartilages via bronchoscopic methods is difficult and the biopsy findings are usually nonspecific.

Therapy of RP has consisted of salicylates, nonsteroidal anti-inflammatory drugs, corticosteroids, and cytotoxic agents. Airway involvement is among the most serious manifestations of RP. Therapy should be individualized because patients present with varying types of respiratory problems. Respiratory involvement usually requires longterm use of systemic corticosteroids and other immunosuppressants. Other treatments of airway problems have included surgery, bronchoscopic intervention (for example, dilatation or stent), and continuous positive airway pressure. Tracheostomy is required in some patients when other forms of treatment fail.

Death attributable to laryngotracheobronchial disease occurred in 10% of patients in the Mayo Clinic series.³⁰ The most frequent causes of death were infection, systemic vasculitis, and malignancy; only 2 of the 41 deaths in the Mayo series were directly attributed to respiratory failure. In another series of 62 patients, 13 died of airway complications despite therapy.³³ Because of the rare occurrence of RP, estimates such as these are always influenced by referral and specialty bias of the reporting institution.

In summary, RP is an uncommon disorder. The airway is involved in about 50% of patients. The degree and severity of respiratory involvement varies from patient to patient. Treatment of airway disease includes corticosteroids and other anti-inflammatory or immunosuppresive agents. Airway stents may be required in selected patients and nasal continuous positive airway pressure may be utilized in some patients particularly, those with supine dyspnea.

Tracheobronchomegaly (Mounier-Kuhn Syndrome)

Tracheobronchomegaly is a rare condition characterized by dilatation of the tracheobronchial tree and recurrent bouts of bronchitis and lung infections. The etiology is unknown, although tracheobronchomegaly has been observed in patients who have Ehlers-Danlos syndrome, generalized elastolysis, marfanoid condition, or ankylosing spondylitis; as a complication of severe pulmonary fibrosis; and in many congenital syndromes involving multiple skeletal abnormalities.

The etiology is unknown, but theories include deficiency of segmental myenteric plexus, genetic predisposition, or congenital spasticity of elastic and muscular elements within the walls of tracheobronchial tree. Approximately 1% of all bronchograms have demonstrated the condition. Both the airway cartilages and membranous portions of the major airways are affected. A decrease in airway smooth muscle and elastic tissue has been observed.

Many patients, particularly men in their third and fourth decades of life, present with symptoms of obstructive airway disease. End-stage bronchiectasis is the result in those with recurrent infections.

Chest radiographs may reveal the diagnosis by demonstrating significantly widened tracheal air bronchograms. The lateral view is more helpful than the posteroanterior view. With compatible clinical features, the diagnosis can be made when the following features are seen on the plain chest radiograph: the anteroposterior and transverse diameters of the trachea exceed 25 and 27 mm, respectively, in men, and 21 and 23 mm, respectively, in women; and the transverse diameters of the right and left mainstem bronchi exceed 21.1 and 18 mm, respectively, in men, and 19.8 and 17.4 mm, respectively, in women.³⁴ Tracheobronchial diverticula occur in some patients and can be demonstrated by CT or MR imaging. Bronchoscopy can reveal the easy collapsibility, large airways, and diverticula.

Infections

Primary infection of the airway cartilages is very rare. However, these structures can be affected by complications of a pulmonary infection. Tracheobronchial involvement by tuberculosis is good example of such a complication. In a case report,³⁵ bronchoscopy revealed caseous matter and loosening of the tracheal cartilages. The patient expectorated the lateral one third of multiple tracheal cartilages several times before and after bronchoscopy. The remaining two thirds of the tracheal cartilage rings seemed to be strong enough to support the tracheal lumen.³⁵

Miscellaneous Disorders

COPD is associated with alterations in biomechanical properties and composition of airway cartilage.³⁶ For instance, maximal expiratory flow is influenced by airway wall stiffness.³⁷ However, in obstructive lung disease, the airway wall is flaccid because of the excessive collapsibility of the posterior membranous trachea and bronchi. Another potential reason for the excessive collapsibility of smaller airways is the loss of cartilaginous tissue secondary to COPD. The quantity of bronchial cartilage has been found to be decreased in some patients with COPD. The most pronounced deficiency has been observed in the segmental and subsegmental airways; these changes seem to be more apparent in the lower lobes than the upper lobes.^38,39

In patients with alkaptonuria (ochronosis), abnormal pigmentation of the tracheobronchial cartilaginous rings has been described. A characteristic slate-gray or coal-black discoloration has been observed at bronchoscopy and autopsy.⁴⁰

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