Physical Examination, Complementary Tests, and Functional Status Assessment

This patient had bronchoscopic evidence of diffuse collapse of the cartilaginous wall of the trachea and mainstem bronchi with sparing of the posterior membrane—findings consistent with a diagnosis of circumferential tracheobronchomalacia (TBM), and classic for relapsing polychondritis (RP). RP is a multisystem disease,* and it is incapacitating and life threatening because of its airway involvement.¹ Auricular chondritis, the most common initial presentation, is seen in 85% to 95% of patients with RP. This patient, however, had no evidence of RP in the eyes, nose, or external ears. Isolated pulmonary presentation, as seen in this case, is not that unusual, and because of its often episodic nature, may result in a significant delay in diagnosis. In a review of 66 patients, the elapsed time from patient presentation for medical care for RP-related symptoms^† to diagnosis was reportedly 2.9 years.¹ In a small case series of five patients with RP and severe airway involvement requiring stent insertion, all patients were given the diagnosis of asthma before RP was diagnosed.²

Malacia, identified as loss of supportive cartilaginous structures, is a chronic consequence of RP and is probably due to recurrent extensive inflammation. It may be asymptomatic in earlier stages and detected only on pulmonary function testing, but it becomes symptomatic when it involves the upper airways.³ Similar to this case, dynamic tracheal collapse might occur suddenly, causing dyspnea, respiratory arrest, and death.⁴ On histology, the airway cartilage shows empty lacunae (empty spaces within the cartilage), a mixed population of inflammatory cells,⁵ and abundant inflammatory exudates that are often noted to invade the periphery of necrotic cartilaginous tissues. An immunologic mechanism is likely responsible for this disease because RP is often associated with rheumatic or autoimmune disease, although the presence of autoantibodies* is inconsistent. Various studies have found circulating antibodies to cartilage-specific collagen types II, IX, and XI to be present in 30% to 70% of patients with RP, with antibodies to type II collagen^† noted and correlating with the severity of acute RP episodes.⁶ Airway wall structural abnormalities in RP are detected by histopathology but can be identified using high-frequency (20 MHz) radial probe endobronchial ultrasonography (EBUS).⁷ EBUS reveals thickened and irregular cartilage, but the posterior membrane is normal (Figure 12-2).⁸ A definitive diagnosis of RP usually is based on the following criteria set by MacAdam et al.*⁵ and Damiani and Levine^†9: (1) bilateral auricular chondritis; (2) nonerosive seronegative inflammatory polyarthritis; (3) nasal chondritis; (4) ocular inflammation; (5) respiratory tract chondritis; and (6) audiovestibular damage.

Figure 12-2 A, Axial computed tomography view shows thickened cartilage. B, High-frequency ultrasound (20 MHz) shows thickened cartilage. C, Coronal T2 magnetic resonance imaging reveals diffusely thickened cartilage (white arrows). Images are obtained from a different patient.

(Courtesy Teruomi Miyazawa and Noriaki Kurimoto, St. Mariana University, Kawasaki, Japan.)

In one case series, the tracheobronchial tree was involved in about 56% of patients, and respiratory symptoms were responsible for the initial presentation in about 14%.⁵ In a larger case series of 145 patients suffering from RP, 31 patients had airway involvement, making the prevalence 21%.¹⁰ In many of these patients, similar to our patient, complaints of respiratory symptoms led to the diagnosis of RP, underscoring the fact that clinically significant airway compromise does not necessarily present late in the course of the disease. RP-related airway disease is more common among women and in patients between 11 and 61 years of age (median age, 42 years) at the time of first symptoms.* In this particular study, respiratory symptoms were the first manifestation of disease in 17 patients (54%), and dyspnea was the most common symptom in 20 patients (64%), followed by cough, stridor, and hoarseness. Airway involvement in remaining patients included subglottic stenosis (n = 8; 26%), focal and diffuse malacia (n = 15; 48%), and focal stenosis in different areas of the bronchial tree.¹⁰

In addition to a thorough review of systems during initial evaluation of a patient suffering from this disease, the treating team should set up realistic expectations, because it is known that the 5 year survival rate associated with RP is reported to be 66% to 74% but could be as low as 45% if RP occurs with systemic vasculitis. Other studies report a survival rate of 94% at 8 years, but these data may represent RP in patients with less severe disease than was observed in patients studied in earlier reports.¹

Dynamic (aka functional) bronchoscopy with dynamic breathing and coughing maneuvers is usually performed to visualize and quantify the airway collapse when patients are evaluated for TBM. The degree of dynamic collapse is estimated by visual inspection but can be objectively quantified using morphometric bronchoscopy.^† If TBM is present, the amount of collapse during passive and forced exhalation, as well as cough, is documented. In our case, complete collapse was clearly seen on bronchoscopy, making other quantifying methods unnecessary (see Figure 12-1).

Paired inspiratory/expiratory dynamic computed tomography (CT) scanning can reveal the degree, and potentially the cause, of expiratory central airway collapse.¹¹ The boundary between normal physiologic dynamic airway compression and abnormal collapse is far from established, however, and disagreement continues regarding how much of a decrease in cross-sectional area actually signals clinically and physiologically significant airway narrowing.¹² Although many investigators use 50% or greater reduction in airway cross-sectional area between inspiration and expiration to identify malacia, recent studies suggest that this definition leads to overdiagnosis, given that 78% of normal people reportedly exceed this criterion.¹³ However, it is noteworthy that in RP, thickened airway wall is noted, and even during inspiration, the lumen caliber is not normal (Figure 12-3) (see video on ExpertConsult.com) (Video III.12.1). In view of this, the use of absolute cutoff values to define abnormal collapse is less relevant, and what matters most when evaluating these patients is the impact on flow dynamics and symptoms. One disadvantage of dynamic CT scanning is that expiratory images can be technically unsatisfactory when patients are unable to cooperate with dynamic breathing instructions, thus failing to coordinate breathing with the timing of the scan. This is particularly the case in patients with respiratory distress or respiratory failure on mechanical ventilation. In these cases, CT is inadequate to evaluate for malacia.¹² Given our patient’s unstable respiratory status, CT scanning was not performed preoperatively.

Figure 12-3 End-inspiratory axial computed tomography in (A) mediastinal window and (B) lung window, showing thickening of the tracheal wall and consequent airway narrowing.

When feasible, however, CT should be performed and may show tracheobronchial wall thickening (see Figure 12-2) with or without calcification (seen in ≈40 % of patients). These findings are not very sensitive (seen in 17 of 30 patients in one study); however, all patients will have sparing of the posterior membrane—a characteristic finding in RP.¹⁰ CT may also reveal varying degrees of tracheal narrowing, often involving multiple segments of the trachea. In addition to its ability to reveal malacia, expiratory images may reveal consequent air trapping. The CT scan is also sensitive in detecting lower airway disease manifested by concentric narrowing in lobar and segmental bronchi and subsegmental bronchi.¹⁴ Dynamic CT scanning should be done according to the institution’s central airways CT investigation protocol, usually without intravenous contrast administration. Images are initially obtained using a standard radiation dose technique at end inspiration (170 mAs, 120 kVp, 2.5 mm collimation, high-speed mode, and pitch equivalent of 1.5). This is followed by a low-dose examination (40 mAs, 120 kVp, 2.5 mm collimation, high-speed mode, and pitch equivalent of 1.5) during the dynamic expiratory phase of respiration. Axial CT data are subsequently used to create a series of multiplanar and three-dimensional (3D) images, which are reviewed in conjunction with the axial images.

Magnetic resonance imaging (MRI) is also a useful adjunct in clinical diagnosis. MRI is better than CT in distinguishing between edema, fibrosis, and inflammation. T1-weighted images, T2-weighted images (see Figure 12-2), and T1-weighted images with gadolinium contrast provide characterization of relapsing polychondritis-related changes in cartilaginous tissues. MRI may be useful in detecting other potential RP-related problems such as thickening of the thoracic aorta before dilation occurs. Because of its lack of ionizing radiation, MRI may be a useful noninvasive test for monitoring the effects of treatment.

Pulmonary function testing (PFT) with flow-volume loop studies were not feasible in our patient but are recommended in patients with RP who present with respiratory symptoms. PFTs may assist in differential diagnoses and provide information about the severity of airway obstruction. PFTs can also be used to monitor disease activity. PFTs in patients with RP who have respiratory involvement demonstrate a nonreversible obstructive pattern with the decrease in forced expiratory volume in 1 second correlating with the degree of dyspnea.¹⁵ In general, both in normal people and in patients with obstructive ventilatory impairment, the flow-limiting segment, called the choke point, tends to be located in a region of minimum cross-sectional area and minimum side pressure within the airway when maximal flow is reached.¹⁶ Because maximum expiratory flow is airway compliance dependent, increased compliance, as is seen in patients with TBM, results in increased airway resistance and decreased maximum expiratory flow. Studies of airflow limitation in experimental models demonstrate that when the collapsing trachea is supported by a rigid tube, airflow improves and the flow-limiting segment migrates from the central airway toward the periphery.¹⁷

In this regard, studies in patients with RP have evaluated dynamic intrathoracic obstruction using a combination of physiologic and imaging modalities consisting of PFT, airway measurements with 3D-CT, and radial probe EBUS. To properly assess the location of the choke point, investigators measured intra-airway pressure and cross-sectional areas of the airway from bronchi to trachea.¹⁸ For seven patients who underwent self-expandable metallic stent insertion, choke points were detected in the trachea, mainstem bronchi, or lobar bronchi. After stent insertion, the flow-volume curves displayed significant improvements in flow limitation. Intraluminal catheter measurements of pressure differences decreased significantly, suggesting that stents had been inserted appropriately at the flow-limiting segments. Expiratory CT scanning revealed mosaic patterns, indicating air trapping due to migration of the choke points to smaller bronchi, as had been demonstrated in previous experimental studies.^17,18

Comorbidities

This patient had no evidence of other organ involvement from RP. The clinical relevance of RP is not limited to airflow obstruction but extends to other systems and may include heart block and vasculitis of both small and larger vessels. Making a prompt diagnosis of heart involvement is essential, especially if patients are scheduled to undergo general anesthesia.¹⁹ The cardiovascular system is reportedly affected in 24% of patients with RP. When possible, a thorough history and physical examination should be performed to evaluate for chest pain, abdominal pain, history of pericarditis, abnormal heart rate or rhythm, syncope, and history of subacute myocardial infarction (found on electrocardiogram [ECG]). Aortic and mitral valve regurgitation, aortic aneurysm, aortitis, aortic thrombosis, pericarditis, first- to third-degree heart block, and myocardial infarction, at times mediated through ostial stenosis of a coronary artery or arteries, have been reported.²⁰ Furthermore, although the life expectancy in all patients with RP is decreased compared with age- and sex-matched healthy individuals, patients with RP and renal involvement have a significantly lower age-adjusted life expectancy. Among those with renal disease (glomerulonephritis* diagnosed on the basis of a diagnostic renal biopsy or the presence of microhematuria and proteinuria), uremia is a common cause of death.²¹

A high prevalence of other autoimmune disorders has been found in patients with RP. These may include systemic vasculitis (≈13%), cutaneous leukocytoclastic vasculitis (≈7%), thyroid disease (≈6%), rheumatoid arthritis (≈5%), and systemic lupus erythematosus (≈4%).²⁰ Association with complex immunologic conditions such as a combination of Crohn’s disease (≈2%), ulcerative colitis (≈2%), and epidermolysis bullosa acquisita has also been described.²²

Support System

The husband was very supportive. He requested more information about her diagnosis and searched Internet support sites for patients with RP and their families. Although we do not take responsibility for quality, the website from the Relapsing Polychondritis Support and Awareness Foundation may be helpful.²³

Patient Preferences and Expectations

For patients with TBM, the need for intervention is determined on a per-patient basis and involves consideration of the identified abnormality, the severity of symptoms, and patient preferences. In this case, the patient’s malacia resulted in respiratory failure. On the basis of previous conversations between the patient and her husband, she desired to undergo further tests and procedures to improve her breathing, and had not selected comfort care in case of respiratory failure or risk of death.

Indications

In general, treatment for patients with expiratory central airway collapse caused by TBM depends on the severity of functional impairment, the cause, the severity of airway narrowing, and the extent of airway collapse. This patient had severe, diffuse circumferential tracheobronchomalacia resulting from RP. She presented with respiratory insufficiency requiring prompt intervention. Weaning from the ventilator without intervention was not feasible in view of central airway obstruction distal to the endotracheal tube, resulting in persistent respiratory acidosis despite positive-pressure ventilation.

Contraindications

No contraindications to rigid bronchoscopy were noted.

Expected Results

Study results show that many patients with severe TBM requiring airway stabilization who are not surgical candidates can benefit immediately from airway stent insertion in terms of improvement in functional status, decreased extent of airway narrowing, and reduced severity of airway collapse.²⁴ In one series, adverse effects from silicone stent insertion were very common; however, a total of 26 stent-related adverse events were noted in 10 of 12 patients (83%) a median of 29 days after intervention, including 6 cases of granulation tissue formation, 8 stent migrations, and 12 cases of partial obstruction from mucus plugs. Five emergent flexible bronchoscopies were necessary, of which 1 prompted an emergent rigid bronchoscopy to manage granulation tissue and post obstructive pneumonia; the other 4 emergent flexible bronchoscopies were done to remove mucus plugging. Six rigid bronchoscopies were performed emergently because of new respiratory symptoms.²⁴ In a different series evaluating only patients with RP and airway involvement, 12 patients (40%) required intervention, including balloon dilation alone (n = 5), stent placement (n = 3), tracheotomy (n = 1), balloon dilation with stent insertion (n = 1), balloon dilation with tracheostomy (n = 1), and tracheostomy with stent insertion (n = 1). Most patients experienced improvement in airway symptoms after intervention, although 1 patient died of progression of airway disease during the follow-up period.¹⁰ Most of the patients treated in this study had stenosis, not malacia; in fact, of 8 patients with bronchoscopically detected TBM in the study, only 3 were treated (2 by stent insertion and 1 by tracheostomy and removal of previously placed stents).¹⁰

Team Experience

Rigid bronchoscopy is performed on a weekly basis at this institution, and TBM is a major focus of the operators’ clinical research. However, such a severe form of diffuse, circumferential TBM resulting in respiratory failure is rarely seen, making it impossible to predict success or failure of the procedure in terms of ability to remove the patient from mechanical ventilation.

Therapeutic Alternatives

As of this writing, no medical, minimally invasive, or surgical treatment that cures RP is available, especially once cartilage destruction and malacia are established. Stents are reserved for patients with airway involvement (stenosis or malacia) and severe functional impairment.² In milder forms of airway involvement, treatment should be optimized before invasive therapies are considered. Continuous prednisone therapy has been shown to decrease the severity, frequency, and duration of relapses but does not stop disease progression.⁵ Prednisone (20 to 60 mg/day) is administered in the acute phase and is tapered to 5 to 25 mg/day for maintenance. Severe relapses may require 80 to 100 mg/day.⁵ Newer immunomodulating agents such as tumor necrosis factor receptor blockers may have a role in treating the inflammatory destruction of cartilaginous structures and can also be used as steroid-sparing agents.²⁵ Despite aggressive medical therapy (prednisone, mycophenolate mofetil, etanercept, and methotrexate), many patients experience symptom progression warranting invasive interventions.