Lung transplantation remains the only curative option for a variety of end-stage lung diseases. Advances in immunosuppression, antimicrobial prophylaxis, and surgical technique have improved posttransplant patient outcomes, however airway complications, including acquired central airway stenosis (CAS), remain a significant cause of posttransplant morbidity.1,2 The incidence of bronchial stenosis after lung transplantation is estimated at 11% to 13% among transplant recipients.1,3 In contrast to other solid organ transplantations, where systemic perfusion is rapidly reestablished, bronchial arteries are not typically revascularized in transplanted lung leading to airway ischemia until collateral blood supply regenerates.4–6 Additional risk factors for posttransplant bronchial stenosis include allograft rejection and infection, particularly with fungi.1,3,4,7,8
The treatment of posttransplant airway stenosis is bronchoscopy and dilation of airway with balloon bronchoplasty. Despite this intervention, some patients endure a challenging cycle of recurrent stenosis due to bronchial inflammation, airway scaring, and fibrosis. Often, these cases of refractory stenosis are treated with airway stent placement.2 Interval reaccumulation of granulation tissue within the stents is common however, and can threaten stent patency and perpetuate a cycle of recurrent stenosis.
Mitomycin C (MMC) is a naturally derived alkylating antibiotic originating from Streptomyces caespitosus. MMC prevents fibroblast proliferation and collagen deposition by crosslinking complementary strands of DNA thereby inhibiting DNA synthesis.9 The medication has been shown to be efficacious in preventing scarring and cicatrical changes when used in nonmalignant tracheobronchial stenosis.10–14 We describe our experience using MMC for treatment of lung transplantation–related CAS in a cohort of patients with refractory airway stenosis.
MATERIALS AND METHODS
We performed a retrospective cohort study of lung transplant patients who presented with recurrent airway stenosis at Duke University Medical Center between January 2013 and December 2016. Institutional review board approval (Duke IRB Protocol no. Pro00021763) was obtained. The orthotopic lung transplantation protocol at our institution has been previously described.5 After standard organ procurement, end-to-end bronchial anastomoses between recipient and donor airways were performed with running suture, followed by standard induction and maintenance immunosuppression.5 Posttransplant routine surveillance bronchoscopy occurred at 1, 3, 6, 9, and 12-month intervals followed by yearly bronchoscopy. Patients included in our study developed CAS defined as a narrowing which limited the passage of a 6.3 mm diameter flexible bronchoscope through a normally traversable central airway including mainstem bronchi, bronchus intermedius, and lobar bronchi. These patients were diagnosed when they developed symptoms of dyspnea or had a worsening of their baseline spirometry. Most patients underwent airway stent placement after 3 recurrent balloon dilations (CRE Boston Scientific; Natick, MA), as previously described.15 However, patients included in this cohort developed stenosis within or at the ends of the airway stents necessitating further dilations and eventually endobronchial MMC application.
MMC was delivered bronchoscopically via submucosal injection within the stenotic airway lesion at a dose of 5 mL of 0.4 mg/mL solution using a 21-G needle (SuperDimension Aspirating Needle; Medtronic, Minneapolis, MN) after balloon bronchoplasty, as shown in Figure 1. Demographics, spirometric, and other data were collected for all patients.
Descriptive statistics are presented as median [interquartile range (IQR)]. Wilcoxon signed-rank test was used to compare the number of balloon dilations before and after MMC application at predetermined intervals of 3 and 6 months. P-value of ≤0.05 was considered to be statistically significant. SAS version 9.4 (Cary, NC) and Microsoft Excel 2011 (Redmond, WA) were used for statistical analysis.
Eleven patients with post–lung transplantation CAS treated with MMC were included in our analysis, as shown in Table 1. Average age was 58 years old and 8 patients were male. The median time from transplantation until CAS diagnosis was 71 days (IQR, 59 to 97 d). Airway stenosis was seen at the surgical anastomosis as well as in distal airways. Eight of 11 patients (73%) had previous airway stent placement and developed stenosis within or at the ends of the stents. The most commonly isolated organisms from bronchoalveolar lavage were Mycobacterium abscessus, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus. The primary transplant team rendered decisions on antibiotic treatment. No change in the immunosuppression therapy was made for any of the patients.
The median time between transplantation and MMC therapy was 909 days (2.5 y; IQR, 169 to 1658 d). Median interval from stenting to MMC treatment was 739 days (2 y; IQR, 459 to 1857 d). Three patients were also treated with endobronchial brachytherapy and one had photodynamic therapy for airway stenosis, but all of these treatments occurred far before the study period.
For each patient, the number of airway dilations performed before MMC therapy was compared with the number performed afterwards, at 3 and 6-month intervals, as shown in both Table 2 and Figure 2. A median of 3 dilations per patient (IQR=1 to 3), were performed in the 3 months before MMC treatment compared with just 1 dilation (IQR=1 to 1) in the subsequent 3 months after therapy (P=0.023). In the 6 months preceding MMC, a median of 3 dilations per patient (IQR, 2.5 to 6.5), were performed compared with median of 2 dilations (IQR, 1 to 3) in the subsequent 6 months (P=0.004). The median number of MMC treatments was 2 per patient (range, 1 to 5). Average follow-up time was 37.5 months (range, 15.8 to 49.6 mo).
Comparison of baseline spirometry to 3 months after MMC showed an average increase in forced expiratory volume in one second from 1.60 L to 1.66 L (P=0.5) and forced vital capacity improvement from 2.56 L to 2.72 L (P=0.4). In comparison at 6 months from baseline, forced expiratory volume in one second improved to 1.78 L (P=0.2) and forced vital capacity increased to 2.77 L (P=0.3).
Endobronchial MMC treatment was well tolerated. There were no episodes of bronchial dehiscence or severe hemorrhage associated with MMC treatment. Despite reported adverse effects associated with systemic MMC therapy, our patients treated with endobronchial administration did not experience myelosuppression or hemolytic uremic syndrome. In addition, no malignancies developed in the airways treated with MMC nor were there increased infections attributed to MMC.
This study showed that endobronchial MMC application decreased the need for airway dilation in patients with lung transplantation–related airway stenosis, including patients with in-stent stenosis from accumulation of granulation tissue. We also showed that submucosal MMC administration in the airway was safe and no complications were seen.
The first report of endobronchial MMC treatment for post–lung transplant CAS was described by Erard et al in 2001.16 They described a lung transplant recipient with refractory airway stenosis failing management with serial dilations and uncovered metal stent placement. The patient was treated with a cotton swab saturated with 2 mg/mL of MMC applied to the stenotic airway for 2 minutes. This led to sustained improvement of stenosis and decreased need for repeated airway dilation. Our study builds on this previous report by presenting a cohort of lung transplant recipients with recurrent airway stenosis and decreased need for airway interventions after MMC application.
MMC has also been topically used for treatment of a variety of airway stenosis syndromes including idiopathic and postintubation tracheal stenosis, sarcoidosis, endobronchial tuberculosis, and other disorders.12–14,17 The experience indicates that MMC may not completely resolve airway stenosis, but delays recurrence and need for multiple subsequent therapeutic procedures.
Most of the patients who developed stenosis had metal stents in the airway. The stents were left in place as these were traditionally difficult to remove and MMC therapy was used to salvage the airway. However, 3 of 11 patients in the cohort developed lobar stenosis. As only metal stents were available at the time for these smaller airways, MMC therapy was utilized to avoid stent placement.
Our institution reserves MMC as adjunct therapy when previous measures have failed which accounts for the delay between initial CAS diagnosis and MMC treatment. Cryotherapy has also been described in patients with lung transplantation–related airway stenosis.18 Steroid injection in regions of airway stenosis have been described19 but some studies point to better efficacy with mitomycin compared with steroids.20 Authors chose MMC based on our anecdotal poor response to cryotherapy and steroids. However, these modalities should be studied in head-to-head trials.
Although others have reported topical application of MMC via rubbing soaked cotton pledgets, our institutional practice has been to inject it bronchoscopically within the submucosa using a flexible needle. Drug injected within the bronchial submucosa has been shown to distribute circumferentially around the bronchus.21 This technique allows precision in drug delivery and decreased risk of unintended treatment to adjacent airway regions. A challenge in interpreting previous studies of MMC for airway stenosis is that the concentration and application time in previous reports varies widely.11
Although parenteral administration of MMC as chemotherapy has adverse effects, including leukopenia and thrombocytopenia, localized therapy at lower doses is well tolerated and has not been associated with systemic toxicities.11,22 We did not observe any side effects; including infections, malignancy, or dehiscence from MMC treatment.
Although our study was limited by its small cohort size and retrospective design, it showed that MMC therapy was associated with a decreased need for subsequent bronchoscopic dilation. To date, this represents the largest published cohort of lung transplant recipients treated with endobronchial MMC for airway stenosis. Owing to its suggested efficacy and lack of associated adverse events, endobronchial treatment with MMC might be considered in the course of CAS, when stenotic lesions do not resolve with serial balloon dilations alone. In addition, MMC can also be used for the treatment of stent-associated granulation tissue and stenosis.
In conclusion, among lung transplant recipients with CAS, endobronchial treatment with submucosal MMC was associated with a decreased need for subsequent bronchoscopic balloon dilation to restore airway patency. Future prospective studies are warranted to determine its role alongside other therapeutic interventions for CAS.
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