Airway complications following lung transplantation

Abstract 

Airway complications post lung transplant account for significant morbidity (between 2 and 18%) and mortality (2 to 4%). The commonly encountered airway complications include necrosis and dehiscence, exophytic granulation tissue, bronchial stenosis, tracheo-broncho-malacia, bronchial fistulae, and airway infections. With growing experience in surveillance bronchoscopy post lung transplant and availability of advanced endobronchial interventional therapies, better management of lung transplant recipients is now possible. In this article, we review the various contributing factors, clinical manifestations, diagnostic modalities, and treatment options for post lung transplant airway complications.

Introduction 

Ever since Professor Hardy performed the first human lung transplantation in 1963, airway complications post-transplant have perplexed pulmonologists across the world as a major contributor to morbidity and mortality. Anastomotic ischemia and necrosis were described by Couraud in 1992, while Shennib and Massard presented a range of complications from early ischemia to fibrotic strictures and bronchomalacia [1, 2]. The incidence of airway complications has reduced from a high incidence of 60 to 80% as reported in the 1980s [3] to recent multicenter data reporting between 2 and 18% [4]. This accounts for 2 to 4% of overall mortality post lung transplantation. In combined heart and lung transplants, the incidence of airway complications is lower, from 3 to 14%, with a mortality of less than 3% [2, 5]. Common airway complications following lung transplantation include necrosis and dehiscence, exophytic granulation tissue, bronchial stenosis, tracheo-broncho-malacia, bronchial fistulae, and airway infections.

Classification of airway complications

Multiple classifications have been proposed to describe airway complications following lung transplantation. Chhajed proposed a TEGLA system in 2004 [6] focusing on thickness of mucosal injury (T), extent of circumferential injury (E), existence of granulation tissue (G), appearance of loose sutures (L), and the presence of distal airway complications (A). Shennib and Massard proposed a more comprehensive system focusing on ischemia and necrosis and described the entire spectrum of airway injury ranging from early ischemia to stricture and bronchomalacia, but the treatment recommendations were limited to managing strictures and simultaneous pathologies were not described [2]. Santacruz and Mehta classified airway complications into 6 categories but did not differentiate dehiscence from necrosis. The MDS grading system proposed by the French Language Pulmonary Society in 2013 used a bronchoscopic description of the airway complications for description, but failed to grade the severity of ischemia and necrosis [7]. In 2018, the International Society for Heart and Lung Transplantation created a workgroup and put forth a consensus statement elaborating the universal definition and description of adult and pediatric airway complications (Table 1). This classification system divides the complications into ischemia and necrosis, dehiscence, stenosis, and malacia, and further describes them on basis of the location in respect to the anastomosis and extent upon the bronchial circumference involved. This is by far the most comprehensive system of classification and description of airway complications post lung transplant. These descriptions are based on bronchoscopic findings in the first 2 to 3 weeks post-transplant and the progression versus healing is described on subsequent assessments.

Table 1.

Adult and pediatric airway complications after lung transplant: International Society for Heart and Lung Transplantation (ISHLT)–proposed grading system. Adapted from J Heart Lung Transplant 2018;37:548–563

	Ischemia and necrosis	Dehiscence	Stenosis	Malacia
Location	a.Perianastomotic—within 1 cm of anastomosis b.Extending > 1 cm from anastomosis to major airways c.Extending > 1 cm from anastomosis into lobar or segmental airways	d.Cartilaginous e.Membranous f.Both	g.Anastomotic h.Anastomotic plus lobar/segmental i.Lobar/segmental only	j.Perianastomotic—within 1 cm of anastomosis k.Diffuse—involving anastomosis and extending beyond 1 cm
Extent	a. < 50% circumferential ischemia b. > 50% to 100% circumferential ischemia c. < 50% circumferential necrosis d. > 50 to 100% circumferential necrosis	e.0 to 25% of circumference f. > 25 to 50% of circumference g. > 50 to 75% of circumference h. > 75% of circumference	i.0 to 25% reduction in cross-sectional area j. > 25 to 50% reduction in cross-sectional area k. > 50% but < 100% reduction in cross-sectional area l.100% obstruction

Pathophysiology

The main event leading to post lung transplant airway complications is donor bronchial ischemia [3]. Bronchial arteries are normally resected during the donor lung retrieval, and bronchial artery anastomosis is seldom performed. Bronchial arteries take origin from the descending thoracic aorta or the intercostal arteries and travel through the pulmonary hilum along the bronchus to form a submucosal plexus with the small arterioles of the pulmonary artery. The implanted lung is totally dependent on the poorly oxygenated, low-pressure pulmonary circulation; thereby, any factor leading to reduced pulmonary blood flow or increased pulmonary vascular resistance adds to bronchial ischemia. The incriminating factors include poor graft preservation, primary graft dysfunction, severe edema, acute rejections, airway infections, and prolonged positive pressure ventilation [8]. Debridement of the peri-bronchial tissue during the anastomosis and a longer donor bronchial length also contribute to increased ischemic injury [2]. Ischemic injury presents initially as mucosal necrosis and sloughing which may lead further to dehiscence, granulation tissue formation, or fibrosis leading consequently to strictures or bronchomalacia [9].

Risk factors

Donor and recipient factors

Donor mechanical ventilation time of more than 50 to 70 h before organ retrieval is associated with a higher rate of airway complications [10]. A mismatch in donor and recipient height, probably due to the resulting mismatch between the donor-recipient bronchial circumference, requiring telescoping or intussusception of the bronchus also adds to the risk [2, 10].

Lung preservation

Organ preservation techniques may also impact bronchial healing and ischemia. Poor preservation may lead to endothelial edema and reperfusion injury causing ischemic anastomotic injury [11]. Low-potassium dextran preservation solutions like Perfadex help prevent deleterious edema and injury pathways during lung procurement [12]. Various studies have established the importance of combining retrograde perfusion with antegrade administration of the perfusate solution to prolong preservation time and improve distribution of perfusate through pulmonary vasodilation [12].

Surgical factors

The earliest technique of tracheal anastomosis for bilateral lung transplant was given up due to extremely high incidence of anastomotic complications due to ischemia [4]. Over the years, a number of anastomotic techniques have been described with an attempt to avoid the post-operative ischemia. Techniques like “end to end,” “telescoping,” use of vascularized tissue wrapped around the anastomosis, and bronchial artery revascularization have all been described, though without any consensus on the recommended technique. In cases of size disparity between the donor and recipient bronchus, the smaller bronchus can be intussuscepted into the larger one, though deliberate telescoping should be avoided as it increases bucking and stenosis of the airway [13]. An end-to-end anastomosis is the preferred technique [14]. Many suturing techniques ranging from running or continuous suture to interrupted sutures with figure-of-eight sutures have been used, with no definite evidence to advantage of one type over the other [3, 14]. A running suture on the membranous portion, with figure-of-eight sutures on the cartilaginous portion, resulted in the significant decrease in the number of post-transplant anastomotic complications in few studies [4].

The length of the donor bronchus needs to be minimized to preserve blood supply [2, 15]. Short donor bronchus with only 1 to 2 rings proximal to the secondary carina and a longer recipient bronchus are the preferred approach to minimize ischemia [2]. Skeletonization of the bronchus by shaving off the peri-bronchial tissue adds to ischemia and should be avoided to avoid disruption of the microcirculation [9].

Bronchial artery revascularization (BAR) has been reported from various single-center studies, with lower rates of ischemia in both adults and children [16], though its role in reducing long-term complications still remains controversial [13]. Moreover, the technical complexity of the procedure, need for prolonged cardiopulmonary bypass, and the increased ischemic time of the graft have not let it become a popular elective choice during lung transplantation.

Right bronchus is only perfused by 1 bronchial artery whereas the left bronchus is perfused by 2 bronchial arteries, thereby making the right anastomoses twice as prone to develop airway complications as compared to the left [17].

Ischemic time

Excess ischemic time and its association with airway complications post-transplant have not been demonstrated as a direct correlation in various studies [18]. Additionally there is no increased incidence of complications in the second anastomosis during a bilateral lung transplant [8, 19].

Post-operative issues

Early data demonstrated that majority of the patients with airway complications had severe post-operative hypotension [19]. Prolonged hypoperfusion due to reduced cardiac output or hypotension may lead to anastomotic ischemia and airway complication.

High positive end expiratory pressure (PEEP) may decrease the anastomotic healing by reducing the bronchial mucosal blood flow and disrupting the airway mucosa [20].

Primary graft dysfunction due to reperfusion injury leads to interstitial edema and reduction of the pulmonary flow, thereby causing increased airway ischemia [9, 15, 21].

Acute cellular rejection

Acute rejection occurring early in the first month post-transplant is associated with increased risk of bronchial complications and stricture formation [22]. Doppler measurements of submucosal blood flow have displayed reduced graft perfusion during acute cellular rejection, due to the submucosal edema caused by acute inflammation as well as increased vascular resistance in the collaterals [23].

Lung infections

Early infections—tracheobronchitis or pneumonias—can cause a delay in bronchial healing. Historically, Burkholderia cepacia was considered a risk factor [24] but recent literature suggests infections from Aspergillus, Candida, Rhizopus, and Mucor species are associated with majority of airway complications [18, 25]. This is mainly due to local ischemia and necrosis due to mucosal damage.

Medications

Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been associated with airway healing disruption and dehiscence. Thus, it is now contraindicated in new lung transplant patients, for at least a duration of 90 days post-transplant, wherein would healing has occurred [26, 27].

Steroid use was considered as a risk factor for wound healing [28], but recent data showed no adverse events, less granulation tissue formation, and improved survival [2, 28, 29].

Management of airway complications

Necrosis and dehiscence

Some mucosal ischemia and necrosis almost always appear post-transplant, usually around the anastomoses or sometimes even distally. The necrosis has a waxing and waning course due to ischemic injury and healing of the bronchial mucosa during week 1 to week 6 post-transplant. The incidence of dehiscence is between 1 and 10% from various centers [7], with partial dehiscence involving defects < 4 mm in up to 24% cases [13] and large or severe defects in < 2% of the patients [7, 17].

Clinically high index of suspicion must be maintained to pick up an early dehiscence. Dyspnea, pneumothorax presenting as fall in forced expiratory volume in 1 s (FEV1) values in extubated patients, and absence of chest rise, drop in saturation, difficulty in weaning from ventilation in patients on mechanical ventilation, pneumomediastinum, persistent air leak, or lung collapse in the early postoperative period are the usual clinical presentations.

Computed tomography (CT) can help identify a dehiscence with almost 100% sensitivity and 94% specificity [30]. Bronchial wall defects or irregularities like narrowing, peri-anastomotic air pockets, poor allograft aeration, pneumothorax or pneumomediastinum or ipsilateral volume loss are some CT features suggesting dehiscence [30–32].

Bronchoscopy still remains the gold standard for diagnosing mucosal necrosis and dehiscence. It is important to look for the mucosal health and appearance of any bronchial wall defects during routine surveillance bronchoscopy.

Management of the dehiscence depends upon the degree of the defect. Smaller defects with no bronchial wall breach can be monitored with surveillance bronchoscopy and antibiotic therapy, both intravenous and inhaled. It is also recommended to reduce steroid dosage to facilitate healing [7]. Intercostal drains are inserted to manage air leaks. More extensive necrosis, larger dehiscence can be managed by short-term placement of a covered or uncovered self-expanding metallic stent (SEMS). [32] Metallic stents stimulate epithelial tissue growth whereas covered stent helps close the breach in the bronchial wall [15, 33]. However, in case of mediastinitis associated with dehiscence, an uncovered stent is preferred as it allows drainage of pus from the mediastinum. Silicone stents are usually avoided as they do not promote neo-epithelialization and the sheer force required for stent placement may increase the size of the defect [34]. Partial dehiscence repair using fibrin glue or α cyanoacrylate glue, sometimes with concomitant stent placement, has also been tried. Failure to response to conservative or bronchoscopic therapy requires surgical correction or re-anastomosis of the bronchus. Due to local ischemia, infection, and inflammation, pericardial, intercostal muscle, or omental flaps have been described to promote healing of the new anastomosis. Resection allograft pneumonectomy and retransplant maybe the last resort for patients failing all other options [35].

Exophytic granulation tissue

Endobronchial obstruction due to endobronchial granulation tissue hyperplasia occurs in around 20% of patients post lung transplant [36]. The proposed pathology is similar to keloid formation with overstimulation of the inflammatory pathways and recruitment of macrophages to the site of bronchial mucosa injury [36]. Anastomotic Aspergillus infections intensify the process of granulation tissue formation and also decrease response to therapy [15]. Clinically, it presents as airway obstruction with dyspnea, cough, hypoxia, drop in FEV1, and post-obstructive pneumonia [36].

Management of the granulation tissue depends upon the growth pattern, whether obstructive or non-obstructive. Use of flexible forceps for precise removal and rigid forceps for debridement of bulkier tissue is the preferred method in the eccentric non-obstructive granulation tissue. Obstructive granulation tissue is managed with cold therapies including cryo-debridement or cryotherapy. The cryotherapy probe can be used to freeze granulation tissue followed by a “yank” or withdrawal of the probe to remove bits of the tissue attached [37]. On the other hand, cryotherapy involves cycles of freezing and thawing of the obstructing tissue. This crystallizes the tissue with intracellular and extracellular ice crystal formation along with microthrombi formation leading to cell death [38]. In weeks following cryotherapy, the devitalized granulation tissue sloughs off leaving undamaged bronchial wall. Hot therapies like neodymium-doped yttrium aluminum garnet (Nd:YAG) laser, argon plasma coagulation, or electrocautery have also been used but they generate additional inflammation and more granulation tissue formation. Other therapies like mitomycin application and brachytherapy have also been tried. Mitomycin, an antineoplastic drug which halts fibroblastic proliferation, has been used post debridement to reduce recurrence of granulation tissue formation [39]. Endobronchial brachytherapy concentrates radiation within the airway and reduces fibroblastic proliferation [40].

Stenosis

Bronchial stenosis is the most common airway complication post lung transplant, occurring in 4 to 24% cases within 2 to 9 months [41]. The pathophysiology of stenosis comprises of airway inflammation with T cell–mediated injury to the bronchial epithelium in addition to the ischemic injury. The resulting low perfusion causes calcification, ossification, and fragmentation of bronchial cartilages [42]. Stenosis typically presents with cough, breathlessness, wheezing, and declining FEV1 values; occasionally post-obstructive pneumonia or lung collapse may occur [43]. Depending upon the location, it is divided into central airway stenosis (CAS), occurring at or within 2 cm of the anastomosis or distal airway stenosis (DAS), which is distal to that [44]. DAS most commonly occurs in bronchus intermedius leading to vanishing bronchus intermedius syndrome (VBIS) [45]. CT scan may demonstrate a fixed narrowing if > 50% bronchial stenosis is present, but bronchoscopy is the gold standard for diagnosis.

Balloon bronchoplasty is the initial treatment for bronchial stenosis. It results in immediate resolution in up to 94% cases and establishes long-term success in 50% patients. Balloon dilatation maybe the only procedure required in 26% cases [46]. In other cases, serial balloon dilatation over multiple sessions maybe required to break the fibrotic strictures. Balloon bronchoplasty causes circumferential stretching of the bronchial wall, which may eventually return back to the stenosed caliber; therefore, combining the procedure with radial incisions or steroid injections at sites of radial incision helps improve long-term outcomes [41]. Common adverse events include bleeding, mucosal tears, bronchial rupture—partial or complete—and prolonged hypoxia [47].

Severe bronchial stenosis, non-responsive to radial incision, steroid injection, and balloon dilatation, is managed with stent placement [48]. Silicone stents are preferred and depending upon the location and contour of the stenosis, a tubular or a Y stent can be used. The stents are left in place for a duration of 2 months to 1 year, allowing airway remodeling and restoration of airway patency. Surveillance bronchoscopy should be performed every 4 to 6 weeks. In areas of severe narrowing excluding the possibility of silicone stent placement, SEMS can be used for serial dilatation to placement of a silicone stent for long term (Fig. 1). SEMS need to be removed within 4 to 6 weeks to avoid excessive granulation tissue formation and tissue ingrowth in an around the uncovered stent, making extraction of the stent difficult.

Fig. 1.

Treatment algorithm for managing bronchial stenosis post lung transplant. Adapted from CHEST 2017; 152[3]:627–638

Although airway stenting is typically reserved for major airways such as the trachea, mainstem, and bronchus intermedius, lobar stenting has also been described. With the adaptation of smaller stents within the airways (i.e., iCAST™ (Atrium, Hudson, NH, USA) and AEROmini® tracheobronchial stent (Merit Medical Endotek, South Jordan, UT, USA))^1,2, stenting of specific lobes is feasible from a technical standpoint. The practice has yet to gain wide adaption since the benefit remains questionable [49]. The largest series was published by Sethi et al.; 122 iCAST™ stents were placed in 38 patients [50]. Thirty-seven percent of patients in this series had bronchial stenosis secondary to lung transplantation. The right middle lobar bronchus was the most common placement location (37%). Symptomatic improvement was reported in 95% of patients. However, the subjective scale that was used to make this determination was not reported in the study. Out of the 38 patients that underwent lobar stenting, 42% had a stent-related complication. A similar series by Majid et al. reviewed 21 iCAST™ stents that were implanted among 18 patients. Thirteen patients from this series had malignant disease. An improvement in the median modified Medical Research Council Dyspnea Scale was noted [51]. In another series that evaluated lobar stenting, subjective symptomatic improvement was reported in 92% of patients [13]. Functional capacity measured by the six-minute walk test was reported to have improved in all patients. There is equipoise when it comes to lobar stenting. A small study showed that lobar stenting did not improve airway function or patency. Future data may help to determine the true efficacy of lobar stenting.

Great promise is put forth in the concept of biodegradable stents with reduced risk of granulation tissue formation and stent-related complications of migration, stent fracture, and restenosis. Refractory bronchial stenosis requires anastomotic reconstruction with or without lobectomy and rarely retransplant.

Bronchomalacia

Airway malacia is defined as > 50% reduction in airway caliber with expiration [44]. This is the result of loss of cartilaginous support in the airways, though the mechanism is not well understood. Autopsy studies have demonstrated atrophy and reduction in the number of longitudinal elastic fibers of the pars membranacea and fragmentation of the tracheal cartilage. The incidence is not well documented but a single-center study has shown it to be between 1 and 4% [52]. Depending upon the site of occurrence, it has been classified into perianastomotic, occurring within 1 cm of the anastomosis and diffuse, which involves the anastomosis and extends beyond 1 cm [44]. Clinical presentation includes dyspnea, especially recumbent, cough often with a specific “barking” character, wheeze, increased sputum production and difficult clearance, recurrent respiratory infections, and decrease in the spirometry values with flow-volume loops showing blunted peak flows. Bronchoscopy is the gold standard for the diagnosis [53]. Visualization of > 50% reduction in airway caliber on forced expiration during flexible bronchoscopy in a structured approach has been described to assess the degree and location of airway malacia. Management depends upon the severity of the collapse and the location (Fig. 2). Only observation with frequent surveillance bronchoscopy suffices for asymptomatic cases. Moderate cases presenting with functional impairment are managed with pulmonary toileting, non-invasive ventilation support, and mucolytic agents. Severe malacic segments associated with clinical symptoms warrant stent placement. Silicone stent is favored and left in situ for 9 to 12 months, providing adequate time for airway remodeling [48]. SEMS can be used as palliative care in cases where the location or airway contour does not allow silicone stent placement [41]. SEMS are optimally removed after 4 to 6 weeks to avoid granulation tissue formation and further airway obstruction. Surgical correction is quite challenging and generally not recommended. For patients failing to improve with stent placement over 10 to 14 days, surgery with approaches including resection, reconstruction, and tracheoplasty may provide favorable outcomes [54].

Fig. 2.

Treatment algorithm for bronchomalacia post lung transplant. Adapted from CHEST 2017; 152(3):627–638

Bronchial fistula

Fistulae are one of the rare and most challenging complications following lung transplantation. Three types of fistulae have been described, namely, broncho-pleural fistula, broncho-mediastinal fistula, and broncho-vascular fistula.

Broncho-pleural fistula occurs due to profound and prolonged ischemia [55]. Clinical presentation ranges from dyspnea, subcutaneous emphysema, hypotension, pneumothorax with a persistent air leak to a tension pneumothorax. Management depends upon the size of fistula and extent of space contamination. Small fistulae can be treated conservatively with antibiotics and chest drain insertion. Mechanically ventilated patients should be put on low tidal volume ventilation and minimal PEEP to aid healing. Bronchoscopic closure of fistulae, 3 to 5 mm in size using glue (fibrin or α-cyanoacrylate), covered SEMS, or bronchial valves, has been described [55].

Broncho-mediastinal fistula presents with systemic inflammatory response syndrome (SIRS) or sepsis and is generally fatal. Treatment consists of inhaled and intravenous antibiotics, and/or anti-fungals, percutaneous drainage, and in some cases mediastinal debridement.

Broncho-vascular fistula is associated with high mortality. Three types—bronchial-aortic, bronchial-pulmonary artery, and bronchial-left atrial fistulae—have been described [56]. Presentation varies from moderate to massive hemoptysis, sepsis, air embolism in bronchial-left atrial fistula to sudden death [2, 56]. Airway Aspergillus infection complicated with hemoptysis or metallic stent erosions can also contribute to broncho-vascular fistula formation. Successful management with bi-lobectomy and pneumonectomy has been reported in individual cases [57, 58].

Anastomotic infections

Immunosuppression following lung transplantation and the concomitant exposure of the allograft to the external environment increases the risk for opportunistic infections. The bronchial anastomosis, due to relative devascularization, poor muco-ciliary clearance, and absent cough reflex post-transplant, disruption of lymphatic drainage, and altered alveolar phagocytic function, is highly susceptible to saprophytic infections [25]. Other complications like ischemia, dehiscence, stenosis, and malacia lead to retention of secretions and promote bacterial and fungal growth [14]. Endobronchial stents may also act as nidus for infections, when present.

Pseudomonas aeruginosa and Staphylococcus aureus are the most commonly isolated bacterial infections. Aspergillus in the first few weeks to 6 months following transplant accounts for 2 to 20% of infections. Strong association has been reported between bronchial complications and Aspergillus infection in the first 30 postoperative days [5]. Aspergillus can cause tracheobronchitis (37%) or anastomotic infection (20%). Colonization is reported in 20% case, of which 3 to 6% cases progress to anastomotic infection. Candida vocal cord infection, tracheobronchitis, mediastinitis, and stent infections have also been reported, and together with Aspergillus, it accounts for 80% of airway infections [5]. Scedosporium is reported in 1% cases and has high mortality despite therapy. Differentiating anastomotic infection from the colonization is a challenge. Bronchoscopy shows airway erythema, bronchial inflammation, ulceration, and pseudo-membrane formation [59].

Antifungal prophylaxis with early and aggressive broad-spectrum antifungal therapy forms the mainstay of treatment. Timing and duration of antifungal prophylaxis is still controversial. A survey in 2004 showed that > 70% programs initiate prophylaxis within 24 h following transplant and continue for 3 to 18 months. The commonly used agents include itraconazole, inhaled amphotericin-B, or voriconazole.

Conclusion

Airway complications form a significant source of morbidity and mortality following lung transplant. Although the incidence is lower than other complications like rejection—acute or chronic—it still presents with a management challenge. Despite significant advances in immunosuppressive strategies and immediate post-operative care, there is no consensus on ideal post-transplant airway complication management. It requires a team effort from the transplant physician and the interventional pulmonologist to identify early and treat airway complications to reduce morbidity and improve the post-transplant outcome and quality of life of the transplant recipient.

Funding

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Conflict of interest

The authors have no financial conflict of interest.