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Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio
Correspondence and requests for reprints should be addressed to Jose Fernando Santacruz, M.D., Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue/A90, Cleveland, Ohio 44195. E-mail: santacj{at}ccf.org
ABSTRACT
Overall survival rates of lung transplantation have improved since the first human lung transplantation was performed. A decline in the incidence of airway complications (AC) had been a key feature to achieve the current outcomes. Several proposed risk factors to the development of airway complications have been identified, ranging from the surgical technique to the immunosuppressive regimen. There are essentially six different airway complications post-lung transplantation. The most frequently reported complication is bronchial stenosis. Other complications include bronchial dehiscence, exophytic excessive granulation tissue formation, tracheo-bronchomalacia, bronchial fistulas, and endobronchial infections. The management of post-transplant bronchial complications needs a multispecialty team approach. Prevention of some complications may be possible by early and aggressive medical management as well as by using certain surgical techniques for transplantation. Interventional bronchoscopic procedures, including balloon bronchoplasty, cryotherapy, laser photoresection, electrocautery, high-dose endobronchial brachytherapy, and bronchial stents are among the armamentarium. Also, medical management, like antibiotic prophylaxis and therapy for endobronchial infections, or noninvasive positive-pressure ventilation in case of bronchomalacia, are used to treat an AC. In some cases, different surgical approaches are occasionally required. In this article we review the risk factors, the clinical presentation, the diagnostic methods, as well as the management options of the most common AC after lung transplantation.
Key Words: lung transplantation • airway complications • bronchial stenosis
In the early years following the first human lung transplantation in 1963, airway complications were a significant source of morbidity and mortality. Reviewing early literature, it is evident that bronchial complications were lung transplant's "Achilles heel," especially for short-term survival (1–4). The reported incidence ranged from 60 to 80% during the transplants performed in the following 2 decades (5–9). Improved surgical techniques, newer immunosuppressive agents and better medical management have led to an improvement in lung transplantation outcomes (3, 8, 10–13). Recently, our center reported an overall survival rate of 80% at 1 year, 50% at 5 years, and 37% at 7 years (11). However, the healing characteristics of the bronchial anastomosis continue to be a source of morbidity and perhaps mortality today.
Incidence and Prevalence
The reported incidence of airway complications varies widely and can be explained partially by the lack of standardized definitions or a universally accepted grading system. The described airway complication incidence has a broad range, from 1.6 to 33%; however, most centers have a 7 to 18% rate with a related mortality of 2 to 4% (3–6, 11–17). Improvement in graft preservation, donor/recipient selection, and surgical and medical advances has resulted in the current improved rate of airway complications. The incidence of airway complications is lower in heart-lung transplant recipients, approximately 3 to 14%, with a mortality rate of less than 3% (1, 16, 18).
RISK FACTORS
Anastomotic healing and ischemia.
Airway complications have been mainly attributed to ischemia of the donor bronchus during the immediate post-transplant period (6, 8). Normal lungs have dual blood supply, and the pulmonary artery component must compensate for the loss of the bronchial flow component postoperatively. The latter arises from the bronchial arteries originating from the intercostals or directly from the descending aorta. They track through the pulmonary hilum and travel with the bronchi. Small arterioles penetrate the muscular portion of the airways and perfuse the submucosal plexus. It is within this plexus that the bronchial and pulmonary circulations collateralize (Figure 1). Whereas the recipient's main bronchus is perfused by native bronchial arteries, the donor's bronchus critically depends on collateral perfusion (6, 19). During lung harvest, the bronchial artery circulation is lost and is not routinely reestablished. Revascularization of the donor organ by the recipient's bronchial arteries may take up 2 to 4 weeks (1–8). Thus, the viability of donor's bronchus during this time is completely dependent on the retrograde, low-pressure blood flow from the recipient's poorly oxygenated pulmonary arterial circulation through collaterals. Additional factors such as low cardiac output, hypotension, dehydration, etc., may further decrease the blood supply, increasing the ischemia. On the other hand, during heart-lung transplantation, the donor's tracheo-bronchial blood supply is adequately preserved through coronary collaterals to the region of the tracheal anastomosis (1, 18, 19). The "coronary collateral" supply to the region of the main carina and proximal bronchi have been demonstrated to arise from atrial branches of both the left and right coronary circulation (20).
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Unfortunately, despite the surgical approach used, the bronchial anastomosis remains quite ischemic post-transplantation. Perhaps the best way to reduce the ischemia is by direct bronchial artery revascularization (BAR), which has been reported to have low airway complication rates (3, 19, 25). With direct BAR, as much as 95% of recipients may demonstrate at least partial restoration of bronchial flow on postoperative arteriography and successful bronchial perfusion by bronchial artery scintigraphic images (6, 26) (Figure 2). This has been successfully described in en-bloc double lung as well as in single lung transplantation (19, 25). Nevertheless, the BAR procedure has not gained popularity because of technical complexity resulting in prolonged graft ischemic time and a need for cardio-pulmonary bypass.
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Donor/Recipient Risk Factors
A significant relationship was found between a higher rate of airway complications and the length of donor's mechanical ventilation time (50–70 hrs), before organ recovery (4). Recipient–donor height mismatch, with a higher recipient height, has also been identified as a risk factor due to relatively larger bronchial circumference (4). Undoubtedly, exaggerated intussusception of the donor bronchus should be avoided. Minimal length of telescoped anastomosis may be the only solution to such a size mismatch (11).
Infections
Preoperative and postoperative pulmonary infections are a significant risk factor for airway complications (6, 16). Post-transplant anastomotic infections predispose to the development of dehiscence, stenosis, malacia, fistulas, and granulation tissue. Organisms present on the donor's airway may influence the development of postoperative recipient infections. In purulent lung diseases, bacterial and fungal airway colonization before transplantation place patients at a higher risk for infections (28, 29). In some, a high inoculum of pathogenic organisms may be present immediately after lung implantation; however, a consistent relationship with airway complications has not been established.
Medications and Immunosuppression
In the early years, the use of corticosteroids during the pre- and postoperative period was believed to significantly increase the incidence of airway complications (1, 10, 21, 30). In fact, regular use of steroids preoperatively was considered an absolute contraindication because extensive animal data described a negative influence on anastomotic healing (30, 31). Postoperative steroids were delayed as long as possible to protect the anastomosis. However, the potential "adverse effects" were not well documented, and successive studies revealed that small-to-moderate doses of steroids in the pretransplant period did not adversely affect the outcome (1, 10, 12). To increase the controversy, the incidence of bronchial stenosis was higher in patients not taking steroids. This is probably due to a protective effect by reducing the formation of granulation tissue (31). Recently, a retrospective cohort analysis showed that the survival of patients receiving pretransplant low-dose prednisone (<0.42 mg/kg/m2) was better than patients receiving the higher doses (32). Other studies demonstrated that postoperative steroids do not increase the rate of airway complications or mortality, probably because of a beneficial effect on rejection control (1, 7, 10, 12, 16, 18, 30). In summary, most authors agree that steroids are not detrimental to the proper healing of the anastomosis and the withholding of corticosteroids is therefore not justified (6).
Sirolimus, a rapamycin derivate, is a macrocyclic lactone with strong immunosuppressive and antiproliferative properties. In theory, when used in conjunction with calcineurin inhibitors, it may reduce nephrotoxicity without affecting acute rejection rates and improve long-term outcomes by reducing the incidence of bronchiolitis obliterans. Randomized trials showed that sirolimus-based immunosuppression in de-novo recipients had an early unacceptable high rate of severe airway complications, including dehiscence. Therefore, sirolimus is contraindicated in new lung transplants. However, it has been used safely at least 90 days after transplantation, once the wound healing has taken place (33, 34).
Miscellaneous
Other commonly described risk factors for airway complications include severe primary graft dysfunction, acute cellular rejection, and positive-pressure mechanical ventilation (4, 6, 17).
Primary graft dysfunction, also called ischemia-reperfusion injury, is a form of acute lung injury with alveolar damage and increased vascular permeability seen after lung transplantation. A grading system has been proposed by the International Society for Heart and Lung Transplantation (35). Reperfusion injury increases interstitial edema and compromise pulmonary flow (6, 12). On top of these hemodynamic changes, severe primary graft dysfunction increases the length of mechanical ventilation as well as the degree of positive end-expiratory pressure (PEEP) required, which contributes to bronchial wall and anastomotic stress. However, PEEP effect on the anastomotic healing is controversial, because animal studies have shown that it may increase the bronchial blood flow involving the trachea and the carina (36).
Reductions in graft perfusion, documented by laser-Doppler measurements of submucosal blood flow, are seen in acute cellular rejection. Furthermore, as with infection, acute inflammation of the bronchial mucosa seen in acute rejection may result in submucosal edema and increased vascular resistance to collateral flow (1, 6).
Positive-pressure mechanical ventilation during the immediate postoperative period produces significant stress on the anastomosis and bronchial wall (11) with the potential of inhibiting collateralization. Studies have demonstrated an airway complication incidence of 7.6% in patients mechanical ventilated for less than 7 days, compared with an 18.6% among those ventilated for longer duration (12). Also, because the pulmonary circulation is a low-pressure system and collateral flow has only minimal perfusion pressure, positive-pressure mechanical ventilation can impair graft perfusion when high inflation pressures are required (6, 17). Meanwhile, reintubation has not been described as risk factor (11).
Nevertheless, the published results vary from center to center and among the time periods. Some centers have not reported a relationship among airway complications with acute cellular rejection, positive-pressure mechanical ventilation, or primary graft dysfunction (3, 8, 10).
Controversy also exists in the literature regarding relationships among airway complications and ischemic time, organ preservation technique, recipient/donor sex or age, indications, use of IL-2 antagonist and body mass index. Of importance is the fact that approximately 35% of patients with a previously treated airway complication will experience a second one, and the chance of three or more after the second is approximately 70% (11). This phenomenon may be related to the fact that any endobronchial treatment has the potential to create further trauma to the airway by itself.
CLASSIFICATION
At least three classification systems addressing airway complications have been published, yet none are universally accepted (1, 37, 38). Also, airway complications have been simply classified as early (<3 mo) or late (>3 mo) (3). Extensive necrosis and dehiscence tends to occur early as a result of ischemia; however, most complications occur late, after the healing and remodeling has taken place; particularly stenosis and malacia (6). The understanding of three concepts is essential to classify and understand airway complications: (1) one complication could be the continuum of an other (i.e., dehiscence complicated by stenosis, etc.); (2) one type of complication may lead to an airway complication of a different kind (i.e., anastomotic infections complicated by bronchial obstruction due to excessive granulation tissue, etc.); and (3) many patients may have a combination of complications. There are six types of basic airway complications (Table 1).
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1. Bronchial stenosis.
Bronchial stenosis is the most common airway complication (16) (Figure 3). The incidence is estimated to be between 1.6 and 32% (14, 40, 41). It is usually seen following necrosis, dehiscence healing, or treated infections. "Telescoped" anastomosis is associated with a 7% incidence of airway stenosis (3). However, bronchial stenosis may develop without a previously documented abnormality (42). Two patterns of bronchial stenosis have been described, the first at the surgical anastomosis, and the second a distal narrowing referred to as segmental nonanastomotic bronchial stenosis. Segmental nonanastomotic bronchial stenosis is rare and is not reported frequently, with an estimated incidence of approximately 2.5 to 3% (2, 41, 43). A caveat is the fact that not all published literature has separated anastomotic from nonanastomotic stenosis and it is therefore difficult to determine if both have the same etiologies or incidence (2, 43). Interestingly, a higher frequency of segmental nonanastomotic bronchial stenosis is seen involving the bronchus intermedius (BI) (40, 41) (Figure 4). Furthermore, a severe form occurs in about 2% of bronchial stenosis cases, referred to as the vanishing bronchus intermedius syndrome (VBIS). Basically, the VBIS is a symptomatic narrowing or complete atresia of the bronchus intermedius, seen as early as 6 months after transplant and associated with high morbidity and mortality, with a mean survival of 25 months after the diagnosis (44) (Figure 5).
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Although flexible bronchoscopy is the gold standard for the diagnosis, it has some limitations. It only provides limited information on the stenosis length and the patency of distal airways, which are important data for planning dilatation or stent placement (46). When significant (>50% of bronchial diameter) stenosis exists, computed tomography (CT) of the chest may demonstrate a fixed, not changing with inhalation–exhalation imaging, bronchial narrowing (45). Occasionally, on a well-penetrated chest x-ray (CXR), luminal compromise due to the stricture formation may be seen (47). Studies have shown that using spiral, three-dimensional and multiplanar reconstruction CT, accurate assessment of the anastomotic site, precise illustration of the bronchial stenosis, and excellent evaluation of stent placement, is achieved (48). In one study, helical CT with multiplanar reconstruction had an accuracy of 94% for detecting bronchial stenosis, whereas axial CT alone had a 91% precision when compared with conventional tomography and bronchoscopy (49, 50). The VBIS in CXR may reveal a collapse of the right middle, lower, or both lobes (44) (Figure 6). Spirometry may show a decline in the forced expiratory flow (FEF 25–75%) and peak expiratory flow (PEF) rates, or a failure to improve in the first few months after transplant (1). Abnormal flow-volume loop patterns have also been described. An initial plateau in the maximal expiratory flow-volume (MEFV) curve suggestive of a variable intrathoracic airway obstruction due to unilateral mainstem bronchial obstruction after a single lung transplant for severe emphysema was described by Neagos and colleagues (51). Anzueto and colleagues (52) described a biconcave flow-volume loop, which indicated that the native lung, although diseased, empties and fills more rapidly than the transplanted stenotic lung. Therefore, the initial portion of the inspiratory and expiratory flow-volume loop represents air movement in the native lung, whereas the latter portions represent the bronchial stenotic one (52) (Figure 7). However, mild abnormalities may not be seen by imaging, spirometry, or the flow-volume loop.
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Electrosurgery or laser photoresection is used in web-like airway strictures where radial incisions are placed before balloon bronchoplasty (Figure 9). Radial electrocautery ablation cuts are precise and limit tissue vaporization. However, extreme caution must be used because it can easily cut through the airway wall. This particular method of mucosal sparing is safe and is most beneficial when used for short (<1 cm) circumferential stenosis without significant associated malacia. If there is no evidence of infection, injection of corticosteroids locally to the stenotic area may be performed in an effort to reduce the incidence of restenosis. Usually, 1 cc of dexamethasone is injected at the base of each radial incision using an endobronchial injection needle (56). In the same way, mitomycin-C can be locally applied for the same purpose. Severe and recurrent stenoses may require concomitant stent placement (40).
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Self-expanding metallic stents (SEMS) in bronchial stenosis allows immediate and long-term maintenance of airway luminal dimensions in 80 and 45% of cases, respectively (40). Immediate dyspnea relief is expected in up to 94% of patients after stent deployment (5, 13). Concerns regarding long-term complications of self-expanding metallic stents for benign airway diseases have been raised (57, 58). Previous reports have shown an overall 54% incidence of complications, of which 16 to 33% are due to infection, 12 to 36% due to granulation tissue formation, and 5% due to stent migration (5, 13, 57). Other complications include halitosis and metal fatigue.
Self-expanding metallic stents, once deployed, become very difficult or impossible to remove if left in place for a long enough time. Consequently, their use in benign disease should be cautious (57). Bacterial bronchitis may occur in up to 33% of patients, likely due to immunosuppression, poor secretions mobilization, and occasionally secondarily to bronchial orifices obstruction. It is usually treated with aerosolized antibiotics, and rarely is stent removal/replacement necessary (5, 13). Stent colonization has been described in up to 78% of patients, occasionally, with biofilms formation. However, even when colonized by pathogenic bacteria, infection may not always develop, yet halitosis can be very compromising for the patient (5, 60). A lower incidence of restenosis has been described with the use of self-expanding metallic stents (39). We found self-expanding metallic stents to be safe, suitable, and effective (13). Another advantage is the possibility of placing stents using flexible bronchoscopy in mechanically ventilated patients (39).
Recently, the self-expanding silicone stent, Polyflex (Boston Scientific; Boston, MA), has been used for bronchial stenosis after lung transplantation. This new stent theoretically combines the advantages of both silicone and self-expanding metallic stents, including the elasticity and good adaptation of the self-expanding metallic stents and the ease of removal of silicone stents; however, this stent requires rigid bronchoscopy for placement. We reported it use in four bronchial stenosis patients with a 100% failure rate due to migration. Also, lobar obstruction and mucous impaction were seen. Thus, we abandoned it use in our practice (59).
Currently, at our center, we reserve the use of any kind of stent for extreme cases only. We consider extreme cases those patients with symptomatic and recalcitrant bronchial stenosis and those for whom other procedures, such as balloon bronchoplasty, have failed.
Self-expanding metallic stents offer excellent early palliation for bronchial stenosis, although their late complications may be worse than the initial obstructive process. As a result, the use of self-expanding metallic stents in this context should be judicious. When needed, a very close clinical, radiological, and bronchoscopic follow-up is performed. Also, every patient in whom a stent has been deployed must received albuterol aerosol treatments four times per day along with 1 ml of 20% nebulized N-acetylcysteine at least twice per day in an effort to avoid complications.
Occasionally all the interventions fail and surgery is required. Surgical strategies include bronchial anastomosis reconstruction, sleeve resections with and without lobar resection, or retransplantation (41). Retransplantation survival is not nearly as favorable as primary lung transplants. Worldwide, only 2% of lung transplants are second-time recipients (6). The surgical options involve very high risk procedures in an already compromised patient.
In summary, the management of bronchial stenosis is challenging. Whereas balloon bronchoplasty is the initial option, other approaches, including stent placement, requires experience and a careful, individualized, multispecialty team approach.
2. Bronchial necrosis and dehiscence.
Bronchial dehiscence is a potentially disastrous complication associated with high mortality (5, 8, 61). Dehiscence represents a continuum of mucosal necrosis that usually occurs early after transplantation, typically within the first 1 to 5 weeks (11, 61). Necrotic changes usually peak early and recede quickly, because the airway cannot remain profoundly ischemic for extended periods without either healing or dehiscing (11). Thus, the anastomosis must be carefully examined at every flexible bronchoscopy after the transplantation. Some degree of ischemic injury and necrosis is almost always seen following the transplantation, usually around the anastomosis or in the lobar bronchi.
Dehiscence may be divided into partial and complete categories; alternatively, a classification for bronchial anastomosis healing has also been adapted for dehiscence (61). The reported incidence is between 1 and 10% (62), and at least some degree of dehiscence has been described in up to 24% of recipients in one series (14). Fortunately, the incidence of grade III to IV dehiscence is low, in our experience approximately 1.6%. The morbidity and mortality vary considerably depending on the severity and associated infections.
Most patients with complete dehiscence succumb secondarily to sepsis. Common presenting features include dyspnea, inability to wean from mechanical ventilation, pneumomediastinum, subcutaneous emphysema, pneumothorax, lung collapse or persistent air leak early post-transplant. In the extubated patient, spirometry may show a drop in the forced expiratory volume in one second (FEV1) (61). Dehiscence can be further complicated by infections or peribronchial abscess formation.
CXR are unreliable due to many factors, including the presence of relative small amount of peribronchial air, gas directly overlying the major airways, or poor portable radiographic technique (63). By helical CT, dehiscence can be identified by the presence of bronchial wall defects, fixed or dynamic bronchial narrowing, bronchial wall irregularities, extraluminal air around the anastomosis, or a combination of these features (45, 47, 49). Bronchial wall defects of 4 mm or less have been shown to have excellent clinical outcomes, whereas the outcome of larger defects is unpredictable (42). Extraluminal air is a common finding immediately after surgery, but images should be carefully evaluated to detect airway complications (42, 47). When extraluminal air is seen in conjunction with wall defects, the amount of air assumes additional importance. Extrabronchial air may or may not be seen contiguous to the bronchial defect, as air tends to dissect along fascial planes and occupy potential spaces following the path of least resistance. Thus the amount, rather than the location, is the key factor (42). Other indirect radiologic findings include poor allograft aeration, pneumothorax, pneumomediastinum, or ipsilateral volume loss (45). Studies have shown that chest CT has 100% sensitivity and 94% specificity for dehiscence detection compared with bronchoscopy (49, 61, 64) (Figure 10). However, because CT does not reliably depict mucosal necrosis, which is the earliest sign and a useful predictor of dehiscence, definitive diagnosis requires flexible bronchoscopy (45, 61). With flexible bronchoscopy, in addition to necrosis, the unraveling of sutures at the anastomosis site is an important finding in establishing the diagnosis of dehiscence (62) (Figure 11).
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Our group reported successful management of grade III to IV life-threatening dehiscence with the temporary placement of uncovered self-expanding metallic stents. Self-expanding metallic stents are easily deployed under direct vision or fluoroscopy using flexible bronchoscopy, eliminating the risk of further trauma to the anastomosis by the use of the rigid bronchoscope. Self-expanding metallic stents are also known to cause excessive granulation tissue, which provides a platform for the healing of the dehiscence (Figure 12). Anastomotic healing can be noticed as early as 1 week after the deployment. The stents are usually removed at 6 to 8 weeks after the healing and prior to their epithelialization. In our experience, the mean time to stent removal was 37.5 days. We only recommend uncovered self-expanding metallic stents to allow drainage of mediastinal and bronchial secretion and ventilation of all involved lobes and avoiding the possibility of bacterial colonization of the polyurethane coating (61).
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3. Exophytic granulation tissue.
Benign hyperplastic endobronchial granulation tissue can cause significant airway obstruction in up to 20% of patients, typically at the anastomotic site, within a few months after surgery (66) (Figure 13). The presumed pathophysiology involves overstimulation of inflammatory mediators and the recruitment of macrophages to the site of injury, a process similar to keloid formation (66, 67). Although the initial granulation reaction is likely due to ischemia and the consequent remodeling process, continued stenosis and granulation tissue may be related to the trauma of the therapeutic interventions (67). The concurrent infection with Aspergillus at the anastomosis seems to intensify the problem and may render it refractory to therapy (6). The airway compromise presents as progressive dyspnea, cough, hypoxia, or postobstructive pneumonia (66). Diagnosis is suspected when decreased spirometry values are seen. It is often recurrent and requires multiple procedures. Debridement is the modality of care. Forceps resection is safe and useful for the excision of eccentric localized mild granulation tissue (18). Also, debridement can be achieved with the use of cryotherapy or neodymium:yttrium-aluminum-garnet (Nd:YAG) laser vaporization (68). When any debridement technique is used, extreme caution must be taken to avoid creating a bronchomediastinal fistula (8).
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Argon plasma coagulation has also been used effectively in treating this complication. Precautions to avoid argon-ignited intrabronchial combustion are important. Reported side effects of argon plasma coagulation include perforation, necrosis, ignition, gas embolism, and bronchoscope damage (71).
The incidence of granulation tissue formation after the placement of uncovered self-expanding metallic stents in lung transplants has been estimated to be from 12 to 36% (5, 13, 57, 66). Granulation tissue may be noted as early as 3 weeks after stent placement (57). Cryotherapy, argon plasma coagulation, and Nd:YAG laser has been used to manage granulation that grows within a stent with success (1, 5, 18, 57). Using those methods, obstruction relief can be quickly achieved; however, a 10 to 50% recurrence rate has been described (67).
Occasionally, suture granulomas may develop at the site of the anastomosis, which are successfully treated with Nd:YAG laser, argon plasma coagulation, cryotherapy, or electrocautery (13) (Figure 14).
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High-dose-rate endobronchial brachytherapy (HDR-EB) is a well-known therapy for malignant processes. Retrospective studies of its use have been reported in lung transplant recipients with excessive granulation tissue formation at the anastomosis and that grows through the stents (66, 67). The idea is to deliver a highly conformal dose of ionizing radiation, using Iridium-192 to the obstructive process, minimizing radiation exposure to the surrounding structures. Brachytherapy allows for precise delivery of high-dose radiation at short distance from the radiation source. The radiation is delivered to a depth of 1 cm, after which there is rapid dose fall-off with essentially no dose absorbed at 5 cm away from the catheter, enhancing normal tissue sparing and limiting complications (66, 67, 75). The literature reports acceptable short-term improvement, yet conflicting long-term outcomes. High-dose rate endobronchial brachytherapy may be more effective if performed within 24 to 48 hours after mechanical removal of granulation tissue by the other means described above. Caution must be taken to ensure the proper technique to minimize toxicity and avoid its use in patients with uncontrolled infections. Few series have been reported, with no prospective randomized trials; however, the therapy appears to be promising for at least refractory cases (66, 67, 75).
4. Tracheo-bronchomalacia.
Tracheo bronchomalacia may present diffusely or at the anastomotic site and not uncommonly combined with bronchial stenosis. It is defined as 50% or greater narrowing of the airway lumen on expiration (76). It is important to differentiated peri-anastomotic malacia from the distal/diffuse form; the latter has been seen in association with obliterative bronchiolitis (77). The mechanism of tracheo-bronchomalacia development, especially the diffuse form, is not well understood. Pathological changes in airways cartilages have been described; however, the implications of those changes are uncertain.
Tracheo-bronchomalacia is usually seen within 4 months after lung transplantation (45). Signs and symptoms include cough, dyspnea, inability to clear secretions, recurrent infections, stridor, and wheezing (58, 76). Usually there is an obstructive defect in spirometry with a decrease in the forced expiratory flow of 25 to 75%, a low peak expiratory flow rate, and reductions in FEV1 (76). The configuration of the flow-volume loop is nonspecific yet occasionally it may demonstrate a decrease in the terminal flow, which may normalize following successful treatment.
Expiratory or a dynamic inspiratory-expiratory chest CT may suggest the diagnosis, yet flexible bronchoscopy remains the gold standard (45, 58, 76). Other promising imaging techniques include dynamic magnetic resonance and multiplanar and three-dimensional CT reconstructions, including virtual bronchoscopy; although further studies are necessary. During flexible bronchoscopy, the dynamic airway collapse may be missed if performed during general anesthesia with positive pressure mechanical ventilation (76).
Symptomatic bronchomalacia represents a significant therapeutic problem. Treatment depends on severity of functional impairment, airway narrowing, and extent of airway collapse. Treatment alternatives include conservative medical management, noninvasive positive-pressure ventilation, and airway stenting. In relatively asymptomatic patients, diagnosed during routine flexible bronchoscopy, no treatment is required. In less severe cases, especially if associated with infection or rejection, medical treatment of these conditions may be beneficial. In recalcitrant cases with severe symptoms that persist despite treatment of related conditions, nocturnal noninvasive positive-pressure ventilation or airway stenting may be required (76, 77).
Stents are effective to restore and maintain airway patency, and are relative well tolerated, although adverse events occur frequently as described above (5, 13, 39, 55, 58, 59). Silicone stent insertion (straight or "Y" shaped) improves functional status and decreases the extent of airway narrowing and the severity of airway collapse (58). They are easily inserted, repositioned, and removed using rigid bronchoscopy (76). The dynamic features of expiratory airway collapse continuously alter the shape of the central airways as well as the contact between the stent and the walls, which puts the patients at higher risk for stent-related complications (58). Complications commonly occur within the first month after insertion, which supports the practice of close follow-up and flexible bronchoscopy as needed. If quality of life and functional status do not improve, the silicone stent may need to be removed (58, 76). Often malacia does not allow a silicone stent to acquire proper position. In these circumstances a self-expanding metallic stent may provide better palliation (6).
We believe that stent insertion should be reserved for patients with severe symptoms and significant functional impairment, as in patients with bronchial stenosis.
5. Bronchial fistulae.
Fistulas involving the endobronchial tree are some of the most challenging complications that follow lung transplantation. Three types of fistulas have been described after a lung transplant. Fortunately, their incidence appears to be low.
A bronchopleural fistula after lung transplantation is rare. Bronchial ischemia, as with all other fistulas, is thought to be a significant contributing factor (78). Generally, it carries a high morbidity and mortality. Clinically, it may present as a life-threatening condition characterized by dyspnea, hypotension, subcutaneous emphysema, tension pneumothorax, or a persistent air leak (79). Many methods have been proposed for its management, from a conservative approach with antibiotics and a thoracostomy tube to surgical interventions (78, 79). The choice of management depends on timing, size, extent of space contamination, and a patient's general condition (78, 80). The key points in bronchopleural fistula treatment are drainage of the empyema and infection control, fistula closure and reinforcement, and pleural space obliteration. Surgical options include chronic open drainage, direct closure with flap reinforcement, trans-sternal bronchial closure, or thoracoplasty (78). In high-risk patients, minimally invasive procedures are recommended as initial therapy. Endoscopic closure techniques with tissue glues, methyl-2-cyanoacrylate, and fibrinogen plus thrombin, have been performed (80). Placement of tissue glue with occlusion of the bronchopleural fistula by flexible bronchoscopy allows for successful closure and is ideal for patients unable to tolerate more invasive procedures (78). Glue closure should be considered when the fistula is small (3–5 mm in diameter). Larger fistulas treated with glue alone are seldom successful due to dislodgment of the plug. Covered metallic stents have been used to occlude and manage airway fistulas. Also, case reports of using endobronchial valves to block persistent air leaks have been published (81).
Sepsis spreading from the mediastinum from a bronchomediastinal fistula with or without dehiscence is almost generally lethal (1). Bronchomediastinal fistlas are rare and may also present as bacteremia, mediastinal abscess, or cavitation. In contrast to bronchial dehiscence, where the communication exists only at the anastomotic site, a bronchomediastinal fistula may occur at any part of the airway.
Bronchovascular fistulas a rare but serious complication associated to high mortality. Bronchial-aortic (82), bronchial-pulmonary artery, and bronchial-left atrial (83) fistulas have been described. They present with a minor premonitory hemoptysis, before the initial and finally fatal bleeding occurs. Or, patients may present with sepsis, moderate hemoptysis, and in the case of bronchial-atrial fistulae, with air embolism (1, 83). A high index of suspicion is necessary for the diagnosis. A fistula should be suspected in cases of infectious complications (especially with Aspergillus) combined with moderate hemoptysis. It has also been reported in association with metallic stent vascular erosions (82). Flexible bronchoscopy may be useful for localizing the fistula. Literature on the therapy of bronchovascular fistulas is limited to case reports. Successful bilobectomy and pneumonectomy have been previously described (85, 86).
6. Anastomotic infections.
Endobronchial infections occur commonly and mainly involve opportunistic pathogens. Unfortunately, the inevitable use of immunosuppressives and steroids significantly increases the risk. The allograft is exposed to a variety of sources that involve not only the external environment but the flora of both, the native and the donor's airways (87). The bronchial anastomosis is particularly susceptible to saprophytic infections, in part due to its relative devascularization after transplant, defense impairment (i.e., mucociliary clearance and cough reflex), disruption of lymphatic drainage, and altered alveolar phagocytic function (87, 88). Anastomotic ischemia and dehiscence impede airway healing, foster bacterial and fungal overgrowth, and restrict clearance of secretions (14). Retention of secretions may contribute to the development of microabscess along the suture line, leading to dehiscence (1, 77). If present, endobronchial stents may provide a nidus for endobronchial infections. Bronchial obstruction may lead to infection by acting as a collection trap (89).
Endobronchial infections represent an airway complication; however, they can also lead to any of the other complications described above. The mechanisms are speculative, yet the infection may not be limited to the luminal epithelium but rather invade directly into the bronchial wall, with the subsequent loss of bronchial wall integrity and cartilaginous support. Such destruction may predispose airway collapse and malacia. Moreover, the reparative mechanism after the insult could result in the proliferation of granulation tissue and the promotion of collagen deposits that may encroach on the airway lumen resulting in stenosis (87). Usually anastomotic infections have a paucity of symptoms and are diagnosed during surveillance by flexible bronchoscopy or when they are accompanied by concurrent pneumonia (90).
Pseudomonas and Staphylococcus aureus are the most frequently involved organisms in bacterial infections. Such an infection may present as tracheitis, bronchitis, or pneumonia. Therapy is combined with bronchoscopic drainage/debridement and systemic antibiotics. Although no prospective trials in transplant populations exist, aerosolized colistin or tobramycin may be a beneficial adjunct treatment for multidrug-resistant gram-negative bacterial infections (91).
Saprophytic fungal organisms are airborne and obtain their nourishment from non-living organic matter, making the ischemic and necrotic debris at the anastomosis the ideal environment for their proliferation and potentially facilitating an invasive infection (87, 89). Their incidence has been reported to be as high as 24%, and is estimated that more than 40% of patients suffering from a fungal infection will develop an airway complication, most commonly bronchial stenosis (87). Aspergillus is the most frequently reported organism and is usually encountered the first few weeks to six months post-transplantation (87, 92). Overall incidence is estimated to be from 2 to 20% of transplants (16, 88). There is a very strong relationship (>50%) between the isolation of Aspergillus in the first 30 postoperative days with the subsequent development of bronchial complications (16). Concomitant bacterial and cytomegalovirus infection may increase the risk of acquiring this infection, due to their immunomodulatory effect (89, 93). Whether Aspergillus infection is present as a consequence of ischemic necrosis, or whether it causes necrosis by itself is unknown, as they both frequently coincide. Nevertheless, when early necrosis is described together with Aspergillus, the airway complications incidence is higher than if there was necrosis alone. Therefore, Aspergillis is likely to be a direct player (16).
Aspergillus infection presents in two patterns: tracheobronchitis (37%) and anastomotic infection (20%) (88) (Figure 15). More than 90% of infections are caused by Aspergillus fumigatus, but other species have been also reported (88, 92). Colonization of the airway is frequent (20%), and is estimated that approximately 3 to 6% will progress to infection at a later time (88, 93). Colonization of the airway by Aspergillus represents a risk factor for the development of invasive aspergillosis (94). The estimated mortality rate of Aspergillus tracheobronchitis or anastomotic infection is between 14 and 24% (88, 92).
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A number of strategies have been used to reduce the incidence and the associated mortality. Antifungal prophylaxis, frequent bronchoscopic surveillance, and aggressive early empiric therapy are among the common approaches undertaken. Because the exposure takes places immediately after transplant, the use of antifungal prophylaxis is crucial (16). The duration of antifungal prophylaxis is controversial. Prophylactic agents commonly used are itraconazole, inhaled amphotericin-B, or voriconazole. Some authors have reported that the use of prophylaxis and early and aggressive treatment with nebulized amphotericin-B reduces the occurrence of airway complications (6, 16). A 2004 survey showed that greater than 70% of lung transplant programs use antifungal prophylaxis starting within 24 hours after the procedure. The duration of prophylaxis is usually not less than 3 months and can be as long as 18 months (95). Also, almost all programs treat airway colonization.
For an Aspergillus infection, systemic plus inhaled antifungals combined with bronchoscopic management are used. Endobronchial amphotericin-B application has been also described (84).
Isolation of non-Aspergillus molds by bronchoalveolar lavage occurs in up to 14.5% of recipients, most commonly Cladosporium. However, non-Aspergillus isolates do not appear to be a risk factor for the development of invasive disease, irrespective of prophylaxis (94). Case reports of Candida vocal cord, tracheobronchitis, mediastinitis and stent infections have been reported (89, 96). Recently, an increased incidence of mucormycosis anastomotic infection has been noted. Using flexible bronchoscopic evaluation, darkly pigmented pseudomembranes (due to its tendency for tissue and angio-invasion with vessel thrombosis and tissue necrosis) and hypertrophic tissue changes have been described. Medical antifungal therapy plus endobronchial therapies has been used with success (97).
Scedosporium ssp has been reported in 1% of lung transplant recipients. Two human pathogens exist; Scedosporium apiospermun, the asexual state of Pseudallescheria boydii, and Scedosporium prolificans. They can colonize the suture material that may act as a nidus at the anastomosis. Bronchoscopic examination may show large, yellowish-white, pseudomembranous type of lesion (Figure 16). Diagnosis is confirmed with culture. Treatment is difficult, because S. prolificans is resistant to all antifungals. P. boydii may be susceptible to miconazole, voriconazole, and posaconazole. It is used in combination with endobronchial therapies. Despite appropriate treatment, it is associated with high mortality (98).
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FOOTNOTES
Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form August 24, 2008; accepted in final form October 20, 2008)
REFERENCES
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