Pleural complications in lung transplantation

INTRODUCTION — Pleural disease is an important consideration in patients undergoing lung transplantation. For some patients being considered as candidates for lung transplant, pre-existing pleural disease may increase their risk of postoperative pleural complications. Even in the absence of pre-existing pleural disease, pleural complications following lung transplantation are common due to disruption of the pleural space at the time of transplant surgery, complications related to rejection of the allograft, and the immunosuppression regimen post-transplant.

The risk factors for pleural complications and the postoperative pleural complications that develop in patients undergoing lung transplantation will be reviewed here. Issues regarding the selection of candidates for lung transplantation and the physiologic changes that occur following lung transplantation are discussed separately. (See "Lung transplantation: General guidelines for recipient selection" and "Physiologic changes following lung transplantation".)

RISK FACTORS FOR PLEURAL COMPLICATIONS — Lung transplant recipients with pre-existing pleural space abnormalities and donor-recipient size mismatch are at increased risk of pleural complications at the time of lung transplant surgery.

Pre-existing pleural space abnormalities — Pleural adhesions due to pre-existing pleural disease may increase the risk of intraoperative and postoperative complications following lung transplantation, but is not necessarily considered a contraindication to lung transplantation [1]. At the time of lung transplantation, a recipient's native lung must be completely removed from that thoracic cavity. Pleural adhesions may make it much more difficult to remove the native lung, increasing operative time and placing the patient at increased risk for intraoperative bleeding.

Pre-existing pleural space abnormalities may be secondary to many different etiologies, such as prior pneumothorax, hemothorax, chylothorax, empyema, or pleural adhesions. Underlying suppurative lung disease and prior surgical lung biopsy can lead to pleural adhesions. In addition, treatment of these pleural space diseases by the placement of chest tubes, pleurodesis, or pleurectomy may further contribute to pleural space abnormalities that may complicate lung transplantation.

Special consideration may be needed in candidates with underlying diseases that are prone to cause pleural adhesions [2-5]. As examples:

●Emphysema – Pneumothorax, treatment of pneumothorax, and prior thoracic surgery (eg, lung volume reduction surgery)

●Interstitial lung disease – Lung biopsy and pneumothorax

●Cystic fibrosis (CF) and non-CF bronchiectasis – Chronic suppurative lung disease and pneumothorax with or without surgical intervention can cause extensive pleural adhesions

●Lymphangioleiomyomatosis (LAM) – Pneumothorax and chylothorax and their treatment (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Lung transplantation'.)

The concern is that lysis of pleural adhesions at the time of lung transplant surgery is technically more difficult and may lead to an increased risk of bleeding and a higher transfusion requirement. However, a few small series are at least partially reassuring in this regard [3,4,6-9].

●In a small series, 16 patients with CF who had a history of pleural interventions to manage pneumothoraces were compared with 16 patients with CF without prior pneumothorax and 16 patients with non-CF lung disease and no history of pneumothorax or pleural procedures [7]. The transfusion requirement was not different among the groups.

●In a series of 61 patients with LAM who underwent lung transplantation, 79 percent had a history of pneumothorax and 15 percent had a history of chylothorax [3]. Twenty patients had moderate to severe intraoperative hemorrhage related to adhesion lysis, but no intraoperative deaths were reported.

●A separate report described the experience with 41 patients with LAM; severe intraoperative hemorrhage due to lysis of extensive adhesions occurred in 21 patients and 13 patients required intraoperative cardiopulmonary bypass [4].

●A retrospective study of lung transplant recipients suggests that pre-existing pleural disease (defined as pleural thickening, plaque, or fibrosis) may be associated with an increased risk of primary graft dysfunction at 0 and 48 hours and worse short term (three month) outcomes, although there was no significant difference in overall survival [10].

Donor-recipient size mismatches — In certain situations, a lung transplant recipient may receive a donor lung that is smaller than the recipient's native lung. This size discrepancy is a risk factor for pleural complications, such as pneumothorax, pleural effusion, and empyema, postoperatively. Specific situations in which size mismatch may occur include the following:

●Recipients with hyperinflated native lung undergoing transplant with relatively smaller sized donor lung – Transplantation of undersized lungs has been reported to result in more frequent pleural effusions following lung transplant in patients with COPD [11].

●Adult lung transplant recipients receiving pediatric donor lungs – Size mismatching, particularly at the sites of the vascular and bronchial anastomoses, can predispose recipients to hemothorax due to bleeding at the vascular anastomosis and empyema due to leakage at the bronchial anastomotic site. The undersized lung can leave a residual pleural space with persistent pneumothorax or accumulation of pleural fluid to fill the space, both of which may require thoracentesis or chest tube reinsertion [12]. As an example, in a series of 38 adult recipients of pediatric lung allografts, 10 required chest tube reinsertion for persistent pneumothorax, pleural fluid, or empyema, and four required thoracentesis for recurrent pleural effusion prior to discharge [12].

●Living donor lobar transplant recipients – Similar to adult recipients who receive pediatric donor lungs, recipients of living lobar lung transplantation are likely to have size discrepancies at the site of the vascular and bronchial anastomoses, and also to have smaller overall lung volumes, placing them at increased risk of pleural space complications [13].

PLEURAL COMPLICATIONS FOLLOWING LUNG TRANSPLANTATION — Pleural complications, such as pleural effusion, hemothorax, and pneumothorax, are common complications following lung transplantation, occurring in 22 to 45 percent of lung transplant recipients [11,14]. Most often, these occur in the first couple of weeks after lung transplant, but they occasionally occur later post-transplant. Rarely, empyema, chylothorax or malignant pleural effusions may occur. The development of pleuroparenchymal fibroelastosis (PPFE) in the late post-transplant period is being increasingly recognized as a potential manifestation of Chronic Lung Allograft Dysfunction (CLAD).

Pleural effusions — Pleural effusions are very common in the early post-transplant period. Pleural effusions are also observed later post-transplant, but due to different etiologies.

Pleural effusions early post-transplant — In the early post-lung transplant period, the most likely contributing factors to the accumulation of pleural fluid include increased alveolar capillary permeability, because of allograft ischemia, denervation, and subsequent reperfusion [15], and disruption of lymphatic flow due to severance of allograft lung lymphatics. It has been reported that 100 percent of lung transplant recipients have pleural effusions post-transplant. As an example, in one series of 100 patients, all had ipsilateral pleural effusions after lung transplant [16]. Thus, all patients have chest tubes in place postoperatively to drain the pleural space and diuretics are commonly utilized to try to reduce pleural fluid accumulation [17].

Postoperative pleural effusions are usually small to moderate in size (image 1), but rarely can be massive [18]. Most resolve with thoracostomy tube drainage within 14 days following transplant, although a small percentage may increase in size over the first three postoperative weeks [15]. Most cells in the effusion are of recipient origin, with donor cells accounting for less than 1 percent of the total pleural cell count by the eighth postoperative day [19].

The characteristics of pleural effusions without clinical evidence of infection or rejection have been studied following single lung transplant in nine patients [20]. The pleural fluid was initially bloody, exudative, and neutrophil-predominant (figure 1). Over the next seven days, the percentage of neutrophils and the lactate dehydrogenase (LDH) concentration decreased, while the percentage of macrophages and lymphocytes rose. Resolution of daily pleural fluid output generally paralleled a decrease in pulmonary edema.

Pleural effusions also may result from abnormalities of the pulmonary venous anastomosis, including stenosis, kinking, or thrombosis. These abnormalities may cause unilateral or bilateral pulmonary edema with pleural effusions.

Pleural effusions late post-transplant — Late post-transplant pleural effusions can occur in association with acute cellular rejection, trapped lung from prior pleural inflammation, or malignancy.

●Acute cellular rejection – Analysis of pleural effusions associated with acute cellular rejection in post-transplant recipients has revealed that the fluid is exudative and often contains more than 90 percent lymphocytes [21]. Pleural effusions may occur with acute lung rejection. However, the presence of a pleural effusion detected by chest computed tomography (CT) has poor sensitivity, specificity, and positive and negative predictive values for the diagnosis of acute lung rejection [22]. A small to moderate sized pleural effusion associated with acute cellular rejection will usually improve within one to two days of treatment of the rejection. The evaluation and treatment of acute lung transplant rejection is discussed separately. (See "Evaluation and treatment of acute cellular lung transplant rejection".)

●Malignancy – Lung transplant recipients are at increased risk of developing malignancies due to long-term immunosuppressive medication. Pleural metastases and primary pleural mesothelioma may manifest as a pleural effusion, which is often hemorrhagic [23]. Pleural effusion is an uncommon manifestation of posttransplant lymphoproliferative disorder [24,25]. (See "Noninfectious complications following lung transplantation", section on 'Malignancy'.)

●Pulmonary venous anastomosis stenosis or thrombosis – Although these pulmonary venous anastomosis problems typically occur in the immediate postoperative period, pleural effusions from pulmonary venous abnormalities have been reported more than one year after transplant [26,27].

●Pleural effusion management – Pleural effusions in lung transplant recipients that do not spontaneously resolve within a short period of time often require drainage as a subset of these effusions can become loculated. There is no consensus on the optimal management strategy of pleural effusions following lung transplant, although thoracentesis alone is often ineffective. Management may require (1) drainage with thoracostomy tube, often with the administration of fibrinolytics, (2) placement of an indwelling pleural catheter, or (3) surgical decortication. The risk of additional procedures and chest tube drainage must be balanced with the risks of the development of lung entrapment potentially necessitating reoperation for decortication or development of a fibrothorax. (See 'Pleural fibrosis and pleuroparenchymal fibroelastosis (PPFE)' below.)

•Thoracostomy tube placement +/- fibrinolytics – Thoracostomy tube placement with administration of intrapleural fibrinolytics following lung transplant appears to be safe and without increased risk of bleeding or infection [11,14]. Pleurodesis via thoracostomy tube is not recommended in these patients, as their immunosuppressed status blunts the inflammatory response to agents such as talc or doxycycline and places them at increased risk of empyema [17].

•Indwelling pleural catheter placement – Use of indwelling pleural catheters for persistent pleural effusions has become more common in post lung transplant patients. One retrospective analysis followed 71 lung transplant recipients after placement of indwelling pleural catheters during the first year after transplant (median 60 days post-transplant) [28]. Eight (11 percent) of patients developed a complication, including five (7 percent) with pleural infection comparable to published infection rates in nonimmunosuppressed patient populations. The autopleurodesis rate was very high (85 percent), allowing for catheter removal in most patients between 30 and 90 days after placement. No patient required surgical decortication.

•Surgical decortication – Lung transplant recipients with longstanding pleural effusions are at risk of the development of a fibrothorax and a chronic decrease in allograft function. In a large retrospective single-center case series, 77 patients required surgical decortication following lung transplant; this represented 16 percent of patients with pleural complications and 7 percent of the total lung transplant population [29]. The most common indications for decortication included loculated, persistent, or recurrent pleural effusions (56 percent), fibrothorax (20 percent), empyema (13 percent), and hemothorax (11 percent). Outcomes were overall favorable, with 88 percent of patients achieving full lung expansion following the surgical procedure and an approximately 10 percent improvement in spirometry during the first year after surgery. Approximately 36 percent of patients undergoing decortication experienced a complication (eg, transfusion, prolonged intubation, respiratory failure), 12 percent required repeat thoracic surgical intervention, and the 30-day in-hospital mortality rate was 5 percent.

Based on these data, surgical decortication is a reasonable strategy to improve allograft function by re-expanding trapped lung, but it does carry significant perioperative risks. Earlier surgical intervention is recommended in the setting of recurrent effusions despite other measures to avoid the development of a fibrothorax, in which case there is a greater risk of extensive bleeding and lack of meaningful lung expansion.

Hemothorax — Hemothorax typically occurs in the immediate postoperative period. Lung transplant recipients are at increased risk for hemothorax given the need for dissection of vascular adhesions to remove the native lung, which can often result in surface oozing; cardiopulmonary bypass with anticoagulation further increases the risk [17]. Close observation of output from the thoracostomy tubes in the immediate postoperative period is important. When significant blood output is observed, spontaneous cessation is unlikely and the risk of retained blood in the pleural space is an important consideration that must be weighed with risks of another surgical procedure and the likelihood of identifying a source of bleeding that can be addressed with early reoperation.

Up to 15 percent of lung transplant recipients have been found to have residual blood in the pleural space [2,16]. Retained blood or a residual hemothorax can serve as a nidus for infection or lead to additional pleural complications such as trapped lung or fibrothorax. (See 'Pleural fibrosis and pleuroparenchymal fibroelastosis (PPFE)' below.)

Pneumothorax — Pneumothoraces post-transplant may occur in a variety of settings:

●Undersized donor lung – Initially post-transplant, the implanted donor lung size may be smaller than the thoracic cavity, thus resulting in residual air in the pleural space [30]. These pneumothoraces are usually small, clinically insignificant, and resolve within days to a few weeks. By one week post-transplant, there appears to be no significant difference in pleural complications between recipients of undersized lungs [31]. In a case series, negative pressure drainage of the pleural space in recipients with undersized donor lungs and poor chest wall compliance resulted in detrimental effects (eg, hyperinflation, decreased elastic recoil, increased airway pressure) during positive pressure ventilation [32]. Thus, complete evacuation of residual air in the pleural space in recipients with undersized donor lungs may not be necessary and may be deleterious.

●Anastomotic leak – A pneumothorax may result from air leaking from the site of the bronchial or tracheal anastomosis. Any significant air leak should be carefully evaluated by flexible bronchoscopy for dehiscence at the site of the airway anastomosis [17]. Approximately 10 percent of lung transplant recipients have an air-leak lasting more than two weeks after surgery [2]. Virtually all of these air-leaks resolve with tube thoracostomy alone and require no further intervention [2]. However, rarely a pneumothorax may result from dehiscence of the bronchial anastomosis. This is a more serious complication, often requiring urgent intervention, such as stenting. (See "Airway complications after lung transplantation", section on 'Bronchial necrosis and dehiscence'.)

●Iatrogenic complications – Lung transplant recipients often undergo multiple bronchoscopic procedures usually with transbronchial biopsies to assess for rejection. A pneumothorax is a well described complication of these procedures, although it may occur less frequently than expected because of postoperative pleural adhesions [33-36].

●Infection – Superimposed pathology, such as invasive fungal disease or other lung infection.

●Disease in the native lung – A pneumothorax may develop due to underlying emphysema or other processes in the native lung of a patient who underwent single lung transplant, especially in patients with obstructive or cystic lung disease. These secondary spontaneous pneumothoraces are rarely treated successfully with tube thoracostomy [37]. Both thoracoscopic talc poudrage and thoracoscopic parietal pleurectomy have been successful [38,39].

Empyema — Pleural space infections or empyemas complicate about 3 to 7 percent of lung transplants, and approximately one-quarter of pleural effusions that develop within 90 days of lung transplantation are infected [16,40,41]. Lung transplant recipients may have a blunted clinical presentation of empyema as a result of their immunosuppressed status, and thus a high clinical suspicion is required for all patients. Pleural fluid analysis should therefore always include bacterial, fungal, and mycobacterial cultures, fungal and mycobacterial polymerase chain reaction (PCR), as well as cell count, LDH, protein, glucose, and triglycerides [17,42]. Other tests, such as pleural fluid adenosine deaminase (ADA) and serum beta-D-glucan and galactomannan may be useful. (See "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults", section on 'Diagnosis' and "Diagnosis of invasive aspergillosis", section on 'Diagnostic modalities' and "Bacterial infections following lung transplantation" and "Fungal infections following lung transplantation".)

In a study of 455 lung transplants, fungal, bacterial, and mycobacterial pathogens accounted for 61, 25, and 8 percent of pleural infections, respectively [40]. Candida albicans was the predominant organism. Empyemas secondary to tuberculosis, Scopulariopsis, and Mycoplasma hominis have been described [40,43,44]. Occasionally, unusual organisms can be donor derived [43].

Patients with pleural space infections have a significantly diminished one year survival compared to those without infection (67 percent versus 87 percent, respectively) [40].

Chylothorax — Chylothorax is the accumulation of chyle (ie, lymphatic fluid) in the pleural space and may occur as an early or late complication of single or bilateral lung transplantation [45]. This is a rare occurrence, generally having been reported in less than 1 percent of recipients [2,16,17,46]. The fluid is characterized by lymphocytosis, a triglyceride level greater than 110 mg/dL, and the presence of chylomicrons. Chylothorax may occur after lung transplant due to disruption of the thoracic duct or its tributaries with chyle leakage into the pleural space [45]. In patients who undergo lung transplant for lymphangioleiomyomatosis, chylothorax may result from leakage of chylous ascites across the diaphragm or more diffuse leakiness of the thoracic lymphatics [45,47,48]. (See "Etiology, clinical presentation, and diagnosis of chylothorax" and "Sporadic lymphangioleiomyomatosis: Treatment and prognosis", section on 'Chylothorax and chylous ascites'.)

Several treatment modalities are utilized for chylothorax, including octreotide infusion, pleurodesis, thoracic duct ligation, oral aminocaproic acid, and pleuroperitoneal and pleurovenous shunting [17,48-52]. For patients with chylothorax following lung transplant for lymphangioleiomyomatosis, sirolimus therapy has been utilized successfully to ameliorate the effusion, although initiation of sirolimus should be delayed for three or more months until the airway anastomosis has completely healed [50,51]. (See "Management of chylothorax".)

Pleural fibrosis and pleuroparenchymal fibroelastosis (PPFE) — The development of pleural fibrosis following lung transplant has been observed for many years [53-56].

●Pleural fibrosis – Lung transplant recipients with a hemothorax or longstanding pleural effusion may develop a fibrothorax that can restrict lung expansion and reduce long-term allograft function and survival [14]. The role of decortication was examined in a series of 1039 lung transplant recipients, in whom 84 decortication procedures were performed for persistent or recurrent pleural effusions (56 percent), fibrothorax (20 percent), empyema (13 percent), and hemothorax (11 percent) [29]. Among those who underwent thoracoscopic decortication (52 patients), full lung expansion was achieved in 90 percent. For the group overall, forced expiratory volume in one second increased from 50 to 60 percent of predicted in the first year after decortication and survival was 87, 68, and 48 percent at one, three, and five years, respectively, after decortication.

●PPFE – Pleural fibrosis can also represent a form of restrictive CLAD with features of PPFE. An experimental study of heart-lung transplants shed some light on the mechanisms that may be involved [54]. Pleural fibrosis developed in animals who received allografts but not in those who received autografts (their own heart-lung bloc). This observation suggests that chronic rejection, not the surgery, was responsible for the pleural fibrosis. A restrictive phenotype of CLAD, restrictive allograft syndrome, is characterized by (sub)pleural thickening on chest CT scan and pathologic findings of pleural fibrosis and PPFE [55,56]. On computed tomography, the features of PPFE include upper lobe predominant pleural thickening with adjacent areas of subpleural consolidation and volume loss [57]. Histopathologic findings in PPFE include upper lobe pulmonary fibrosis with intra-alveolar fibrosis and alveolar septal elastosis [57]. No proven treatment for PPFE exists. Increasing immunosuppression has been associated with increased risk of infection. Clinical trials are currently ongoing studying the use of the antifibrotic medication pirfenidone [58,59].

INTERPLEURAL COMMUNICATION — Interpleural communication can be a consequence of heart-lung transplantation (HLT) and sequential bilateral lung transplantation performed through bilateral anterolateral thoracotomies and transverse sternotomy (clam-shell) due to severing of the anterior pleural reflections. The interpleural communication allows air or fluid to move between the pleural spaces [60-63]. This phenomenon persists for more than two years after HLT [61,62] and is most likely permanent. (See "Clinical presentation and diagnosis of pneumothorax", section on 'Pneumothorax appearance and types'.)

Awareness of the interpleural communication after transplant is important because pleural disease in these recipients must be managed aggressively.

●Empyemas need to be diagnosed early and drained promptly, so that infected pleural contents do not contaminate the contralateral pleural space.

●A tension pneumothorax in such recipients is likely to be bilateral and therefore life-threatening.

●A single thoracostomy tube may be sufficient to drain bilateral pneumothoraces when an interpleural communication is present [24,64].

SUMMARY AND RECOMMENDATIONS

●Risk factors for pleural complications – Pre-existing pleural space abnormalities can place lung transplant recipients at increased risk for pleural complications, especially bleeding due to lysis of adhesions at the time of surgery. However, the overall long-term outcome of lung transplantation does not appear to be adversely affected by a previous pleural disease or interventions. Donor size mismatch can lead to pleural problems such as pneumothorax, pleural effusion, and empyema. (See 'Risk factors for pleural complications' above.)

●Early postoperative pleural effusions – Following lung transplant, pleural effusions have been reported in up to 100 percent of patients. Potential causes include increased alveolar capillary permeability (because of allograft ischemia, denervation, and subsequent reperfusion) and disruption of lymphatic flow due to severance of allograft lung lymphatics. Most postoperative pleural effusions resolve within 14 days with tube thoracostomy drainage. (See 'Pleural effusions' above.)

●Persistent or recurrent pleural effusions – Persistent or recurrent pleural effusions may develop post lung transplant, associated with acute cellular rejection. These effusions are typically exudative and lymphocytic (eg, 90 percent lymphocytes). (See 'Pleural effusions' above and "Evaluation and treatment of acute cellular lung transplant rejection".)

Occasionally, pleural effusions in lung transplant recipients may become loculated, leading to entrapment of the lung allograft. Management may require drainage with thoracostomy tube, indwelling pleural catheter, or surgical decortication. (See 'Pleural effusions' above.)

●Hemothorax – Hemothorax can occur in the immediate postoperative period and is usually due to bleeding from adhesions that were lysed when the native lung was removed or from coagulopathy. Blood should be evacuated from the pleural space as completely as possible to avoid compromise of ventilation or later problems with lung entrapment. Early reoperation may be required to stop pleural bleeding. (See 'Hemothorax' above.)

●Pneumothorax – Pneumothoraces can result from a variety of etiologies from anastomotic leaks to iatrogenic complications of procedures. Most immediate post-transplant pneumothoraces resolved within a few days to weeks, however a significant air leak should prompt rapid evaluation for anastomotic dehiscence. (See 'Pneumothorax' above and "Airway complications after lung transplantation".)

●Empyema – Empyema has been associated with increased mortality in post lung transplant recipients, and a high clinical suspicion is required in the evaluation of these immunosuppressed patients. (See 'Empyema' above.)

●Pleural fibrosis and pleuroparenchymal fibroelastosis (PPFE) – Pleural fibrosis and PPFE may occur in chronic lung rejection as one manifestation of chronic lung allograft dysfunction (CLAD). (See 'Pleural fibrosis and pleuroparenchymal fibroelastosis (PPFE)' above.)

●Risks of interpleural communication – Interpleural communication is typically present after heart-lung transplantation and after sequential bilateral lung transplantation performed through bilateral anterolateral thoracotomies or transverse sternotomy (clam-shell). The significance of this communication is that a tension pneumothorax is likely to be bilateral and pleural space infection can be transmitted to the contralateral side. (See 'Interpleural communication' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc A Judson, MD and Steven Sahn, MD, who contributed to earlier versions of this topic review.