Pulmonary Medicine

Non-Infectious Complications of Lung Transplantation

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What every physician needs to know:

Lung transplantation is an established therapeutic option for select patients with advanced lung disease. It offers recipients the potential for dramatic improvement in lung function, exercise capacity, and quality of life. According to the 2016 report of the International Society for Heart and Lung Transplantation (ISHLT), nearly 4000 adult lung transplants are now performed annually. The median survival rate in the recent years is 5.7 years. However, there is a marked difference in survival rates according to the type of transplant procedure, with a median survival of 7.3 years for bilateral lung transplant (BLT) recipients compared to 4.6 years for those who underwent a single lung transplant (SLT) procedure. The recipients who survived for 1 year after primary transplant had a conditional median survival of 8 years (9.8 years for bilateral recipients and 6.4 years for single lung recipients). This chapter reviews the non-infectious complications of lung transplantation.

Classification:

Non-infectious complications can be classified into several broad categories:

  • Technical (i.e., related to surgery)

    • primary graft dysfunction

    • phrenic nerve injury

  • Airway

    • Dehiscence

    • Stenosis

  • Rejection

    • hyperacute

    • acute cellular

    • acute humoral

    • chronic lung allograft dysfunction (CLAD)

      • Restrictive allograft dysfunction

      • Obstructive allograft dysfunction

  • Post-transplant lymphoproliferative disorder (PTLD)

Are you sure your patient has a non-infectious complication of lung transplantation? What should you expect to find?

Primary graft dysfunction (PGD)

PGD refers to the development of noncardiogenic pulmonary edema in the lung allograft(s) within seventy-two hours of transplantation in the absence of identifiable causes. PGD is characterized by the presence of diffuse radiographic opacities in the allografts and hypoxemia. PGD is a diagnosis of exclusion; the condition usually occurs hours to 3 days after LT, whereas rejection and infection are more common after the first 24 hours. The severity of PGD is graded according to the magnitude of reduction in the PaO2/FIO2 ratio as follows: grade 1 (P/F > 300); grade 2 (P/F 200-300); grade 3 (P/F < 200). When the acute lung injury definition of acute respiratory distress syndrome (ARDS)—a PaO2/FIO2 ratio of less than 200—is used to define the most severe form of PGD (grade 3), it is estimated that as many as 5% to 25% of transplant recipients can develop PGD (grade 3).

Phrenic nerve injury

Unilateral phrenic nerve injury with attendant diaphragmatic paralysis is often asymptomatic in bilateral lung transplant recipients with otherwise normal allograft function. Phrenic nerve injury manifests only as elevation of the hemidiaphragm on chest x-ray. By contrast, single-lung transplant recipients with ipsolateral phrenic nerve injury and bilateral recipients with injury to both phrenics are typically symptomatic with manifestations that include difficulty in weaning from mechanical ventilation due to low tidal volumes and hypercapnia, dyspnea, and orthopnea. Clinically this can be also suspected in lung transplant recipients who have paradoxical breathing on the spontaneous breathing trials. For patients who do not require ventilation, the diagnosis of phrenic nerve dysfunction can be made with a fluoroscopic “sniff test,” and more recently with the use of bedside ultrasound. If the injury is the result of stretching of the phrenic nerve or trauma to the nerve during the surgical procedure but the nerve is not completely transected, a slow recovery can be anticipated. Complete transection is rare, but the damage is permanent. Diaphragmatic plication or pacing can be performed in some cases.

Airway complications

Because of the lack of revascularization of bronchial circulation, anastomotic complications, such as bronchial dehiscence, bronchial stenosis, and bronchial infection, are the main airway complications reported in the first few weeks to months after LT. Most recent series suggest a range of 7% to 18%, with a related mortality rate of 2% to 4%. Airway complications can be classified as early or late and they assume two general forms: bronchial anastomotic dehiscence and airway stenosis. Bronchial dehiscence may cause prolonged air leaks in the early post-transplantation period. In some cases, the dehiscence may also lead to infection or the formation of peribronchial abscesses or fistulas. The results of chest radiographs and computed tomography (CT) scans are usually nonspecific; however, the appearance of extraluminal air on chest CT scans is very sensitive and specific for the diagnosis of anastomotic dehiscence. It should be suspected in a lung transplant patient who develops a spontaneous pneumothorax or pneumomediastinum within the first few weeks after transplantation. When extensive, bronchial dehiscence can present with or lead to mediastinitis, pneumothorax, hemorrhage, and death.

Bronchial stenosis, which also typically presents within the first 3 months after transplantation, can result from excessive granulation tissue, fibrous stricture, or bronchomalacia. It is usually the result of surgical complications, ischemia, or infections of the bronchial anastomosis. Bronchial stenosis may also be seen on chest radiographs or CT scans, or by bronchoscopy. The most common site of narrowing is at the bronchial anastomosis, but fibrous strictures can also occur in more distal parts of the airway. Clues to the presence of significant bronchial narrowing include dyspnea, focal wheezing on the involved side, recurrent episodes of pneumonia or purulent bronchitis, and suboptimal spirometric values.

Hyperacute rejection

Hyperacute rejection is a rare and often fatal complication that occurs within minutes to hours of implantation of the allograft. The allograft appears dusky, mottled, grossly edematous on direct inspection, and densely consolidated on chest x-ray. Copious amounts of pink, frothy pulmonary edema fluid are often apparent in the endotracheal tube. The patient is profoundly hypoxemic and may demonstrate hemodynamic instability.

Acute rejection

As many as 50% of patients experience acute rejection during the first postoperative month, and as many as 75% will experience at least one episode of acute rejection within the first year. Episodes may be clinically silent in up to 40 percent of cases and detected only on surveillance biopsies. When clinically evident, manifestations are nonspecific and include low-grade fever, dyspnea, and cough. A less common form of acute rejection, mediated by donor-specific anti-HLA antibodies, may present in a clinically indistinguishable manner. Hemoptysis, present in 25 percent of cases of acute humoral rejection, provides an important clue. Acute rejection usually does not occur as frequently after the first postoperative year.

Chronic Lung Allograft Dysfunction

Chronic lung allograft dysfunction (CLAD) encompasses varied presentations of progressive allograft dysfunction with obstructive and restrictive physiology. The most common form of CLAD has been equated with the histologic finding of obliterative bronchiolitis (OB); and this form of chronic rejection is a primary cause of morbidity and mortality after LT and the leading single cause of death more than 1 year after transplantation. OB has been defined clinically by an obstructive functional defect and histologically by obliteration of terminal bronchioles. OB generally occurs at a mean of 16 to 20 months after LT, but it has been reported as early as 3 months after transplantation. More than 50% of recipients will experience some degree of OB within 5 years after transplantation. It typically presents with insidious onset of dyspnea on exertion, often accompanied by cough and recurrent episodes of bronchitis. The functional hallmark of BOS is a sustained drop in FEV1 with an obstructive pattern on spirometry.

A less common form of CLAD, restrictive allograft syndrome (RAS), contributes to approximately 25% to 35% of the reported cases and carries a worse prognosis than BOS. It is characterized by various stages of diffuse alveolar damage and extensive fibrosis in the alveolar interstitium, visceral pleura, and interlobular septae. RAS presents radiologically as upper lobe dominant fibrosis and/or interstitial opacities, sometimes often with associated pleural thickening and with a restrictive pattern in the lung function tests (TLC below 90% of the best baseline post-transplant).

PTLD

In most cases, PTLD encompasses a spectrum of abnormal proliferative responses involving B cells, ranging from benign polyclonal hyperplasia to malignant lymphoma. The incidence of PTLD after LT reportedly ranges from 1.8% to 9.4% . In approximately 90 percent of cases, Epstein-Barr virus can be detected as the stimulus for B cell proliferation. PTLD usually presents with one or more nodules or masses in the allografts, often accompanied by intrathoracic adenopathy. The gastrointestinal tract is another common site of involvement, presenting with bowel obstruction, gastrointestinal bleeding, or bowel perforation. Involvement of the central nervous system and widely disseminated disease are encountered less frequently.

The incidence of PTLD is greatest in the first post-transplant year, but up to half of all cases develop beyond this point. The majority of early-onset (< 1 year) cases involve the lungs, while gastrointestinal and disseminated forms of disease predominate in late-onset cases.

Beware: there are other diseases that can mimic non-infectious complications of lung transplantation.

Primary graft dysfunction

Other causes of radiographic infiltrates in the early post-operative period that must be excluded are volume overload, pneumonia, aspiration, atelectasis, hyperacute rejection, localized pulmonary edema resulting from stenosis of one or multiple pulmonary vein anastomosis, and a pulmonary venous outflow obstruction.

Airway complications

Bronchial stenosis is in the differential of disorders that lead to airflow obstruction after lung transplantation. The other disorder that can produce a similar pattern on PFTs is acute rejection or later bronchiolitis obliterans syndrome (BOS), but this disorder does not typically present until after the first year. Occasionally, viral bronchiolitis causes airflow obstruction.

Hyperacute rejection

Hyperacute rejection must be distinguished from other disorders that cause severe allograft dysfunction within minutes to hours after transplantation. These other disorders include volume overload, aspiration, pneumonia, cardiogenic pulmonary edema, and pulmonary venous outflow obstruction.

Acute rejection

Acute rejection must be distinguished from pneumonia, pleural effusion, or pneumothorax, with which it often shares the features of hypoxemia, drop in PFT values, and pulmonary infiltrates.

BOS

BOS is a diagnosis of exclusion. Other disorders that can present with airflow obstruction on PFTs include bronchial stenosis and viral bronchiolitis.

PTLD

Radiographically, PTLD may appear similar to certain infections that present with a nodular character, such as those that are due to aspergillus, mycobacteria, actinomycosis or nocardia. On small tissue specimens, such a transbronchial lung biopsies, PTLD must be distinguished from the aggregates of normal lymphoctyes that are associated with acute cellular rejection.

How and/or why did the patient develop a non-infectious complication of lung transplantation?

Primary graft dysfunction

PGD is assumed to result from ischemia-reperfusion injury to the allograft. Other possible contributing factors include inflammatory events triggered by donor brain death, surgical trauma, and lymphatic disruption.

Phrenic nerve injury

Injury to the phrenic nerve can result from intraoperative traction, thermal damage associated with use of an iced slurry to cool the allograft in the chest cavity prior to reperfusion, or more commonly inadvertent surgical transection in the setting of extensive adhesions and difficult hilar dissection.

Airway complications

Bronchial dehiscence and bronchial stenosis are believed to be manifestations of an underlying ischemic insult to the airways. The bronchial anastomosis and the recipient airway are particularly prone to ischemic injury because of interruption of the bronchial arterial supply at the time of transplantation that means that the airway is dependent on collaterals from the low pressure pulmonary venous bed. Blood flow can be further limited by perioperative hypotension. Risk factors for airway complications include ischemia of the donor bronchus during the post-transplant period due to loss of bronchial blood flow, surgical techniques for the anastomosis, length of the donor bronchi, acute rejection, and bronchial infections.

Hyperacute rejection

Hyperacute rejection is mediated by preformed antibodies of recipient origin that are directed against HLA antigens on donor tissue. The pulmonary microvascular endothelium is the principle target of these antibodies, leading to complement activation, neutrophil-mediated damage, and widespread deposition of platelet fibrin thrombi.

Acute rejection

Acute cellular rejection, which is the principle manifestation of recipient alloimmmunity against the donor allograft, is mediated by activated recipient T lymphocytes. Risk factors for acute rejection are poorly defined, but HLA mismatches may be correlated with its occurrence as well as the occurrence of viral infections, particularly cytomegalovirus (CMV) pneumonia.

BOS

BOS reflects the presence of underlying injury to the small airways, which injury leads to fibroproliferative obliteration of the airway lumen. The causes of and risk factors for OB remain unclear. Several possible risk factors have been proposed, including uncontrolled acute rejection, lymphocytic bronchiolitis, CMV pneumonitis, CMV infection without pneumonitis, community acquired respiratory viruses, gastroesophageal reflux disease, PGD, antibody-mediated rejection, HLA-A mismatches, total HLA mismatches, absence of donor antigen-specific hyporeactivity, non-CMV infection, older donor age, and bronchiolitis obliterans with organizing pneumonia. The most consistently identified risk factor is acute rejection, particularly in those patients who experience recurrent, high-grade episodes of acute rejection.

PTLD

In the majority of cases, PTLD is a consequence of Epstein-Barr virus infection, which drives the proliferation of B cells. This process continues unchecked because of impaired or absent Epstein-Barr virus-specific cytotoxic T cell response in the immunosuppressed patient.

Which individuals are at greatest risk of developing a non-infectious complication of lung transplantation?

Primary graft dysfunction

A number of risk factors for development of PGD have been identified. Donor risk factors include female gender, African-American race, older age, and low donor P/F ratio. Elevated levels of interleukin-8 in bronchoalveolar lavage fluid from the donor have been associated with an increased risk of severe PGD. Recipient risk factors include an underlying diagnosis of idiopathic pulmonary arterial hypertension, as well as the presence of secondary pulmonary hypertension independent of diagnosis. An association between graft ischemic time and PGD has not been consistently demonstrated; rather than a linear relationship, ischemic time may become a major factor only when it exceeds a certain threshold, suggested to be beyond six hours.

Phrenic nerve injury

The reported incidence of phrenic nerve injury ranges from 3 percent to 30 percent, depending on whether screening is restricted to clinically suspected cases or to all recipients. While risk factors have not been rigorously identified, this complication is most likely to occur in the setting of a difficult surgical explantation of the native lung because of mediastinal adhesions. Such technical challenges are commonly, albeit not exclusively, posed by patients with cystic fibrosis and sarcoidosis.

Airway complications

Patients who demonstrate evidence of significant ischemic injury on initial postoperative bronchoscopy are at greatest risk for developing subsequent airway complications. Risk factors for airway complications include ischemia of the donor bronchus during the post-transplant period due to loss of bronchial blood flow (only the pulmonary vessels are revascularized during LT surgery), surgical techniques for the anastomosis, length of the donor bronchi, acute rejection, and bronchial infections.

Hyperacute rejection

Hyperacute rejection is seen exclusively in recipients who have preformed antibodies to HLA antigens that are present in the donor. Such preformed antibodies are the result of prior blood transfusions, pregnancies, or transplantation. The complication is rarely encountered because of the universal practices of screening for anti-HLA antibodies in all candidates and of avoiding donors who have incompatible antigens.

Acute rejection

Risk factors for acute cellular rejection are not well defined. Studies conflict on whether the degree of HLA discordance between donor and recipient represents a risk factor. Polymorphisms in toll like receptor 4 that lead to down-regulation of innate immunity have been associated with a decreased incidence of acute rejection. Acute humoral rejection is encountered in some patients who develop donor-specific anti-HLA antibodies de novo following transplantation.

BOS

Frequent or severe episodes of acute cellular rejection have been consistently identified as the major risk factor for subsequent development of BOS, supporting the view that BOS is a consequence of alloimmune injury. However, non-immune factors, including CMV pneumonitis, lower respiratory tract infections that are due to community viral pathogens, silent aspiration from gastroesophageal reflux, and primary graft dysfunction, have also been implicated as risk factors for BOS.

PTLD

Recipients who have never had Epstein-Barr virus and who develop primary infection from an Epstein-Barr virus-infected organ are at greatest risk for developing PTLD. Use of higher-intensity immunosuppression and, in particular, use of anti-lymphocyte globulin, have also been implicated as risk factors.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Hyperacute rejection

Demonstration of donor-specific anti-HLA antibodies in serum or incompatibility on retrospective cross-matching is important in supporting a diagnosis of hyperacute rejection. Pathology specimes are usually not available in these events.

Acute rejection

Demonstration of donor-specific anti-HLA antibodies in serum is important in supporting a diagnosis of acute humoral rejection.

PTLD

Some studies suggest that measurement of Epstein-Barr viral load in peripheral blood may be a useful diagnostic tool. However, the available assays have not been standardized, and uniform thresholds for positive results have not been established, limiting the utility of these techniques.

What imaging studies will be helpful in making or excluding the diagnosis of a non-infectious complication of lung transplantation?

Primary graft dysfunction

Chest radiographs are the most important screening test for PGD, as the presence of diffuse pulmonary infiltrates involving the allograft (and, in the case of single-lung transplantation, sparing the native lung) is necessary to establish a diagnosis.

Phrenic nerve injury

Demonstration of an elevated hemidiaphragm, often with associated basilar atelectasis, is suggestive of phrenic nerve injury and diaphragmatic paralysis. The diagnosis can be confirmed by either fluoroscopic or ultrasound observation of diaphragmatic excursion with tidal breathing and the "sniff" maneuver.

Airway complications

The presence of a pneumothorax or pneumomediastinum on chest x-ray or chest CT should alert the clinician to the possible development of bronchial dehiscence. Bronchial stenosis can sometimes be detected on CT scan, particularly with use of multi-slice image acquisition and three-dimensional airway reconstruction.

Hyperacute rejection

A chest x-ray demonstrating extensive opacification of the allografts within hours of transplantation should raise concern about possible hyperacute rejection.

Acute rejection

Chest x-ray and chest CT findings in acute cellular rejection, which include interstitial, ground-glass, or alveolar opacities, are non-specific. Pleural effusions or pneumothorax may be the only abnormality or may accompany parenchymal opacities.

BOS

BOS is not associated with significant findings on chest x-ray, other than hyperinflation in association with advanced airflow obstruction. In contrast, chest CT can provide helpful clues to the presence of BOS. The most characteristic finding is air trapping on expiratory imaging, but other findings include tree-in-bud opacities and areas of bibasilar bronchiectasis.

PTLD

Chest x-ray and CT are useful in detecting the presence of intrathoracic PTLD. Single or multiple nodules or masses are most characteristic and are often accompanied by mediastinal or hilar adenopathy. Cavitation of parenchymal lesions is distinctly uncommon and should prompt consideration of alternative diagnoses, such as invasive fungal or nocardial infection. Pleural effusions are also uncommon.

CT scan of the abdomen is useful in demonstrating gastrointestinal involvement, which can present as diffuse bowel-wall thickening, bowel obstruction, discrete ulceration, or perforation. The stomach, small intestine, and colon are all potential sites of involvement.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of a non-infectious complication of lung transplantation?

Airway Complications

The development of airflow obstruction on spirometry within the first several months following transplantation in a bilateral recipient or single-lung recipient with native lung fibrotic lung disease strongly suggests the possibility of bronchial stenosis. Flattening of the expiratory limb of the flow volume loop, a pattern consistent with variable intrathoracic obstruction is an important clue that distinguishes bronchial stenosis from other forms of airflow obstruction (e.g., BOS).

Acute rejection

Lung transplant recipients are typically instructed to monitor their lung function via a microspirometry device at home and to undergo formal spirometry with each clinic visit. Within the first 6-12 months after transplantation, an abrupt decline in FEV1 and FVC by at least 10 percent should alert the clinician to the possible presence of acute rejection, but similar findings also accompany infectious events.

BOS

Spirometry is an essential component in establishing a diagnosis of BOS. Because the characteristic histology of bronchiolitis obliterans is difficult to demonstrate on transbronchial lung biopsy, spirometry is used as the "gold standard" surrogate marker. BOS was originally defined as an otherwise unexplained and sustained drop in FEV1 by more than 20 percent from post-transplant baseline levels. Recently, the designation of "BOS-potential" was added to identify patients with a decline in FEV1 between 10-20 percent who are at risk of progressing to more advanced and possibly less treatable stages.

What diagnostic procedures will be helpful in making or excluding the diagnosis of a non-infectious complication of lung transplantation?

Primary graft dysfunction

PGD is a diagnosis of exclusion. In cases of suspected PGD, bronchoscopy may be helpful in excluding pneumonia and aspiration of gastric contents. Transesophageal echocardiography is useful in visualizing the pulmonary veins and excluding pulmonary venous outflow obstruction. Measurement of pulmonary artery occlusion pressure via a pulmonary artery catheter is important when volume overload or cardiogenic pulmonary edema is suspected.

Phrenic nerve injury

As above, observation of the direction and magnitude of diaphragmatic excursion by either fluoroscopy or ultrasound is an important non-invasive means of diagnosing phrenic nerve injury. In equivocal cases, phrenic nerve conduction studies and diaphragmatic electromyography can often provide a definitive diagnosis

Airway complications

See previous sections for the role of imaging and spirometry in suggesting the presence of bronchial dehiscence and stenosis. The definitive procedure is bronchoscopy, which allows direct visualization of the bronchial anastomosis and more distal bronchial tree.

Hyperacute rejection

Surgical lung biopsy, the definitive means of establishing a diagnosis of hyperacute rejection, is often impractical because of the presence of severe hypoxemic respiratory failure. Therefore, the diagnosis of hyperacute rejection often rests on a compatible clinical picture and time course, demonstration of an incompatible retrospective cross-match or donor-specific anti-HLA antibodies in the serum of the recipient, and exclusion of other entities that cause immediate postoperative allograft opacification.

Acute rejection

Bronchoscopy with transbronchial lung biopsy is the procedure of choice in diagnosing acute cellular rejection. Transbronchial lung biopsies may also provide a diagnosis of acute humoral rejection, but larger tissue specimens provided by surgical lung biopsy may be necessary to demonstrate the characteristic changes.

BOS

The diagnosis of BOS is based on demonstration of a drop in FEV1, typically in a pattern of airflow obstruction, in the absence of other causes. Transbronchial lung biopsies have an extremely low yield in demonstrating the histological changes of bronchiolitis obliterans, bronchoscopy is performed to exclude other causes of allograft dysfunction (bronchial stenosis, infection, rejection), rather than to diagnose BOS.

PTLD

Video-assisted thoracoscopic lung biopsy provides the most definitive means of diagnosing PTLD involving the lung allografts. Less invasive approaches, such as transbronchial biopsies, transbronchial needle aspiration of mediastinal lymph nodes, and CT-guided percutaneous needle aspiration, are limited by the small biopsy or cytology samples they provide, but the yield can be enhanced through use of flow cytometry and immunohistochemical staining for the presence of Epstein-Barr virus.

Depending on the site of involvement, upper endoscopy or colonoscopy can sometimes establish the diagnosis of gastrointestinal PTLD. When the initial presentation is bowel obstruction or perforation, the diagnosis is typically established at the time of surgical exploration.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of a non-infectious complication of lung transplantation?

Primary graft dysfunction

Surgical lung biopsy is rarely indicated to establish a diagnosis of PGD. When the diagnosis has been obtained through surgical lung biopsy, the prevailing histological pattern is diffuse alveolar damage.

Hyperacute rejection

Characteristic histopathologic findings in hyperacute rejection include a neutrophilic interstitial infiltrate, widespread platelet and fibrin thrombi in the microvasculature, and demonstration of antibody and C4D complement deposition on the endothelial surface by immunohistochemical staining.

Acute rejection

The histological hallmark of acute cellular rejection is the presence of a lymphocytic infiltrate surrounding the capillaries and venule and (in more advanced cases) spilling over into the alveolar interstitium. Lymphocytic bronchiolitis may accompany the parenchymal infiltrates or may be an independent feature. In severe acute cellular rejection, there can be evidence of acute lung injury in the form of diffuse alveloar damage ().

See Table I for the Histological Classification of Acute Rejection.

Table I.

Histological Classification of Acute Rejection

Histological Classification of Acute Rejection

Lymphocytic bronchiolitis:

  • Grade 0—none

    In Grade B0 there is no evidence of bronchiolar inflammation

  • Grade 1R—low grade

    There are mononuclear cells within the sub-mucosa of the bronchioles, which can be infrequent and scattered or forming a circumferential band. Occasional eosinophils may be seen within the sub-mucosa. There is no evidence, however, of epithelial damage or intra-epithelial lymphocytic infiltration.

  • Grade 2R—high grade

  • Grade B2R (High-grade Small Airway Inflammation)

    In Grade B2R the mononuclear cells in the sub-mucosa appear larger and activated, with greater numbers of eosinophils and plasmacytoid. In addition, there is evidence of epithelial damage in the form of necrosis and metaplasia and marked intraepithelial lymphocytic infiltration. In its most severe form, high-grade airway inflammation is associated with epithelial ulceration, fibrino-purulent exudate, cellular debris, and neutrophils.

  • Grade BX (Ungradeable Small Airways Inflammation)

In Grade BX the changes are ungradeable due to sampling problems, infection, tangential cutting, artifact, etc.

Acute humoral rejection presents histologically as a neutrophilic capillaritis with CD4 deposition on the endothelial cell surface.

BOS

The histological pattern underlying BOS is bronchiolitis obliterans, appearing as submucosal deposition of collagen that narrows and ultimately obliterates the airway lumen. Since transbronchial lung biopsies are usually insufficient to demonstrate this pathology, the diagnosis of BOS rests on spirometric, not histological, abnormalities.

See Table II for BOS Stage Classification.

Table II.

BOS Classification

*Each stage is divided into “a and b,” where a is without histologic diagnosis and b is with histologic diagnosis. Adapted from the ISHLT staging system.

PTLD

Examination of tissue specimens provides the most definitive means of diagnosing PTLD. Histologically, PTLD can be divided into polymorphic and monomorphic subtypes. In polymorphic PTLD, the cellular population includes lymphocytes in varying stages of maturation and B cells that are admixed with reactive T cells. Monomorphic PTLD appears as sheets of clonal B cells of uniform appearance.

Demonstration of Epstein-Barr virus RNA by in situ hybridization techniques is helpful in confirming the diagnosis, particularly when dealing with small tissue biopsies (e.g., transbronchial biopsies) or cytological specimens. Because not all cases of PTLD are due to Epstein-Barr virus, negative in situ hybridization testing does not exclude the diagnosis. Cytogenetic studies should be performed on tissue and cytological specimens to establish the monoclonal nature of the B cell (or in rare cases, T cell) population. It is essential to determine whether the B cells are CD20 positive, as this information will enter into decisions about treatment.

If you decide the patient has a non-infectious complication of lung transplantation, how should the patient be managed?

Primary graft dysfunction

PGD is managed supportively with diuretics and mechanical ventilation, often with protective ventilatory strategies. Because endogenous nitric oxide (NO) activity decreases after LT, there are several reports of the use of inhaled NO for hypoxemia and for pulmonary hypertension as a consequence of graft dysfunction after transplantation. However, in one randomized, placebo-controlled trial (84 patients), the prophylactic inhalation of NO 10 minutes after reperfusion and for a minimum of 6 hours was not shown to be beneficial for hemodynamic variables, reperfusion injury, oxygenation, time to extubation, length of intensive care or hospital stay, or 30-day mortality. The use of artificial surfactant replacement has also been examined. An open randomized prospective trial studying the use of instilled bovine surfactant immediately after establishment of the bronchial anastomosis showed improved oxygenation and decreased PGD, shortened intubation time, and enhanced early post-LT recovery in the treatment group, although an unusually high incidence of PGD was found in the control group. ECMO is also used for severe PGD unresponsive to protective lung ventilation, with a hospital survival rate of 42% in an analysis by the Extracorporeal Life Support Organization registry study. When used in this setting, ECMO should be initiated early to minimize the complications associated with prolonged mechanical ventilation. Veno-venous ECMO is the most commonly used ECMO for PGD, particularly since PGD usually resolves in a relatively short period of time. Retransplantation has also been performed, but the outcome for patients undergoing retransplantation for PGD has been very poor.

Phrenic nerve injury

In cases associated with significant symptoms (dyspnea, orthopnea) or persistent hypoxemia/hypercapnia, non-invasive mechanical ventilatory support, often used at night, may be helpful. Rarely, diaphragmatic plication may be indicated to relieve symptoms.

Airway complications

Pneumothorax associated with bronchial anastomotic dehiscence should be managed with insertion of a chest tube; when limited in extent, dehiscence will often heal without additional intervention. Previously, extensive dehiscence prompted attempts at surgical repair, but this risky undertaking has largely been supplanted by temporary placement of a bare metal stent to promote formation of granulation tissue to seal the breach. Bronchial stenosis is managed with a variety of bronchoscopic techniques, including balloon dilatation, laser debridement, brachytherapy, and stent placement.

Hyperacute rejection

Therapeutic interventions that have been used to treat hyperacute rejection include plasmapheresis, antilymphocyte globulin, and cyclophosphamide.

Acute rejection

Standard treatment of acute cellular rejection consists of a three-day pulse of methyprednisolone, typically in a dose of 10-15 mg/kg daily, and usually followed by a transient increase and subsequent taper of the maintenance prednisone dose. Some clinicians use a similar prednisone course in lieu of high-dose methylprednisolone for mild, subclinical episodes of acute rejection detected on surveillance biopsies. Anti-lymphocyte globulin is reserved for cases of severe acute cellular rejection refractory to high-dose corticosteroids.

First-line therapy for acute humoral rejection is high-dose intravenous methylprednisolone, identical to what is employed for acute cellular rejection. In refractory cases, plasmapheresis is initiated. Intravenous immunoglobulin (IVIg) and anti-CD20 antibodies (rituximab) have also been used as adjuvant therapy in refractory cases.

BOS

Treatment of BOS once centered on attempts to augment immunosuppression with such interventions as high-dose methylprednisolone, anti-lymphocyte globulin, photopheresis, and total lymphoid irradiation. However, definitive evidence of the efficacy of any of these interventions is lacking, and excessive immunosuppression carries considerable risk of infection. More recently, macrolides have become popular in treating BOS, as the potential beneficial effects of macrolides are believed to relate to their ability to down-regulate airway inflammation, rather than to their antimicrobial effects. Azithromycin is usually prescribed at a dose of 250 mg three times weekly. The only definitive treatment for BOS is retransplantation.

PTLD

The initial step in management of PTLD involves reduction in the doses of immunosuppressive agents in an attempt to restore host cellular immunity against Epstein-Barr virus. Regression of tumor may be seen in up to two-thirds of cases as a result of this strategy, but there is an attendant risk of provoking acute rejection or BOS. For patients with CD20+ tumors who fail to achieve complete remission, who cannot tolerate reduced immunosuppression, or who have aggressive disease, treatment with anti-CD20 monoclonal antibodies (rituximab) is the preferred approach.

Conventional chemotherapy is employed in CD20-negative cases and in cases refractory to rituximab, but tolerance of these agents is poor among transplant recipients, with up to a quarter of patients dying from treatment-related complications. Surgical resection is often necessary to address bowel obstruction and perforation associated with gastrointestinal PTLD, but it should ideally be combined with systemic therapy. There is no proven role for antiviral therapy in treating established PTLD.

What is the prognosis for patients managed in the recommended ways?

Primary graft dysfunction

PGD is a leading cause of early death following lung transplantation, as short-term mortality associated with severe PGD is 30-40 percent. The risk of death remains higher for survivors of severe PGD than for unaffected recipients even beyond the first year. Recovery from severe PGD may be protracted and incomplete; although achievement of normal allograft function and exercise tolerance is possible. Survivors of PGD have an increased risk of developing bronchiolitis obliterans syndrome (BOS).

Phrenic nerve injury

Phrenic nerve injury has been associated with increases in ventilator days, tracheostomy rates, and length of ICU stay. Recovery of normal phrenic nerve and diaphragmatic function is possible for those with stretch or thermal injury, but it may take weeks or months. However, severing of the phrenic nerve leads to permanent loss of function.

Airway complications

Most cases of limited bronchial dehiscence will close either spontaneously or with use of temporary stents. Anastomotic dehiscence is rarely fatal in the current era of lung transplantation.

Bronchoscopic interventions are usually successful in re-establishing airway patency in cases of bronchial stenosis. However, recurrent stenosis is common, necessitating repeated interventions and occasionally leading to compromised functional outcomes and increased mortality. A particularly challenging problem is the development of extensive fibrous strictures beyond the anastomosis, typically involving the bronchus intermedius or lobar bronchi and at times completely obliterating the airway lumen. When these strictures are extensive, retransplantation may offer the only solution.

Hyperacute rejection

Hyperacute rejection is associated with a high mortality rate, although there are case reports of successful outcomes.

Acute rejection

In the majority of instances, treatment of acute cellular rejection with high-dose corticosteroid therapy results in rapid improvement in symptoms, pulmonary function, and radiographic abnormalities. However, follow-up transbronchial lung biopsies demonstrate histologic evidence of persistent rejection in up to a quarter of patients. Patients who have experienced one or more episodes of acute cellular rejection are at increased risk for the subsequent development of BOS.

There is limited information on the outcomes following development of acute humoral rejection. In the largest series, that of forty patients, approximately 40 percent demonstrated a favorable response to corticosteroids alone, and two-thirds of the refractory cases responded to the addition of plasmapheresis. A mortality rate of 12 percent within three months following the episode was reported in this series. Acute humoral rejection was not associated with long-term adverse consequences on allograft function among survivors.

BOS

The natural history of BOS is highly variable. Onset within the first two years following transplantation is associated with a median survival from diagnosis of only 1.5 years, compared to 2.5 years for patients who develop BOS beyond the second year. There is preliminary evidence suggesting that the use of macrolides may lead to short-term improvement in FEV1 in 30-40 percent of patients, but many of these favorable responses were transient. Responders may also experience better survival rates than non-responders do, although the true impact of macrolide therapy on the natural history of BOS remains uncertain.

PTLD

Use of rituximab for treatment of CD20-positive cases of PTLD is associated with a 60 percent complete remission rate. The ultimate prognosis associated with PTLD is difficult to define precisely since available studies do not typically include a control group without PTLD for comparison. One series of lung transplant recipients documented a 37 percent mortality rate directly attributed to PTLD. Factors that have been associated with a poor prognosis include older age, elevated plasma lactate dehydrogenase levels, severe dysfunction of the involved organ, presence of B symptoms, and multi-organ involvement.

What other considerations exist for patients with non-infectious complications of lung transplantation?

No other considerations.

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