Lung Transplantation (include selection, evaluation, process of organ acquisition, etc.)

What every physician needs to know

General description of procedure, equipment, technique

Lung transplantation has been performed successfully for over three decades. More than 50,000 lung transplants have been performed worldwide, and approximately 4,000 new lung transplants are performed each year. Lung transplantation offers patients with advanced, debilitating, and often life-threatening lung disease the possibility of extended survival, improved functional status, and enhanced quality of life.

Indications and patient selection

Indications for lung transplantation include a broad spectrum of pulmonary disorders. Idiopathic pulmonary fibrosis (IPF) is the most common indication for lung transplantation, accounting for 33% of transplants worldwide. Chronic obstructive pulmonary disease (COPD), once the most common indication, now accounts for 25% of transplants, and cystic fibrosis (CF) for 14%. Non-IPF interstitial lung diseases (8%), lung re-transplantation after graft failure (4%) and alpha-1 antitrypsin deficiency-associated emphysema (2%) are the other major indications, while a variety of other disorders of the lung parenchyma, airways, and vasculature each account for a small percentage of transplants annually.

Idiopathic pulmonary arterial hypertension (IPAH), once a leading indication accounting for 10% of transplants, now accounts for only 2% as the number of transplants for IPAH has remained relatively constant, while the numbers have increased dramatically for most other indications.

Given the considerable risks associated with lung transplantation, including a mortality rate that approaches 50 percent at five years, this option should be reserved for patients whose lung disease poses a significant risk of short-term mortality. Disease-specific guidelines for referral of patients to a lung transplant center, and for active listing for transplantation, are shown in Table I. These guidelines are drawn from consensus expert opinion based on disease-specific prognostic data. In addition, other factors that should be considered include the clinical trajectory of the patient’s disease (i.e., stable vs. deteriorating), functional status, quality of life, and the patient’s willingness to accept the risks, uncertainties, and commitments of transplantation. Candidates should be functionally limited (New York Heart Association functional class III or IV) but, ideally, still ambulatory.

Table 1.

Historically, most programs had an age cutoff, typically age 65, for eligible candidates, but there has been an increasing willingness to accept older candidates, focusing more on their functional, rather than chronological age. Patients 65 years and older now account for over 25% of the recipient pool in the U.S., and patients over age 70 are considered potential transplant candidates at many centers.

Contraindications

Absolute Contraindications:

Absolute contraindications to lung transplantation have evolved and decreased over time. Notably, HIV, HBV and HCV infection have been removed as absolute contraindications in the most recent expert guidelines. Consensus contraindications include:

• Recent (within 2-5 years) malignancy other than non-melanoma skin cancer

• Severe dysfunction of another major organ or organ system (including severe uncorrected atherosclerotic disease and severe skeletal abnormalities of chest wall). The presence of significant extrapulmonary vital organ dysfunction can sometimes be addressed with multi-organ transplants (e.g., heart-lung, liver-lung) in select candidates.

• Uncontrolled infection with highly virulent or resistant microorganisms

• Severe debilitation that is unlikely to improve with post-transplant rehabilitation

• Psychiatric illnesses, including substance abuse or dependence, that may interfere with post-transplant care

• Inadequate social support or other social circumstances that may interfere with post-transplant care

• Non-adherence to medical therapy

Relative Contraindications:

Relative contraindications are numerous and may vary substantially between centers. These include severe respiratory failure, colonization or controlled infection with certain virulent or resistant microorganisms, and the burden of other medical comorbidities (diabetes, hypertension, vascular disease, osteoporosis, gastroesophageal reflux or dysmotility, etc.) that have not led to organ failure but may collectively impact post-transplant outcomes depending on their severity and extent of control with therapy.

Respiratory failure that requires mechanical ventilation or extracorporeal life support (ECLS) prior to transplantation is a risk factor for increased short-term post-transplant mortality. In the U.S. and other countries that utilize the Lung Allocation Score (LAS) for donor lung allocation, such patients are generally assigned a high priority and often receive organs in an expedited fashion. Initial experience with such patients was poor, but increasing expertise, improved technology and the advent of “ambulatory ECLS” has led to a growing utilization of ECLS to bridge select critically ill patients to transplantation with acceptable post-transplant outcomes.

Both malnutrition and obesity are considered contraindications, but cutoffs vary from center to center. Among obese patients, truncal obesity is often more concerning than other distributions of body fat.

HIV, HBV and HCV infection, once considered absolute contraindications, are now considered manageable in select patients in whom viral control can be demonstrated and who are treated at centers with expertise in transplantation in such patients.

Selection of patients with CF has always raised unique concerns about the risk that chronic airways infection poses on post-transplant outcomes. Experience has demonstrated that the risk of post-transplant pneumonia is no greater among CF patients compared to other patient populations. However, CF patients who are infected with pan-resistant Pseudomonas aeruginosaexperience slightly inferior post-transplant survival rates compared to those of CF patients with sensitive organisms. Since these outcomes are still favorable, the presence of pan-resistant P. aeruginosa should not contraindicate transplantation.

In contrast, infection with certain species of Burkholderia cepacia complex (especially B. cenocepacia) has been associated with excessive post-transplant mortality as a direct consequence of lethal infections with these organisms. As a result, the majority of lung transplant centers exclude patients with B. cenocepacia. Mycobacterium abscessus infection has similarly been associated with increased post-transplant morbidity and mortality, and transplantation of patients infected with M. abscessus remains controversial.

Patients for whom collagen vascular disease is the underlying cause for their lung disease are usually considered suitable for transplantation if they do not have significant extrapulmonary involvement that could compromise the outcome of transplantation.

Prior pleurodesis is associated with an increased risk of intraoperative bleeding, particularly when cardiopulmonary bypass is used, but it is not a contraindication to transplantation. Pleural thickening associated with aspergillomas, a common issue in sarcoidosis, similarly complicates explantation of the native lung and carries the additional risk of soiling the pleural space with fungal organisms if the cavity ruptures during removal. Some patients with extensive pleural reaction and/or cavities abutting the pleural surface may be excluded from consideration for this reason.

Age is one of the most controversial relative contraindications to lung transplantation and age cutoffs vary substantially between centers and regions. Consensus guidelines suggest that patients over age 75 are rarely suitable candidates.

Donor selection

Lungs have been the most challenging of all the vital organs to successfully harvest for transplantation because of a variety of insults that occur with or leading up to brain death–aspiration, ventilator-associated pneumonia, chest trauma, volume overload, and neurogenic pulmonary edema–as well as the potential consequences of prior smoking. There are no universally accepted criteria for the acceptability of donor lungs, although such criteria have been proposed and are widely referred to as standard criteria (Table II).

Table 2.

Use of these criteria has resulted in lung harvest rates of only around 20 percent from donors who are otherwise suitable for donation of other vital organs. However, it is clear that these criteria are too stringent, and lung harvest rates have increased by liberalizing these criteria. Use of these “extended criteria” donors has been associated with outcomes similar to those achieved with standard criteria donors.

Implementation of special donor-management protocols that include judicious fluid management, therapeutic bronchoscopy, and lung recruitment maneuvers on the ventilator have led to increased harvest rates. In addition, lung harvest rates can be enhanced by employing a lung-protective ventilatory strategy (tidal volume 6-8 ml/kg, 8-10 cm PEEP), rather than more conventional ventilator settings (tidal volume 10-12 ml/kg, 3-5 cm PEEP).

Ex vivo lung perfusion (EVLP) is a developing technology that involves harvesting suboptimal lungs and connecting them to an apparatus that permits continuous perfusion and ventilation, as well as assessment of gas exchange and even radiographic imaging. A hyperosmolar perfusate draws fluid out of the extravascular space, decreasing the amount of pulmonary edema and improving oxygenation. In this way, donor lungs that are initially considered unacceptable can be optimized, re-evaluated and subsequently transplanted successfully. EVLP is being increasingly utilized at multiple transplant centers with generally excellent outcomes and it is hoped that widespread use will increase the number of available donor lungs.

Another increasing utilized donor strategy is the use of “donation after cardiac death” (DCD) donors. In such cases, family members request withdrawal of care from a patient with devastating neurological injury (but not brain death) or another unrecoverable condition. With the family having independently consented to organ donation, life support is withdrawn in a controlled fashion, typically in an operating room, and organs are harvested after circulatory arrest ensues and death is pronounced. Experience with DCD lung donors has demonstrated excellent outcomes and utilization of DCD lungs has been increasing.

Organ allocation

Rules governing organ allocation vary from country to country. Prioritization of candidates can be based on waiting time, urgency (i.e. risk of death without transplantation), net transplant benefit (i.e. the additional lifespan afforded by transplant versus no transplant), or combinations of these.

A system based on a combination of net transplant benefit and urgency was implemented in the U.S. in 2005, in place of a previous system based on waiting time. The U.S. allocation system uses statistical models to predict one-year survival with and without transplantation for each patient. These models use approximately a dozen objective parameters, the most influential of which are underlying diagnosis, oxygen requirements at rest, and need for mechanical ventilation. These survival projections are used to calculate a lung allocation score (LAS) for each candidate, using the equation “raw” LAS = [net transplant benefit (one-year survival with transplantation minus one-year survival without transplantation)] minus [medical urgency (1-year survival without transplantation)].

The score is then normalized to a 0-100 scale for ease of use, with higher scores corresponding to higher priority. Because one-year survival without transplant is factored into both the net transplant benefit and the medical urgency measures, it has more impact on the LAS than post-transplant survival does. The system was designed to minimize death on the waiting list while also avoiding futile transplants in patients who were unlikely to survive.

By prioritizing patients with more advanced and imminently life-threatening disease, the LAS system has significantly decreased the death rate of patients on the waiting list. It has facilitated transplantation of patients with IPF, previously the group at greatest risk for dying while awaiting transplantation, while assigning lower priority to patients with COPD. The system also has also made it feasible to transplant candidates expeditiously who develop respiratory failure requiring mechanical ventilation or ECLS, although it remains controversial whether outcomes in this high-risk population are sufficient to justify this practice.

In addition to the LAS score, lungs are allocated on the basis of blood group and size compatibility. Prospective HLA matching is not performed, but candidates identified to have anti-HLA antibodies at the time of listing must avoid donors with incompatible antigens.

Following the U.S. experience with the LAS system, several European countries have implemented schemes that incorporate the LAS into a more complex allocation system that includes organ sharing across national borders.

Details of how the procedure is performed

Four surgical techniques are used to varying degrees: heart-lung, single-lung, bilateral-lung, and living-donor bi-lobar transplantation. The choice of procedure is dictated by factors such as underlying disease, age of the patient, survival and functional advantages of the procedure, and center-specific preferences.

Heart-Lung Transplantation (HLT)

While HLT was the first procedure to be performed successfully, it now accounts for less than 1.5% of all lung transplant procedures. The main indication is Eisenmenger’s syndrome with associated surgically uncorrectable cardiac defects. HLT is still occasionally performed in patients with IPAH, but it has become clear that the right ventricle has a remarkable capacity to recover once pulmonary artery pressures have normalized. As a result, bilateral lung transplantation (BLT) has supplanted HLT for the vast majority of IPAH patients. HLT is also occasionally used for patients with advanced lung disease and concurrent severe left ventricular dysfunction or extensive coronary artery disease.

Single-Lung Transplantation (SLT)

SLT was once the most commonly performed procedure. It is usually performed via a standard posterolateral thoracotomy incision, but some surgeons now prefer a less invasive axillary muscle-sparing thoracotomy incision. Technically the most straightforward procedure, SLT is best-suited for frail patients who would have difficulty enduring the rigors of BLT. It also provides the most efficient use of the limited donor pool, permitting two recipients to benefit from a single donor.

SLT is an acceptable procedure for patients with IPF and COPD, although native lung hyperinflation in COPD can (rarely) compromise the function of the allograft. SLT is contraindicated for patients with CF and other suppurative lung diseases because of concerns that a native lung left in place could infect the allograft. SLT is also avoided in patients with severe idiopathic or secondary forms of pulmonary hypertension; the allograft would have to accommodate the entire cardiac output because of the high vascular resistance in the native lung, which can lead to exaggerated reperfusion pulmonary edema.

Bilateral Lung Transplantation (BLT)

BLT is the most commonly performed of the available procedures, accounting for approximately 75% of lung transplants. Rather than en bloc transplantation of both lungs, it involves two sequential single-lung procedures during a single operative session. In the absence of significant pulmonary hypertension, cardiopulmonary bypass (and the attendant bleeding complications) can often be avoided by sustaining the patient on the contralateral lung during implantation of each allograft.

Surgical approaches include a transverse thoracosternotomy (clamshell) incision, bilateral anterior thoracotomies (sparing the sternum), and median sternotomy. BLT is the exclusive procedure for CF and non-CF bronchiectasis and for severe idiopathic and secondary forms of pulmonary hypertension. BLT is also commonly utilized in patients with COPD and pulmonary fibrosis, in particular in younger patients. There are conflicting data with regards to the survival benefit of BLT versus SLT in COPD and IPF patients, though some studies do suggest a small survival benefit with BLT, at least in select patient groups.

Living-donor Bi-lobar Transplantation (LDT)

LDT was developed under the prior time-based allocation system in the U.S., largely to serve the needs of candidates whose rapidly deteriorating status made it unlikely that they would survive to receive organs from a cadaveric donor. The procedure involves donation of a lower lobe from each of two living, blood-group-compatible donors, and in order to ensure that the lobes are sufficient to fill the hemithoraces, the donors are ideally taller than the recipient. Therefore, patients with CF are well-suited to this procedure because of their small stature even as adults.

Outcomes following living-donor transplantation approximate those achieved with cadaver organs. The procedure is now performed rarely in the US and Europe since it offers no survival advantage to recipients, it poses risk to two otherwise healthy donors, and its chief purpose of expediting transplantation has been addressed by new allocation systems.

Post-transplant Management: Immunosuppression

Individuals involved in the care of lung transplant recipients must be familiar with the administration, side effects, and drug interactions of the immunosuppressive agents employed to prevent lung allograft rejection (Table III). While the specifics of the preferred regimen vary among transplant centers, the most commonly used regimens include a calcineurin inhibitor (CNI), purine synthesis inhibitor, and corticosteroid. mTOR inhibitors are also used, though generally only after sufficient time has elapsed to allow the surgical sites, especially the airway anastomoses, to fully heal. The intensity of immunosuppressive therapy generally decreases over time after transplant, but substantial immunosuppression is still maintained life-long because of the ongoing risk of allograft rejection.

Table 3.

The CNIs tacrolimus and cyclosporine form the cornerstone of therapy, but they also pose the greatest challenges with respect to safe and tolerable administration. The bioavailability of these agents is poor and unpredictable, requiring frequent monitoring of trough blood levels to ensure appropriate dosing. These agents are metabolized via the hepatic cytochrome P450 enzyme system, and blood levels are affected by concurrent administration of other drugs that up- or down-regulate this pathway. Some degree of nephrotoxicity due to calcineurin inhibitors is nearly universal.

Post-transplant Management: Antimicrobial Prophylaxis

Antimicrobial prophylactic therapies are used to counteract the increased infectious risks associated with immunosuppression required after lung transplantation, especially in the early post-transplant period when immunosuppression is most intense. Pneumocystis jiroveci, cytomegalovirus, and invasive mold infections, especially Aspergillus species, are the microorganisms most frequently targeted with prophylactic strategies. Azole antifungals with anti-Aspergillus activity, including voriconazole and posaconazole, have significant interactions with CNIs that require close monitoring of CNI levels when starting or stopping the antifungal.

Post-transplant Management: Medical Comorbidities

In addition to specific issues related to maintenance and monitoring of lung allograft health, management of medical comorbidities is an essential component in the care of lung transplant recipients. In particular, the immunosuppressive agents administered post-transplantation often exacerbate pre-existing medical conditions or lead to their de novo development. Common medical issues encountered include osteoporosis, hypertension, chronic kidney disease, coronary artery disease, diabetes, gastroparesis, gastroesophageal reflux disease, and hyperlipidemia.

Interpretation of Results

Not applicable

Performance characteristics of the procedure (applies only to diagnostic procedures)

Not applicable

Outcomes

Survival

In a large, international database, survival rates following lung transplantation in the most recent decade are 83 percent at one year, 67 percent at three years, 55 percent at five years, and 33 percent at ten years, with a median survival of 6.1 years. Although one-year survival approximates that of heart and liver transplant recipients, five-year survival remains considerably below the 75 percent rate associated with these other procedures. Mortality is highest in the first post-transplant year, with primary graft dysfunction and infection as the leading causes of early deaths. Beyond the first year, chronic lung allograft dysfunction (chronic rejection), infection and malignancy account for the majority of deaths.

The limitations on long-term survival following lung transplantation have raised the important question of whether and for whom transplant actually confers a survival advantage over the natural history of the underlying lung disease. In the absence of randomized trials, this question has been addressed by using statistical modeling to compare observed post-transplant survival to survival of wait-listed patients or by simulating survival with and without transplantation using predictive equations.

In the case of IPF, a disease associated with a median survival of only four or five years, studies have consistently suggested that lung transplantation confers a survival advantage.

For the CF population, studies have suggested that only adults who have a predicted five-year natural history survival of less than 50 percent and who do not have Burkholderia cenocepacia are likely to derive a survival advantage from transplantation. While controversial, some studies have suggested that lung transplantation rarely confers a survival advantage for CF patients under age eighteen. In the LAS era, data suggest that most adult CF patients do derive a survival benefit from lung transplantation and that the magnitude of this benefit is, as expected, proportional to the LAS at the time of transplantation.

Since long-term survival is possible even in the advanced stages of COPD, it is not surprising that studies have yielded conflicting results on whether lung transplantation confers a survival advantage in this population.

Pulmonary Function

Pulmonary function tends to peak 3-9 months following transplantation, as the adverse effects of post-operative pain, weakness, and initial graft injury subside. Recipients of BLT tend to achieve normal spirometric parameters, while SLT recipients experience marked but incomplete improvement, with FEV1 typically reaching 50-60 percent predicted. Oxygenation improves rapidly, permitting the majority of patients to be weaned off of supplemental oxygen during the first post-transplant week. Hypercapnia can take longer to resolve because of residual impairment of central respiratory drive.

Exercise Capacity

The majority of lung transplant recipients achieve functional independence and can resume an active lifestyle. On average, BLT recipients demonstrate greater improvement in six-minute walk test distance than SLT recipients do, but this may reflect, at least in part, the generally younger age of BLT recipients. Differences in peak exercise performance assessed by cardiopulmonary exercise testing are less apparent. Specifically, both SLT and BLT recipients typically achieve a maximum oxygen consumption of 40-60 percent predicted.

Suboptimal peak exercise performance persists in recipients tested as late as two years following transplantation, suggesting that deconditioning is not likely playing a major role. Characteristically, breathing reserve, oxygen saturation, and heart rate reserve remain normal at the time that exercise is terminated, while anaerobic threshold is reduced, a pattern suggestive of skeletal muscle dysfunction. Several studies have suggested that calcineurin inhibitors impair muscle mitochondrial respiration and account for the limitation in peak exercise performance.

Hemodynamics

Elevated pulmonary artery pressures normalize almost immediately following transplantation; failure to do so suggests the presence of significant acute lung injury or pulmonary arterial or venous anastomotic narrowing. With normalization of pulmonary pressures, right ventricular geometry and performance normalize more gradually. A threshold of pre-transplant right ventricular dysfunction, below which recovery is unlikely, has yet to be defined.

Alternative and/or additional procedures to consider

Not applicable

Complications and their management

This section highlights the most common complications following lung transplantation. More detailed discussions of infectious and noninfectious complications are discussed in other chapters.

Infectious Complications

Bacterial pneumonia is a common complication encountered in the early post-transplant period. Pseudomonas aeruginosa and Staphylococcus aureus are responsible for the majority of these infections. Bacterial infections in the lower respiratory tract in the form of purulent bronchitis, bronchiectasis, and pneumonia re-emerge as a late complication in patients who develop bronchiolitis obliterans syndrome (BOS).

Community acquired respiratory virus (CARV) infections are common after lung transplantation and have been associated both with respiratory failure as a consequence of the infection itself, as well as with accelerated allograft rejection.

Cytomegalovirus (CMV) predominates as the most common opportunistic viral pathogen. Infection can result from acquisition of virus from the donor or from reactivation of latent infection remotely acquired by the recipient. Seronegative recipients who receive lungs from seropositive donors are at greatest risk for CMV infection, and it is these primary infections that tend to be the most severe. Administration of valganciclovir for the initial 6-12 months following transplantation has been shown to be an effective prophylactic strategy for these recipients, as well as for seropositive recipients.

CMV infections can be asymptomatic; when clinically apparent, they can present with generalized symptoms of fever and malaise, or with organ-specific symptoms reflecting involvement of the lungs, gastrointestinal tract, or central nervous system. Treatment consists of intravenous ganciclovir or oral valganciclovir.

Lung transplant recipients are uniquely predisposed to aspergillus infection of the bronchial anastomosis and the bronchial mucusa. These airway infections usually respond to treatment with appropriate azole antifungals (voriconazole, posaconazole or isavuconazonium). Inhaled nebulized amphotericin has also been used to treat fungal infections of the bronchial anastomoses. Such infections can occasionally lead to anastomotic strictures or, rarely, to formation of a bronchial-to-pulmonary-artery fistula with massive hemoptysis.

Invasive aspergillosis is a far more serious form of infection. Most cases involve the lung parenchyma, presenting as one or multiple nodular or cavitary opacities on CXR and CT. Extrapulmonary and disseminated disease may accompany primary pulmonary infection or may occur independently. Voriconazole is the treatment of choice, while echinocandins and lipid formulations of amphotericin B are second-line. Despite the availability of these agents, invasive aspergillosis is associated with a 60 percent mortality rate in the lung transplant population.

Non-Infectious Complications

Primary graft dysfunction (PGD). PGD is a form of acute allograft injury characterized by the development of non-cardiogenic pulmonary edema within 72 hours of transplantation in the absence of identifiable secondary causes like volume overload, aspiration, pulmonary venous outflow obstruction, or hyperacute rejection. PGD is thought to be a consequence of ischemia-reperfusion injury, but inflammatory events associated with donor brain death, surgical trauma, and lymphatic disruption may be contributing factors. In most cases, the injury is mild and transient, but in approximately 10 percent of cases, hypoxemia is severe and the course is protracted. Mortality associated with severe PGD is in the range of 30-40 percent.

Airway complications. Dehiscence of the bronchial anastomosis is an uncommon early complication. Mild forms are often asymptomatic and noted only on surveillance bronchoscopy. More extensive dehiscence, heralded by spontaneous pneumothorax or pneumomediastinum, can be lethal if it is progressive. Treatment includes chest tube evacuation of pneumothoraces, prophylactic antibiotics to prevent mediastinitis, and reduction of corticosteroids to facilitate healing. In severe cases, bare metal bronchial stents can be inserted across the dehiscence in an attempt to induce formation of granulation tissue.

The most common airway complication is bronchial stenosis that is due to fibrous stricture, excessive granulation tissue, or bronchomalacia. Bronchial stenosis typically occurs at the site of the bronchial anastomosis, but fibrous strictures can also involve more distal airways. Most cases can be managed with balloon dilatation, laser debridement, and stent placement via flexible or rigid bronchoscopy.

Acute rejection (AR). AR commonly occurs in the first post-transplant year, with the frequency declining markedly beyond this point. AR is clinically silent in up to 40 percent of cases and detected only on surveillance biopsies. When clinically overt, symptoms include low-grade fever, dyspnea, and cough. Accompanying features include a decline in oxygenation and spirometric parameters, and the presence of opacities on chest x-ray and chest CT.

Transbronchial lung biopsy, the standard for diagnosis, demonstrates perivascular lymphocytic infiltrates that, in severe cases, spill over into the adjacent interstitium and alveolar airspaces. Treatment consists of high-dose corticosteroids, typically administered as a three-day pulse of intravenous solumedrol. This treatment usually leads to rapid improvement in symptoms, pulmonary function, and radiographic abnormalities, although follow-up biopsies demonstrate persistent rejection in up to a quarter of patients.

Chronic lung allograft dysfunction (CLAD). This entity is thought to represent chronic alloimmune injury (chronic rejection) of transplanted lungs. CLAD was once thought to primarily manifest as bronchiolitis obliterans syndrome (BOS), a progressive and largely irreversible airflow obstruction resulting from fibroobliteration of small airways. More recently, another form of CLAD has been described that manifests as progressive restriction and is characterized by interstitial fibrosis. This restrictive phenotype has been termed restrictive chronic lung allograft dysfunction (rCLAD) or restrictive allograft syndrome (RAS). While both the obstructive and restrictive forms of CLAD can lead to graft failure and death, rCLAD/RAS is associated with far higher mortality than BOS.

The diagnosis of both BOS and rCLAD/RAS rests upon a sustained and otherwise unexplained decline in pulmonary function testing from an established post-transplant baseline rather than on histopathologic findings. High-resolution chest CT findings such as air trapping or peripheral fibrotic changes can be supportive of the diagnosis. Recurrent or severe episodes of AR are the major risk factor for subsequent development of CLAD, which has led to the notion that CLAD is a form of chronic allograft rejection. However, a number of non-immunological insults, including aspiration, CARV infections, CMV pneumonitis, and PGD, have also been identified as risk factors. The mechanisms by which these insults lead to CLAD remain to be elucidated.

CLAD is uncommon in the first post-transplant year, but there is a steady rise in its prevalence beyond this point. Once CLAD is present, its course is highly variable, with some patients experiencing rapid decline in lung function over weeks to months and others experiencing prolonged periods of stability. Treatment once involved augmentation of immunosuppression, but there is no convincing evidence that this treatment is effective. Macrolides improve lung function in a subset of patients with BOS, though the durability of these effects and whether they will lead to improved survival remain open questions. CLAD is the major cause of late allograft failure and recipient death, and it is the leading indication for retransplantation.

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