Lung Transplantation

106

LUNG TRANSPLANTATION ROBERT M. KOTLOFF, MD • SHAF KESHAVJEE, MD, MSc

INTRODUCTION INDICATIONS AND CANDIDATE SELECTION TIMING OF REFERRAL AND LISTING ALLOCATION SYSTEM BRIDGING TO TRANSPLANTATION: ARTIFICIAL LUNG TECHNOLOGIES DONOR SELECTION AND MANAGEMENT LUNG PRESERVATION AVAILABLE SURGICAL TECHNIQUES Heart-Lung Transplantation Single-Lung Transplantation

Bilateral-Lung Transplantation Living Donor Bilobar Transplantation ROUTINE POSTTRANSPLANTATION MANAGEMENT AND OUTCOMES Survival Pulmonary Function Exercise Capacity Hemodynamics Quality of Life COMPLICATIONS Primary Graft Dysfunction Airway Complications

INTRODUCTION Human lung transplantation was first attempted in 1963, but it was not until nearly 2 decades later that extended survival was achieved. Further refinements in patient selection, surgical technique, immunosuppression, and postoperative care have since facilitated the successful application of lung transplantation to a wide variety of advanced disorders of the airways, lung parenchyma, and pulmonary vasculature. The field has realized dramatic growth, with more than 47,000 procedures performed worldwide to date with approximately 3700 now performed annually.1 Nonetheless, serious problems persist that limit the utility of this procedure. The donor pool remains insufficient to meet the demands of the many desperately ill patients awaiting transplantation. Immunosuppressive therapy is associated with a number of troubling side effects, most notably a significant risk of infection and malignancy. Despite the use of immunosuppressive agents, rejection develops frequently and continually threatens organ function. Though lung transplantation offers the prospect of improved functional status and quality of life, long-term survival remains an elusive goal, with only half of recipients living beyond 5 years. In order to optimize outcomes in the face of these shortcomings, judicious selection of candidates is essential and care of recipients must be rendered in a meticulous and vigilant fashion by clinicians familiar with the hazards of posttransplant life.

INDICATIONS AND CANDIDATE SELECTION Lung transplantation is a therapeutic option for a broad spectrum of chronic debilitating pulmonary disorders of the airways, parenchyma, and vasculature. Leading indications include chronic obstructive pulmonary disease (COPD; 1832

Phrenic Nerve Injury Native Lung Hyperinflation Infection Rejection and Chronic Allograft Dysfunction Posttransplantation Lymphoproliferative Disorder Lung Cancer Recurrence of Primary Disease RETRANSPLANTATION FUTURE DIRECTIONS

28% of cases), idiopathic pulmonary fibrosis (IPF; 29% of cases), and cystic fibrosis (CF; 15% of cases).1 Other less common indications include emphysema due to alpha1antitrypsin deficiency, sarcoidosis, non-CF bronchiectasis, and lymphangioleiomyomatosis. Once a common indication for transplantation, idiopathic pulmonary arterial hypertension now accounts for less than 3% of procedures, reflecting major advances in the medical management of these patients. Transplantation of patients with lung involvement due to collagen vascular disease remains controversial due to concerns that extrapulmonary manifestations of the systemic disease could compromise the posttransplant course. In particular, the esophageal dysmotility and reflux that frequently characterize scleroderma could increase the risk of aspiration and accelerated graft loss. The demonstration that posttransplantation survival of scleroderma patients is comparable with other patient populations provides some reassurance that carefully selected patients can benefit from this procedure.2,3 Use of lung transplantation for locally advanced bronchioloalveolar carcinoma (now referred to as adenocarcinoma in situ) has largely been abandoned due to an unacceptably high rate of cancer recurrence.4 Many transplant centers define an age cutoff for transplant eligibility, typically 65–70 years. In support of this policy, advanced recipient age has been consistently identified as a risk factor for increased posttransplant mortality.1 Nonetheless, there has been a growing trend to expand the age range on the basis of the argument that “functional” rather than chronologic age should be considered. This trend has been most pronounced in the United States, where patients 65 years and older accounted for 27% of transplant recipients in 2011 compared with 3% in 2001.5 Two recent single-center case series involving 50 and 78 patients, respectively, who were 65 years or older found no difference in 1-year and 3-year posttransplant survival rates compared with younger cohorts.6,7 However, the United Network for Organ Sharing (UNOS) database of U.S.

106  •  Lung Transplantation 1833

transplants documents a 10-year survival rate among recipients 65 and older of only 13% compared with 23% for those 50 to 64 years and 38% for those younger than 50 years.8 There are surprisingly few remaining absolute contraindications to lung transplantation. There is general consensus that the following contraindicate transplantation: (1) recent malignancy (other than nonmelanoma skin cancer); (2) active infection with hepatitis B or C virus associated with histologic evidence of significant liver damage; (3) active or recent cigarette smoking, drug abuse, or alcohol abuse; (4) severe psychiatric illness; (5) repeated noncompliance with medical care; and (6) absence of a consistent and reliable social support network.9 Infection with human immunodeficiency virus (HIV) is still viewed by most centers as an absolute contraindication, but promising results with liver, kidney, and heart transplantation in HIV-positive recipients, as well as a recent case report of successful lung transplantation, may soon remove this barrier.10 The presence of significant extrapulmonary vital organ dysfunction precludes isolated lung transplantation, but multiorgan procedures such as heart-lung or lung-liver can be considered in highly selected patients. Both obesity and underweight nutritional status increase the risk of posttransplant mortality, but cutoffs for exclusion of candidates vary among centers.11 The risk posed by other chronic medical conditions such as diabetes mellitus, osteoporosis, gastroesophageal reflux, and coronary artery disease must be assessed individually on the basis of severity of disease, presence of end-organ damage, and ease of control with standard therapies. Prior pleurodesis is associated with an increased risk of intraoperative bleeding, particularly when cardiopulmonary bypass is used, but is not a contraindication to transplantation in experienced surgical hands. Pleural thickening associated with aspergillomas similarly complicates anatomic dissection and explantation of the native lung and carries the additional risk of soiling the pleural space with fungal organisms. Among candidates with CF, colonization with certain species comprising the Burkholderia cepacia complex, in particular Burkholderia cenocepacia (previously known as genomovar III), is considered a strong contraindication by the majority of centers, owing to the demonstrated propensity of this organism to cause lethal posttransplant infections.12,13 In contrast, the presence of pan-resistant Pseudomonas aeruginosa in this patient population is associated with acceptable outcomes and should not be viewed as a contraindication.14 Transplantation of patients on mechanical ventilation is associated with increased short-term posttransplant mortality though it does not appear to affect outcomes beyond the first year.1 Although transplantation of these patients was previously discouraged, the new lung allocation system in the United States has prompted reconsideration of this perspective by assigning high allocation scores to ventilatordependent patients. Many programs are now willing to maintain some ventilator-dependent patients on their active waiting list, anticipating that the high allocation score will expedite transplantation, but reserving the option of de-listing patients who develop intercurrent complications or progressive debility. An analysis of 586 ventilator-

dependent patients in the UNOS database documents inferior but not necessarily prohibitively poor short-term outcomes; 1-year and 2-year survival rates were 62% and 57%, respectively, compared with 79% and 70% for nonventilated patients.15 Even more controversial is transplantation of patients on extracorporeal membrane oxygenation (ECMO) support, for whom 1-year and 2-year posttransplant survival rates were only 50% and 45%, respectively, in the UNOS database. More recent single-center reports document more promising outcomes,16,17 and increasing availability of ambulatory ECMO techniques may improve outcomes in the future.

TIMING OF REFERRAL AND LISTING Listing for transplantation is considered at a time when the lung disease limits basic activities of daily living and is deemed to pose a high risk of death in the short term. Disease-specific guidelines for timely referral and listing of patients, based on available predictive indices, have been published (Table 106-1).9 The imprecise nature of these predictive indices can make decisions about transplant listing problematic for all but the most severely ill patients. The patient’s perception of an unacceptably poor quality of life is an important additional factor to consider but should not serve as the sole justification for listing of a patient whose disease is not deemed to be at an advanced and potentially life-threatening stage.

ALLOCATION SYSTEM Rules governing allocation of organs vary among countries but typically employ a time-based or need-based ranking of candidates on the waiting list, or some combination of the two systems. Examination of the systems that have been operative in the United States permits an appreciation of the advantages and limitations of both approaches. From 1990 to 2005, lung allocation in the United States prioritized candidates on the basis of the amount of time they had accrued on the waiting list, without regard to severity of illness. Based on a simple and objective parameter, this system was easily understood but was ultimately called into question because it failed to accommodate those patients with a more rapidly progressive course who often could not survive the prolonged waiting times.18 In response to the perceived inequities of the time-based system, and under mandate of the federal government, a new system was implemented in 2005. It allocates lungs on the basis of both medical urgency (risk of death without a transplant) and “net transplant benefit” (the extent to which trans­plantation will extend survival). It uses predictive models, incorporating more than a dozen variables, to generate predictions for a given patient of 1-year survival with and without transplantation.19 A raw lung allocation score (LAS) is then calculated on the basis of these survival predictions and normalized to a scale of 0 to 100 for ease of use. Because 1-year survival without transplantation is factored into net transplant benefit and medical urgency measures, it affects

1834 PART 3  •  Clinical Respiratory Medicine Table 106-1  Disease-Specific Guidelines for Listing for Lung Transplantation CHRONIC OBSTRUCTIVE PULMONARY DISEASE ■ BODE index of 7–10 or at least one of the following: ■ History of hospitalization for exacerbation associated with acute hypercapnia (PCO2 > 50 mm Hg) ■ Pulmonary hypertension or cor pulmonale, or both, despite oxygen therapy ■ FEV1 < 20% and either DLCO < 20% or homogeneous distribution of emphysema IDIOPATHIC PULMONARY FIBROSIS ■ Histologic or radiographic evidence of UIP and any of the following: ■ DLCO < 39% predicted ■ ≥10% decrement in FVC during 6 months of follow-up ■ Decrease in pulse oximetry to < 88% during a 6MWT ■ Honeycombing on HRCT (fibrosis score > 2) CYSTIC FIBROSIS FEV1 < 30% of predicted or rapidly declining lung function if FEV1 > 30% (females and patients < 18 yr have a poorer prognosis; consider earlier listing) and/or any of the following: ■ Increasing oxygen requirements ■ Hypercapnia ■ Pulmonary hypertension

■

IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION ■ Persistent NYHA class III or IV on maximal medical therapy ■ Low (350 m) or declining 6MWT ■ Failing therapy with intravenous epoprostenol or equivalent ■ Cardiac index < 2 L/min/m2 ■ Right atrial pressure > 15 mm Hg SARCOIDOSIS ■ NYHA functional class III or IV and any of the following: ■ Hypoxemia at rest ■ Pulmonary hypertension ■ Elevated right atrial pressure > 15 mm Hg BODE, [b]ody mass index, airflow [o]bstruction, [d]yspnea, [e]xercise capacity; DLCO, diffusing capacity for carbon dioxide; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HRCT, high-resolution computed tomography; 6MWT, 6-minute walk test; NYHA, New York Heart Association; PCO2, pressure of carbon dioxide; UIP, usual interstitial pneumonia. Modified from Orens JB, Estenne M, Arcasoy S, et al: International guidelines for the selection of lung transplant candidates: 2006 update. J Heart Lung Transplant 25:745–755, 2006.

the LAS more than posttransplantation survival, which is used only in the net transplant benefit calculation. As designed, the system preferentially allocates lungs to sicker patients while attempting to avoid situations in which outcomes are so poor that there would be no meaningful survival benefit. Since its implementation, the LAS system has had a profound and favorable effect on the dynamics of lung transplantation in the United States.20 Because there is no longer an incentive to place patients on the active waiting list simply to accrue time (many of whom were ultimately deactivated rather than transplanted), the number of actively listed patients has fallen to approximately one half of the previous level. Median waiting time, which had ranged from 2 to 3 years under the time-based allocation system, has decreased to less than 6 months, and one quarter of patients are waiting less than 35 days. Importantly, there has been a significant reduction in the annual death rate

Hypercapnic failure

Hemodynamic status stable

Hypoxic failure

Hemodynamic status unstable

Hemodynamic status stable

PH (severe RV dysfunction) Support level A Arteriovenous (pumpless)

PA-LA (pumpless)

Support level C Veno-Arterial (pump-driven)

Support level B Veno-Venous (pump-driven)

Figure 106-1  Selection of extracorporeal lung support device and configuration. The choice of support device is largely dependent on the type of respiratory failure (hypercarbic or hypoxic) and the hemodynamic status (stable or unstable). LA, left atrium; PA, pulmonary artery; PH, pulmonary hypertension; RV, right ventricle. (From Cypel M, Keshavjee S: Extracorporeal life support pre and post lung transplantation. ECMO Extracorporeal Cardiopulmonary Support in Critical Care (ELSO Red Book), ed 4. Ann Arbor, MI, 2011, Extracorporeal Life Support Organization.)

of patients on the waiting list, one of the stated objectives of the new system. Notably, preferential transplantation of sicker patients has not resulted in an increase in early mortality following transplantation. Further experience will be required to determine the impact of the new system on long-term outcomes following transplantation.

BRIDGING TO TRANSPLANTATION: ARTIFICIAL LUNG TECHNOLOGIES As mentioned earlier, ECMO has been used to bridge critically ill patients to lung transplantation, though, historically, outcomes following transplantation have been suboptimal. Advances in artificial lung technology, including improved membranes, improved pumps, and even ambulatory support systems, make it increasingly possible to support selected patients successfully, permitting them to survive the wait for a suitable donor lung, and, importantly, to achieve a successful posttransplant outcome.21-24 Patients with isolated hypercapneic failure can be bridged with pumpless devices such as the interventional lung assist (iLA) from Novalung, a low-resistance device with a meshwork of hollow fibers maximizing blood/gas diffusion; with this device, blood is propelled by arterial pressure. Patients requiring oxygenation support can be supported with veno-venous configured pump devices. Patients requiring circulatory support, as well as gas exchange support, can be managed with a conventional veno-arterial configuration. It is important to understand the underlying physiology of the patient and to select the device configuration that provides the necessary support (Fig. 106-1). An application unique to patients with pulmonary arterial hypertension is the application of the pumpless iLA device from pulmonary artery to left atrium

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Table 106-2  Standard Lung Donor Criteria Age < 55 yr Clear chest radiograph ■ PaO2 > 300 mm Hg on FIO2 1.0, PEEP 5 cm H2O ■ Cigarette smoking history < 20 pack-years ■ Absence of significant chest trauma ■ No evidence of aspiration or sepsis ■ No prior thoracic surgery on side of harvest ■ Absence of organisms on sputum Gram stain ■ Absence of purulent secretions and gastric contents at bronchoscopy ■ Negative for HIV antibody, hepatitis B surface antigen, and hepatitis C antibody ■ No active or recent history of malignancy (excluding localized squamous or basal cell skin cancer, localized cervical cancer, and primary brain tumors with low metastatic potential and in the absence of invasive procedures to the brain and skull) ■ No history of significant chronic lung disease ■ ■

FIO2, fractional concentration of oxygen in inspired gas; HIV, human immunodeficiency virus; PaO2, arterial oxygen pressure; PEEP, positive end-expiratory pressure.

to offload the right ventricle and provide an “oxygenating septostomy” physiology. This strategy has effectively abolished wait list mortality in the group of patients that traditionally has the highest mortality on the wait list.22,25

DONOR SELECTION AND MANAGEMENT In addition to meeting strict criteria for declaration of brain death, cadaveric lung donors are selected on the basis of established guidelines (Table 106-2).26 Lungs are a particularly fragile organ in the brain-dead patient and are frequently compromised by volume overload, contusion, aspiration of gastric contents, or pneumonia, as well as by extensive prior smoking. As a result, the vast majority of donors fail to meet standard criteria for lung donation, leading to a historical recovery rate of only 15% from cadaveric organ donors deemed able to donate other organs. Although it is reasonable to be conservative with patient safety in mind, there is mounting evidence that these standard criteria may in fact be too stringent, leading to unnecessary wastage of suitable lungs. In one study, 29 pairs of lungs that had been rejected for transplantation were assessed for the magnitude of extravascular water content, intactness of alveolar fluid clearance capacity, and presence of pneumonia or emphysema.27 Twelve pairs (41%) were found to have minimal or no abnormalities and thus to be “potentially suitable” for transplantation. Additional evidence comes from published reports documenting that outcomes with use of “extended criteria” donors are similar to those achieved with use of donors meeting standard criteria.28-32 Use of modified donor management protocols to optimize lung function through judicious fluid management, therapeutic bronchoscopy, and lung recruitment maneuvers has also been shown to enhance lung retrieval rates.33,34 Additionally, a recent multicenter, randomized trial demonstrated that use of a low tidal volume, lungprotective ventilatory protocol (6 to 8 mL/kg; PEEP 8 to

10 cm H2O) in brain-dead potential organ donors resulted in a doubling of lung harvest rates (54% vs. 27%) compared with a conventional ventilatory protocol (10 to 12 mL/kg; PEEP 3 to 5 cm H2O).35 Despite increases in the number of organs successfully retrieved, the demand for organs continues to outstrip supply, prompting a search for alternatives to the braindead donor pool. One emerging source is the non–heartbeating or donation after cardiac death (DCD) donor who has experienced either an out-of-hospital (i.e., uncontrolled) arrest or a planned withdrawal of life support in the operating room. Currently only 1% of lung transplants performed in the United States utilize DCD donors5; in contrast, DCD donors account for 12% of lung transplants in Australia.36 Data suggest that short- and medium-term outcomes are as good as or better than those associated with use of traditional brain-dead donors.36,37 Once a donor has been identified, matching with potential recipients is based on size and ABO blood group compatibility. Prospective human leukocyte antigen (HLA) matching is not performed. However, potential candidates identified through standard pretransplant screening as having preformed circulating antibodies to foreign HLA antigens require either prospective donor-recipient lymphocytotoxic cross-matching or avoidance of donors with specific incompatible antigens.38

LUNG PRESERVATION The standard of lung preservation is hypothermic flush preservation. The most commonly used solution is Perfadex (Vitrolife, Sweden). Cold flush preservation at 4° C decreases the metabolic rate to 5% of normal and hence slows down the dying process of the lung. Although this approach has been useful for clinical lung transplantation, cold static preservation has significant limitations: (1) a decision regarding utilization must be made quickly with limited information in the donor hospital; (2) once the organ is flushed, there is no second chance to reevaluate the organ before removal of the cross clamp at reperfusion; and (3) the focus is on slowing down the dying process and it does not address or take advantage of opportunities to diagnose, treat, repair, or regenerate the donor lung. Ex vivo lung perfusion has been developed to address these limitations. It is now possible to perfuse lungs ex vivo at normothermia for extended periods, thus creating a platform for more detailed assessment of lung function, more accurate diagnosis, and targeted treatment of donor lung injuries to improve the function of the lung after transplantation.39-41 This creates the opportunity to engineer donor organs with gene therapy, cell therapy, and other advanced treatments to create “super-organs” that hopefully will one day afford the recipient long-term allograft function.42,43 Ex vivo lung perfusion has been shown to increase donor lung utilization of lungs that previously could not be used.40,44 Short-term outcomes using lungs conditioned in this fashion have been highly favorable.40,41 Ex vivo lung perfusion is now standard practice in the Toronto Lung Transplant Program41 and is being increasingly applied worldwide.45 The U.S. Food and Drug Administration

1836 PART 3  •  Clinical Respiratory Medicine

recently approved the XVIVO Perfusion System for use in the United States.

Four surgical techniques have been developed: heart-lung transplantation (HLT), single-lung transplantation (SLT), bilateral-lung transplantation (BLT), and living donor bilobar transplantation. The choice of procedure is dictated by such factors as the underlying disease, age of the patient, survival and functional advantages, donor organ availability, and center-specific preferences. Currently, SLT and BLT account for more than 97% of all procedures performed.1

Surgical approaches include transverse thoracosternotomy (“clamshell”) incision, bilateral anterolateral thoracotomies (sparing the sternum), and median sternotomy. In the absence of severe pulmonary hypertension, cardiopulmonary bypass can often be avoided by sustaining the patient on the contralateral lung during implantation of each allograft. The principal indications for this procedure are CF, other forms of bronchiectasis, and severe primary and secondary forms of pulmonary hypertension. In addition, many programs now advocate its use for patients with COPD, arguing that it offers functional and survival advantages over SLT.46-49 Although it is also being employed with increasing frequency in treatment of fibrotic lung disorders, the justification for this is less clear.50,51 As a result of these trends, BLT now accounts for three quarters of all procedures performed worldwide.1

HEART-LUNG TRANSPLANTATION

LIVING DONOR BILOBAR TRANSPLANTATION

HLT was the first procedure to be performed successfully, but it has largely been supplanted by techniques to replace the lungs alone. Currently, fewer than 100 procedures are performed worldwide annually.1 Indications are largely restricted to Eisenmenger syndrome with surgically uncorrectable cardiac lesions and to advanced lung disease with concurrent severe left ventricular dysfunction or extensive coronary artery disease. In the past, the presence of profound right ventricular dysfunction in the setting of severe pulmonary hypertension was deemed to be an indication for heart-lung transplantation. However, subsequent experience with isolated lung transplantation has demonstrated the remarkable ability of the right ventricle to recover once pulmonary artery pressures have normalized.

Living donor bilateral-lobar transplantation was developed chiefly to serve the needs of candidates with far-advanced or deteriorating status that would not allow them to tolerate a protracted wait for a cadaveric donor. The procedure involves transplantation of lower lobes from each of two living, blood group–compatible donors. In order to ensure that the lobes will adequately fill the hemithoraces, it is preferable to employ donors who are taller than the recipient. Patients with CF are particularly well suited as a target population because, even as adults, they tend to be of small stature. Intermediate-term functional outcomes and survival among recipients are similar to those achieved with cadaveric transplantation.52,53 Concerns about excessive risk to the donor have thus far proved to be unfounded. In the two largest series published to date involving a combined total of 315 donors, there were no deaths or episodes of postoperative respiratory failure, and only 9 donors (2.9%) experienced complications of sufficient magnitude to warrant surgical reexploration.54,55 Donation of a lobe results in an average decrement in vital capacity of 17%, a degree of loss that should be of little functional significance in an otherwise normal individual.56 Despite the apparent low risk posed to the donor, living donor transplantation has not gained widespread acceptance. Its use has been further undermined by the LAS allocation system, which expedites transplantation of more severely ill candidates; only nine living-donor transplantation procedures have been performed in the United States since implementation of the LAS system.5

AVAILABLE SURGICAL TECHNIQUES

SINGLE-LUNG TRANSPLANTATION SLT was, until recently, the most commonly performed procedure. Traditionally, a standard posterolateral thoracotomy was utilized, but some surgeons now employ a less invasive anterior axillary muscle-sparing approach in selected cases. Three anastomoses are executed—mainstem bronchus, pulmonary artery, and left atrium (incorporating the two pulmonary veins). Compared with BLT, SLT permits more efficient use of the limited donor supply and is better tolerated by less robust patients, but it provides less functional reserve in the setting of allograft dysfunction. It is an acceptable option for patients with pulmonary fibrosis and COPD. SLT has also been performed successfully in carefully selected patients with severe pulmonary hypertension. In this setting, however, there is an increased risk of perioperative allograft edema because the freshly transplanted lung must bear the burden of nearly the entire cardiac output. This concern has prompted the vast majority of centers to abandon this approach in favor of the bilateral procedure. Because of infectious concerns, SLT is contraindicated in patients with suppurative lung disorders such as CF.

BILATERAL-LUNG TRANSPLANTATION BLT involves the performance of two single-lung transplant procedures in succession during a single operative session.

ROUTINE POSTTRANSPLANTATION MANAGEMENT AND OUTCOMES Care of the lung transplant recipient requires close surveillance to ensure that the allograft is functioning properly, that immunosuppressive medications are properly administered and tolerated, and that complications are detected early and treated expeditiously. Most centers require patients to return frequently for office visits, blood tests, and chest

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radiographs during the initial 2 to 3 months following transplantation and to participate in an intensive pulmonary rehabilitation program during this time. Analogous to home glucose monitoring of the diabetic patient, lung transplant recipients chart their pulmonary function on a daily basis with a handheld microspirometer and are instructed to contact the transplant center if a sustained fall of greater than 10% in the forced expiratory volume in 1 second (FEV1) or forced vital capacity is documented. Many transplant programs employ frequent surveillance bronchoscopies and transbronchial lung biopsies within the first posttransplant year as a means of monitoring the allograft. Such an approach has been demonstrated to detect low-grade rejection and subclinical cytomegalovirus (CMV) pneumonitis in up to 30% of asymptomatic, clinically stable patients.57 However, it has yet to be determined whether treatment of clinically silent disease has a beneficial impact on long-term graft function. Immunosuppressive therapy is initiated immediately at the time of transplantation and is maintained lifelong. No consensus currently exists on the role of induction therapy with lymphocyte/thymocyte-depleting globulin preparations or interleukin-2 (IL-2) receptor antagonists (basiliximab and daclizumab), and only half of all centers currently employ this strategy.1 The lack of consensus reflects insufficient and conflicting data on the ability of these agents to reduce the incidence of acute rejection and bronchiolitis obliterans syndrome (BOS) in the lung transplant population. Maintenance therapy consists of a calcineurin inhibitor (cyclosporine or tacrolimus), purine synthesis inhibitor (azathioprine or mycophenolate), and prednisone. Sirolimus (also known as rapamycin), an inhibitor of IL-2-stimulated T-cell proliferation, is the newest immunosuppressive agent to be introduced into clinical practice. Use of this agent in place of a purine synthesis inhibitor does not reduce the incidence of acute rejection or BOS and is associated with a number of bothersome side effects that commonly lead to discontinuation of the drug.58 Lacking inherent nephrotoxicity, sirolimus has been successfully substituted for calcineurin inhibitors in patients with renal insufficiency, leading to recovery of renal function without undue risk of rejection.59,60 Sirolimus impairs wound healing and has been associated with life-threatening bronchial anastomotic dehiscence when used immediately following transplantation.61 As a result, the drug should never be initiated until complete healing of the bronchial anastomosis has been documented. Individuals providing care to transplant recipients must be familiar with the administration, side effects, and drug interactions of these immunosuppressive agents (Table 106-3). Although serving as the cornerstone of therapy, the use of calcineurin inhibitors is particularly challenging. When administered orally, the bioavailability of these agents is poor and unpredictable, necessitating frequent monitoring of blood levels to ensure appropriate dosing. These drugs are metabolized via the hepatic cytochrome P-450 system, and blood levels are influenced by the concurrent administration of other drugs that affect this enzymatic pathway. Adverse effects of these agents, as well as of the other drugs commonly utilized, are legion and contribute significantly to the morbidity associated with transplantation.

Management of medical comorbidities is an essential component of the care of the lung transplant recipient. Common medical issues that emerge in this population include osteoporosis, hypertension, renal insufficiency, coronary artery disease, diabetes mellitus, and hyperlipidemia.62 Treatment of these conditions is similar to that of the general population.

SURVIVAL Current 1-, 5-, and 10-year survival rates following lung transplantation are 82%, 55%, and 33%, respectively. Survival rates have steadily improved over time, as indicated by an increase in median survival from 3.9 years in 1990–1997 to 6.1 years in 2005–2012.1 Disease-specific differences in survival are apparent but may be confounded by differences in severity of illness, comorbidities, and average age among these populations. In descending order, median survival is 8.3 years for CF, 6.4 years for alpha1antitrypsin deficiency, 5.7 years for sarcoidosis, 5.5 years for COPD and IPAH, and 4.7 years for IPF.1 Mortality is highest during the first year, with primary graft dysfunction and infection representing the most common causes of death. Factors portending an increased risk of early death include ventilator dependence of the recipient before transplantation, a pretransplant diagnosis of pulmonary arterial hypertension, elevated bilirubin, and advanced recipient age.1 Beyond the first year, attrition slows to an annual rate of approximately 5% to 8%. Most late deaths are attributable to the development of BOS, the lethal effects of which are due to both progressive respiratory failure and an increased susceptibility to infection. Whether lung transplantation truly extends survival compared with the natural history of the underlying disease remains a matter of some debate. In the absence of randomized trials, this question has been approached by comparing observed posttransplant survival to survival of wait-list patients or by simulating survival with and without transplantation by statistical modeling; both of these approaches suffer from significant methodologic shortcomings. In the case of IPF, a disease with an extremely poor short-term prognosis, studies have suggested that lung transplantation does confer a survival advantage.18,63 This has been more difficult to demonstrate for COPD, which typically follows a protracted course even in the advanced stages, and available studies comparing wait list and posttransplant survival have yielded conflicting results.18,64,65 A more complex analysis of this issue, employing prognostic models of survival with and without transplantation, found that approximately 45% of COPD patients would gain a survival benefit of at least 1 year by undergoing BLT; only 22% would derive such a benefit if SLT were employed.49 Survival benefit was heavily influenced by pretransplant FEV1, as well as a number of other functional and physiologic parameters. As an example, nearly 80% of patients with an FEV1 less than 16% but only 11% of those with an FEV1 greater than 25% were predicted to gain at least a year of life with BLT. Adults with CF also appear to derive a survival advantage from lung transplantation, though one study found that this was limited to those patients with a predicted 5-year survival without transplantation of less than 50% and without

1838 PART 3  •  Clinical Respiratory Medicine Table 106-3  Commonly Used Immunosuppressive Medications Medication (Class)

Dosing*

Adverse Effects

Drug Interactions

Cyclosporine and tacrolimus (calcineurin inhibitors)

Cyclosporine: dosed to achieve a whole blood trough level of 250–350 ng/mL (first year), then 200–300 ng/mL† Tacrolimus: dosed to achieve a whole blood trough level of 10–12 ng/mL (first year), then 6–8 ng/mL

Nephrotoxicity Hypertension Neurotoxicity (tremor, seizures, white matter disease, headache) Hyperkalemia Hypomagnesemia Hyperuricemia/gout Hemolytic-uremic syndrome Gastroparesis Hyperglycemia Hirsutism (cyclosporine) Gingival hyperplasia (cyclosporine) Thrombocytopenia Anemia Hyperlipidemia Peripheral edema Rash Impaired wound healing Interstitial pneumonitis

INCREASED BLOOD LEVELS Macrolide antibiotics (except azithromycin) Azole antifungals Diltiazem, verapamil Grapefruit juice

Leukopenia Macrocytic anemia Thrombocytopenia Hepatotoxicity Pancreatitis Hypersensitivity reaction (fever, hypotension, rash) Diarrhea Leukopenia Anemia

Synergistic bone marrow suppression when administered with allopurinol

Sirolimus (mTOR inhibitor)

Dosed to achieve a whole blood trough level of 6–12 ng/mL

Azathioprine (purine synthesis inhibitor)

2 mg/kg/day

Mycophenolate mofetil (purine synthesis inhibitor)

1000–1500 mg bid

Prednisone (corticosteroid)

0.5 mg/kg/day for 6–12 wk, then tapered to 0.15 mg/kg/day

Polyclonal antilymphocyte or antithymocyte globulin

Dose depends on specific preparation used

Basiliximab (monoclonal IL-2 receptor antagonist)

20 mg IV on days 1 and 4

Hyperglycemia Hypertension Hyperlipidemia Weight gain Osteoporosis Avascular necrosis Myopathy Mood changes Insomnia Cataracts Leukopenia Thrombocytopenia Anaphylaxis Serum sickness “Cytokine release syndrome”— fever, hypotension Hypersensitivity reactions (rare)

DECREASED BLOOD LEVELS Phenobarbitol Phenytoin Rifampin Same as calcineurin inhibitors

Concurrent use of cyclosporine may decrease serum concentrations of mycophenolate by limiting biliary secretion/enterohepatic recycling No significant interactions

No significant interactions

No significant interactions

*Dosing is based on the protocol used at the Hospital of the University of Pennsylvania; dosing may vary among transplant centers. † Measured by high-performance liquid chromatography assay. IL-2, interleukin-2.

B. cepacia and CF-arthropathy.66,67 In contrast, modeling studies have suggested that CF patients younger than 18 years old rarely achieve a survival benefit.66,68 This contention has been challenged by several authors, who point out potential methodologic shortcomings of these studies.69,70

PULMONARY FUNCTION The peak effect of lung transplantation on pulmonary function parameters is usually not realized until 3 to 6 months following the procedure, at which time the adverse impact of such factors as postoperative pain, weakness, altered

chest wall mechanics, and ischemia-reperfusion lung injury has dissipated. Complete normalization of pulmonary function is the anticipated result of BLT. Following SLT for COPD, the FEV1 increases several fold to a level of approximately 50% to 60% of the predicted normal value (Video 106-1). Similarly, SLT for pulmonary fibrosis results in marked but incomplete improvement in lung volumes, with persistence of a restrictive pattern. Transplantation also leads to correction of gas exchange abnormalities. Oxygenation improves rapidly, permitting the majority of patients to be weaned off of supplemental oxygen within the first week. Hypercapnia may take longer

106  •  Lung Transplantation 1839

to resolve, due to lingering abnormalities in the ventilatory response to carbon dioxide.71

EXERCISE CAPACITY Exercise tolerance improves sufficiently to permit the majority of transplant recipients to achieve functional independence and resume an active lifestyle. Although free of limitations with usual activity, transplant recipients with normal allograft function demonstrate a characteristic reduction in peak exercise performance as assessed by cardiopulmonary exercise testing. Specifically, patients typically achieve a maximum oxygen consumption at peak exercise of only 40% to 60% of predicted.72 Suboptimal exercise performance persists in subjects tested as late as 1 to 2 years following transplantation. Despite the greater magnitude of improvement in pulmonary function experienced by bilateral transplant recipients, there is no significant difference in peak exercise performance between this group and those who receive only one lung.73 Characteristically, breathing reserve, oxygen saturation, and heart rate reserve remain normal during exercise while anaerobic threshold is reduced, a pattern most consistent with skeletal muscle dysfunction. Factors possibly contributing to this include chronic deconditioning, steroid myopathy, and calcineurin inhibitor-induced impairment in muscle mitochondrial respiration.72,74

HEMODYNAMICS When performed in patients with pulmonary hypertension, both SLT and BLT lead to immediate and sustained nor­ malization of pulmonary arterial pressure and enhanced cardiac output.75 In response to a decrease in afterload, right ventricular geometry and performance gradually normalize in the majority of patients.76,77 A threshold of right ventricular dysfunction below which recovery will not happen has yet to be defined.

QUALITY OF LIFE After successful lung transplantation, quality of life measures improve markedly across most domains, achieving levels approximating that of the general population.78-82 Nonetheless, several important limitations have been observed. Although improved from pretransplant status, impairments in psychological functioning—including increased levels of depression and anxiety, and poor perception of body image—persist.78,79 In addition, troubling side effects from immunosuppressive medications adversely affect quality of life.79,82 Finally, the development of BOS is associated with a significant deterioration in quality of life measures.81 Despite improvements in performance status and quality of life, fewer than half of lung transplant recipients return to the workforce.83,84 Factors cited by recipients as barriers to employment include employer bias against hiring an individual with a chronic medical condition, the potential loss of disability income or medical benefits, side effects of medications, concerns about risk of infection in the workplace, and prioritization of recreational activities over work as a posttransplantation goal.

COMPLICATIONS PRIMARY GRAFT DYSFUNCTION Primary graft dysfunction (PGD) is a term applied to the development within 72 hours of transplantation of radiographic opacities in the allograft(s) associated with impaired oxygenation, in the absence of identifiable insults such as volume overload, pneumonia, rejection, atelectasis, or pulmonary venous outflow obstruction.85 PGD is presumed 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. Supporting the concept of PGD as a form of acute, nonimmunologic lung injury, histologic examination of lung tissue from affected patients reveals a prevailing pattern of diffuse alveolar damage.85 A widely used grading system classifies the severity of PGD based on the arterial oxygen pressure-to-fractional concentration of oxygen in inspired gas (arterial PO2/FIO2) ratio (Table 106-4).86 In most cases, the process is mild and transient, but in approximately 10% to 20% of cases, injury is sufficiently severe to cause life-threatening hypoxemia (PGD grade 3) and a clinical course analogous to the acute respiratory distress syndrome. A recent prospective, multicenter cohort study identified a number of risk factors for development of severe PGD.87 Many of these were procedure-related factors: use of an elevated FIO2 during reperfusion, use of cardiopulmonary bypass, SLT, and administration of large volume blood product transfusions. Recipient risk factors were a diagnosis of sarcoidosis, presence of pulmonary hypertension, and overweight or obese body habitus. The only donor-related risk factor identified was a history of smoking. Notably, graft ischemic time was not identified as a risk factor in this study. In another study, an elevated level of IL-8 in bronchoalveolar lavage (BAL) fluid recovered from the donor was associated with the development of severe PGD, supporting the notion that inflammatory events preceding organ harvest may play a role.88 Treatment of severe PGD is supportive, relying on conventional mechanical ventilation utilizing low tidal volume strategies, as well as on such adjunct measures as independent lung ventilation and extracorporeal life support for selected patients who otherwise cannot be stabilized.89,90

Table 106-4  Grading System for Primary Graft Dysfunction Grade

PaO2/FIO2

Radiographic Evidence of Pulmonary Edema

0

>300

Absent

1

>300 200–300

Present

2 3

<200

Present Present

PaO2/FIO2, ratio of arterial oxygen pressure to fractional concentration of oxygen in inspired gas. From Christie JD, Carby M, Bag R, et al: Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part II: Definition. A consensus statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 24:1454–1459, 2005.

1840 PART 3  •  Clinical Respiratory Medicine

A

B

Figure 106-2  Bronchial anastomotic dehiscence. A, Bronchoscopic view immediately distal to the main carina demonstrates partial dehiscence of the right bronchial anastomosis at the 1 o’clock position. B, After several weeks of expectant management, a repeat bronchoscopy demonstrates nearcomplete healing of the dehiscence.

The use of nitric oxide in patients with established graft injury has been associated with sustained reduction in pulmonary artery pressures and improvement in oxygenation.91 However, the prophylactic administration of nitric oxide to all recipients at the time of reperfusion does not reduce the incidence of severe PGD.92 Results of emergency retransplantation in this setting have been poor.93,94 With an associated perioperative mortality rate of 20% to 40%, severe PGD is a leading cause of early deaths among transplant recipients.87,95,96 The risk of death remains excessive even beyond the first year, suggesting that PGD has lingering adverse consequences well after resolution of the acute event. Recovery among survivors is often protracted and incomplete, though attainment of normal lung function and exercise tolerance is possible.97 There appears to be an increased risk of BOS following development of PGD, but data are conflicting on whether the increased risk spans all grades of PGD or is seen exclusively following the most severe grade.98,99

AIRWAY COMPLICATIONS During implantation of the allograft, no attempt is routinely made to reestablish the bronchial arterial circulation. As a consequence, the donor bronchus is precariously dependent on retrograde blood flow through low-pressure pulmonary venous to bronchial vascular collaterals, placing the airway at risk for ischemic injury. Rarely, this may result in bronchial anastomotic dehiscence, which, when extensive, can lead to mediastinitis, pneumothorax, hemorrhage, and death. Treatment of this life-threatening complication previously required risky and often unsuccessful surgical intervention to buttress the anastomosis. More recently, success has been reported with temporary placement of a bare metal airway stent across the dehiscence in order to provide a scaffolding on which granulation tissue can form.100 For lesser degrees of dehiscence, conservative management with reduction in corticosteroid dosing and chest

Figure 106-3  Bronchial anastomotic stricture. Bronchoscopic view of a left main-stem bronchial anastomosis demonstrates marked narrowing of the lumen due to formation of a fibrous web. The true outer margin of the bronchus is outlined by the suture material.

tube evacuation of associated pneumothorax will often lead to successful healing (Fig. 106-2). Ischemic injury to the airway more commonly manifests as necrosis of the anastomotic cartilage and as patchy areas of bronchial mucosal ulceration and pseudomembranes. These devitalized areas in turn place the patient at increased risk for fungal superinfection of the airway (see later). The most common airway complication currently encountered is bronchial anastomotic stenosis, with a reported frequency of 10% to 15% in contemporary series.101,102 Narrowing can be due to excessive granulation tissue, fibrotic stricture (Fig. 106-3), or bronchomalacia

106  •  Lung Transplantation 1841

(the latter two mechanisms likely a sequela of prior ischemic injury). Occasionally, fibrotic strictures can extend beyond the anastomosis, leading to narrowing of the bronchus intermedius (eFig. 106-1) or lobar bronchi. Anastomotic narrowing typically develops within several weeks to months following transplantation. Clues to its presence include focal wheezing on the involved side, recurrent bouts of pneumonia or purulent bronchitis, and suboptimal pulmonary function studies demonstrating airflow obstruction and truncation of the flow-volume loop. Bronchoscopy both confirms the diagnosis and permits therapeutic interventions including balloon dilation, laser debridement, endobronchial brachytherapy, and stent placement.103 Although these measures are often successful in the short term, recurrent stenosis is common, necessitating repeated interventions and leading to compromised functional outcomes and excess mortality.104

PHRENIC NERVE INJURY Phrenic nerve injury following lung transplantation can result from intraoperative traction, use of an iced slurry to cool the allograft in the chest cavity before reperfusion, or transection of the nerve in the setting of extensive fibrous adhesions and difficult hilar dissection. Depending in part on whether screening is restricted to clinically suspected cases or more broadly to all recipients, the reported incidence of phrenic nerve injury ranges from 3% to 30%.105-108 Important albeit nonspecific clues to the presence of phrenic nerve injury include difficulty in weaning from mechanical ventilation, persistent hypercapnia, orthopnea, and radiographic evidence of persistent elevation of the diaphragm and associated basilar atelectasis. Phrenic nerve injury has been associated with increases in ventilator days, tracheostomy rates, and intensive care unit length of stay.106 Achievement of a normal functional outcome is ultimately possible for those with reversible injury, but recovery in some cases may be protracted or incomplete. For severely impaired patients, nocturnal noninvasive ventilatory support and diaphragmatic plication have been successfully employed.109,110

NATIVE LUNG HYPERINFLATION Acute hyperinflation of the native lung leading to respiratory and hemodynamic compromise in the immediate postoperative period has been reported in 15% to 30% of emphysema patients undergoing SLT.111,112 Although risk factors remain poorly defined, the combination of positivepressure ventilation and significant allograft edema serves to magnify the compliance differential between the two lungs and may predispose to this complication. Acute hyperinflation can be rapidly addressed by initiation of independent lung ventilation, ventilating the native lung with a low respiratory rate and a long expiratory time to facilitate complete emptying. Beyond the perioperative period, some SLT recipients with underlying emphysema demonstrate exaggerated or progressive native lung hyperinflation that more insidiously compromises the function of the allograft. In this setting, surgical volume reduction of the native lung can result in significant functional improvement.113

INFECTION Infection rates among lung transplant recipients are several fold higher than among recipients of other solid organs. The greater risk is likely related to the unique exposure of the lung allograft to microorganisms via inhalation and aspiration and to the higher level of immunosuppression maintained in these patients. A comprehensive discussion of infectious complications is beyond the scope of this chapter; only the most common pathogens are discussed.

Bacteria Bacterial infections of the lower respiratory tract account for the majority of infectious complications and have a bimodal temporal distribution.114,115 Bacterial pneumonia is most frequently encountered within the first month posttransplantation. In addition to the immunosuppressed status of the recipient, factors that predispose to early bacterial pneumonia include the need for prolonged mechanical ventilatory support, blunted cough due to postoperative pain and weakness, disruption of lymphatics, and ischemic injury to the bronchial mucosa with resultant impairment in mucociliary clearance. Although passive transfer of occult infection with the transplanted organ is an additional concern, the presence of organisms on Gram stain of donor bronchial washings is not predictive of subsequent pneumonia in the recipient.116 Bacterial infections, in the form of purulent bronchitis, bronchiectasis, and pneumonia, reemerge as a late complication among patients who develop BOS. Gram-negative pathogens, in particular P. aeruginosa (see eFig. 91-1), are most frequently isolated in association with both early and late infectious events.114,115 Cytomegalovirus CMV is the most common viral pathogen encountered following lung transplantation, though in the era of effective prophylaxis, its incidence and impact have diminished considerably.115 Infection can develop by transfer of virus with the allograft or transfused blood products or by reactivation of latent virus remotely acquired by the recipient. Seronegative recipients who acquire organs from seropositive donors are at greatest risk for developing infection, and these primary infections tend to be the most severe. Although donor-positive/recipient-negative mismatching has been identified as a risk factor for increased mortality in the International Society for Heart and Lung Transplantation Registry,1 this may no longer be the case with the current widespread use of effective prophylactic regimens.117 In the absence of prophylaxis, CMV infection typically emerges 1 to 3 months following transplantation; antiviral prophylaxis shifts the onset to later in the course, often in the initial months after the antiviral agent is discontinued. Infection is often subclinical, evidenced only by silent viremia or shedding of virus in the respiratory tract. Clinical disease may present as a mononucleosis-like syndrome of fever, malaise, and leukopenia (“CMV syndrome”) or as organ-specific invasion of the lung, gastrointestinal tract, central nervous system, or retina. Detection of virus in peripheral blood by either the pp65 antigenemia assay or polymerase chain reaction (PCR) techniques establishes a diagnosis of CMV infection but does not necessarily reflect

1842 PART 3  •  Clinical Respiratory Medicine

events at the tissue level. A diagnosis of CMV pneumonia, the most common manifestation of invasive disease in the lung transplant recipient (see eFigs. 91-2 and 91-3), is unequivocally established only by demonstration of characteristic viral cytopathic changes on lung biopsy or on cytologic specimens obtained by BAL, but the sensitivity of these findings is relatively low. Caution must be exercised in interpretation of a positive viral culture or PCR of BAL specimens because virus can be shed into the respiratory tract in the absence of tissue invasion. Standard treatment of CMV syndrome and tissue-invasive disease consists of a 2- to 3-week course of intravenous ganciclovir at a dose of 5 mg/kg twice daily, adjusted for renal insufficiency. Monitoring of peripheral blood viral load should be performed weekly to confirm response to therapy. Treatment should be continued until at least 1 week after an undetectable viral load is documented.118 Some experts advocate the addition of CMV hyperimmune globulin in treatment of severe disease, but evidence supporting this practice is scant. Although treatment is effective, relapse rates of up to 60% in primary infection and 20% in seropositive recipients have been reported.119 Initiation of oral valganciclovir as secondary prophylaxis after completion of definitive treatment is a common practice, but its impact on relapse rates is uncertain. In an attempt to minimize the adverse impact of CMV infection on the posttransplantation course, emphasis has shifted to preventive strategies. Numerous prospective, randomized trials have documented the efficacy of antiviral prophylaxis in delaying the onset and reducing the incidence and severity of CMV infection.120 Oral valganciclovir has largely replaced intravenous ganciclovir as the prophylactic agent of choice, due to its excellent bioavailability, ease of administration, and demonstrated efficacy.121 Universal prophylaxis of all donor-seropositive/recipientseronegative patients is recommended because the risk of CMV disease is high.118 Because the risk of disease is significantly lower in seropositive recipients (independent of donor status), it has been argued that universal prophylaxis of this group leads to overtreatment, increasing costs and unduly exposing patients to the risk of drug toxicity. In this population, preemptive strategies targeting antiviral therapy exclusively to patients demonstrating a rising viral load in peripheral blood have been advocated, but many programs still adhere to a universal prophylaxis strategy.122 Consensus guidelines recommend a minimum of 6 months of prophylaxis for donor-positive/recipient-negative patients and 3 to 6 months for recipient-positive patients.123 However, a recent randomized, controlled trial of at-risk lung transplant recipients (either donor or recipient seropositive) demonstrated a marked reduction in the incidence of CMV disease with use of a 12-month course of valganciclovir prophylaxis compared with a 3-month course (4% vs. 32%).124 Additional studies are required to determine whether 12 months is necessary or excessive and whether all at-risk subgroups require the same regimen. Emergence of ganciclovir-resistant strains of CMV has been reported in 5% to 15% of lung transplant recipients with CMV infection.125,126 Risk factors that have been identified include donor-positive/recipient-negative CMV status, use of potent immunosuppressive agents such as antilymphocyte antibodies and daclizumab, increased number of

CMV episodes, and prolonged exposure to ganciclovir.127,128 Foscarnet, administered alone or in combination with ganciclovir, is the agent of choice for treatment of ganciclovirresistant disease.126 The drug is potentially nephrotoxic, and careful monitoring of renal function is essential. Although treatment is often successful, the presence of ganciclovirresistant disease is associated with decreased survival in lung transplant recipients.128,129

Aspergillus Aspergillus species are the most frequently encountered fungal pathogens among lung transplant recipients. As a ubiquitous organism acquired by inhalation, Aspergillus colonizes the airways of approximately one quarter of transplant recipients.130 Airway colonization itself does not appear to pose a major risk of subsequent progression to invasive disease.130 Whether this is due to the inherently benign nature of colonization or to the common practice of initiating fungal prophylaxis when colonization is detected is unclear. Aspergillus infects the bronchial tree in approximately 5% of lung transplant recipients.130 In most cases, infection is localized to the bronchial anastomosis, where devitalized cartilage and foreign suture material create a nurturing environment. Less commonly, infection may present as a more diffuse ulcerative bronchitis with formation of pseudomembranes, typically following in the wake of a severe ischemic injury to the bronchial mucosa. Clustered within the first 6 months posttransplantation, these airway infections are usually asymptomatic and detected only by surveillance bronchoscopy. Although usually responsive to oral azoles or to inhaled or intravenous amphotericin, airway infections have rarely progressed to invasive pneumonia or have resulted in fatal erosion into the adjacent pulmonary artery.130,131 An increased risk of subsequent bronchial stenosis or bronchomalacia has also been reported, but it is unclear whether this is a consequence of the infection or of an underlying ischemic injury to the bronchus that predisposed to infection.132,133 Invasive aspergillosis, a far more serious form of infection, develops in 5% of lung transplant recipients, most commonly within the first year.130 It nearly always involves the lung but may disseminate to distant sites, particularly the brain, in a minority of patients. Symptoms are nonspecific and include fever, cough, pleuritic chest pain, and hemoptysis. Radiographically, pulmonary aspergillosis may appear as single (see eFigs. 91-7 and 91-8B) or multiple nodular (see eFig. 91-8A) or cavitary opacities or as alveolar consolidation (Fig. 106-4). The “halo sign”—a rim of ground-glass attenuation surrounding a central nodular opacity—is a suggestive but uncommon finding on chest computed tomography (CT) scans. Diagnosing invasive pulmonary aspergillosis can be challenging. As discussed previously, many lung transplant recipients are colonized with Aspergillus, making it difficult to interpret the significance of positive fungal stains and cultures derived from BAL specimens. Conversely, the sensitivity of bronchoscopic studies has been reported in the range of only 45% to 62% in solid organ transplant recipients with invasive disease.134 Measurement of galactomannan levels in serum or BAL fluid has been touted as a useful test for establishing a diagnosis of invasive disease in certain

106  •  Lung Transplantation 1843

ate descriptor (i.e., hyperacute rejection, acute cellular rejection, antibody-mediated rejection). However, the pathogenetic mechanisms underlying chronic forms of allograft dysfunction are less clear and both immunologic and nonimmunologic insults have been implicated. Although still part of the transplant lexicon, the term “chronic rejection” is misleading because it oversimplifies both the mechanism and the spectrum of phenotypes that characterize long-term allograft impairment. The term chronic lung allograft dysfunction (CLAD) is emerging as a preferred descriptor, comprising the most commonly encountered form, BOS, as well as newly recognized variants such as restrictive allograft syndrome. The various forms of rejection and CLAD are described in detail in the following sections. Features of the two most commonly encountered entities—acute cellular rejection and BOS—are summarized in Table 106-5. Figure 106-4  Invasive aspergillosis. Bilateral lung transplant recipient with a large right upper lobe cavity containing an air-fluid level. Transthoracic needle biopsy demonstrated fungal elements morphologically consistent with Aspergillus species. The patient failed to respond to antifungal therapy and and required surgical resection for definitive cure.

patient populations; preliminary experience in lung transplant recipients suggests an unacceptably low sensitivity for both serum and BAL, though specificity appears to be high.135,136 In the context of compatible clinical and radiographic features and/or demonstration of Aspergillus in respiratory secretions by culture or cytology, the clinician must exercise judgment in deciding whether to initiate an empirical trial of antifungal therapy or pursue more definitive proof by means of transthoracic needle biopsy or surgical lung biopsy. Amphotericin B was traditionally the mainstay of therapy for invasive aspergillosis. More recently, however, the triazole voriconazole has been shown to have superior efficacy and less toxicity than amphotericin B and has emerged as the treatment of choice.137 Voriconazole is a potent inhibitor of the cytochrome P-450 hepatic enzyme system and can lead to dangerously high blood levels of concurrently administered calcineurin inhibitors and sirolimus if appropriate adjustments in the dosing of these agents are not made. The echinocandins (e.g., caspofungin) represent a third class of agents that have been successfully employed in the treatment of invasive aspergillosis.138 Despite the availability of antifungal therapy, mortality rates in the range of 60% to 80% have been reported.130,139 The therapeutic role of surgical resection remains uncertain, but surgery has been advocated in cases of localized infection refractory to medical therapy.140,141

REJECTION AND CHRONIC ALLOGRAFT DYSFUNCTION Despite the use of potent immunosuppressive agents, allograft rejection and chronic allograft dysfunction remain pervasive problems that constrain long-term graft and patient survival. Humoral and cellular alloimmune mechanisms have been defined to varying degrees for the more acute insults, and thus the term “rejection” is an appropri-

Hyperacute Rejection Hyperacute rejection is a rare but highly lethal complication mediated by preformed antibodies of recipient origin directed against HLA antigens contained in donor tissue. The pulmonary microvascular endothelium is the principal target, leading to complement- and neutrophil-mediated damage and widespread deposition of platelet/fibrin thrombi.142 Hyperacute rejection becomes clinically manifest within minutes to hours of establishing perfusion to the freshly implanted lung. The allograft appears dusky, mottled, and grossly edematous on direct inspection and densely opacified on chest radiograph. Reflecting the severity of pulmonary edema, copious amounts of pink, frothy edema fluid often are produced by the allograft and must be frequently suctioned from the endotracheal tube. Profound graft dysfunction and hemodynamic instability ensue. Four of the five cases reported in the literature resulted in death.143 The one surviving patient was successfully managed with a combination of plasmapheresis, antithymocyte globulin, and cyclophosphamide.144 Routine screening of all lung transplant candidates for preformed anti-HLA antibodies and either avoidance of donors with the targeted antigens or prospective cross-matching before transplantation have proved to be highly effective in minimizing the risk of hyperacute rejection. Acute Cellular Rejection Frequent surveillance of the allograft by transbronchial biopsy has demonstrated that most transplant recipients experience at least one episode of acute cellular rejection in the first year.57 Beyond this initial period, the incidence of acute cellular rejection declines considerably. Risk factors for development of acute rejection remain poorly defined. Data are conflicting on whether the degree of HLA discordance between donor and recipient represents a risk factor.57,145,146 Polymorphisms in Toll-like receptor 4 that down-regulate recipient innate immune responsiveness are associated with a lower incidence of acute cellular rejection.145 Episodes of acute cellular rejection may be clinically silent in up to 40% of cases.57 When present, clinical manifestations are nonspecific and include malaise, low-grade fever, dyspnea, cough, and leukocytosis. Radiographic opacities (eFig. 106-2), a decline in arterial oxygenation at

1844 PART 3  •  Clinical Respiratory Medicine Table 106-5  Features of Acute Cellular Rejection and Bronchiolitis Obliterans Syndrome (BOS) Feature

Acute Cellular Rejection

BOS

Onset after transplant

Beyond first year

Risk factors

Days to months; less common beyond the first year Uncertain

Histology

Perivascular lymphocytic infiltrates

Signs and symptoms

Pulmonary function testing

Low-grade fever, dyspnea, cough, impaired oxygenation, leukocytosis Alveolar or interstitial opacities, pleural effusions Ground-glass or alveolar opacities, interlobular septal thickening Proportional decline in FEV1 and FVC

Yield of transbronchial biopsy Treatment Outcome

High High-dose corticosteroids Favorable response to treatment

Chest radiograph High-resolution CT

rest or with exercise, and an abrupt fall of greater than 10% in spirometric values are important clues to the possible presence of rejection, but similar findings accompany bouts of infection. Reliance on clinical and radiographic criteria alone runs the risk of misdiagnosis and needless augmentation of immunosuppression. Transbronchial lung biopsy represents the “gold standard” for diagnosis of acute cellular rejection. The procedure is safe, can be performed in serial fashion over time, and has a high sensitivity and specificity. The histologic hallmark is the presence of perivascular lymphocytic infiltrates that, in more severe cases, spill over into the adjacent interstitium and alveolar air spaces. Lymphocytic bronchiolitis may accompany the parenchymal involvement or may be an independent feature. A histologic classification system has been universally adopted to grade the severity of acute cellular rejection (Table 106-6).147 Conventional treatment consists of a 3-day pulse of intravenous Solu-Medrol at a daily dose of 15 mg/kg. In most cases, this results in rapid improvement in symptoms, pulmonary function, and radiographic abnormalities, but follow-up biopsies show histologic evidence of persistent rejection in 30% of patients with prior mild (A2) acute rejection and 44% of patients with prior moderate (A3) acute rejection.148 Asymptomatic and functionally stable patients with minimal (A1) rejection have typically been observed without treatment, but data demonstrating progression to a higher grade of acute rejection in one quarter of cases and an increased risk of developing BOS have challenged this approach.149 A variety of modalities have been employed for refractory or recurrent acute rejection including antilymphocyte antibody preparations and photopheresis, an immunomodulatory treatment using leukapheresis to collect white blood cells (WBCs), which are then treated with an ultraviolet light sensitizer, exposed to ultraviolet light, and returned to the body where they suppress T-cell function.

Acute rejection, lymphocytic bronchiolitis, community respiratory viruses, primary graft dysfunction, silent aspiration, CMV pneumonitis, airways colonization with Aspergillus or Pseudomonas species Bronchiolar submucosal inflammation and fibrosis; luminal obliteration Dyspnea, chronic cough, recurrent bouts of purulent bronchitis Clear lung fields (may show hyperinflation) Tree-in-bud opacities, bronchiectasis, air trapping Disproportionate decline in FEV1 with worsening obstructive pattern Low Uncertain: azithromycin is a popular but unproven option Poor response to treatment; progressive allograft dysfunction in many cases

Table 106-6  Histologic Grading System for Acute Cellular Rejection Grade

Description

0 (none) 1 (minimal)

Normal pulmonary parenchyma Scattered, infrequent perivascular mononuclear infiltrates Frequent perivascular mononuclear infiltrates surrounding venules and arterioles; readily recognizable at low magnification Easily recognizable cuffing of venules and arterioles by dense perivascular mononuclear cell infiltrates, with extension of the inflammatory cell infiltrate into perivascular and peribronchiolar alveolar septa and air spaces Diffuse perivascular, interstitial, and air space infiltrates of mononuclear cells with prominent alveolar pneumocyte damage and endothelialitis

2 (mild)

3 (moderate)

4 (severe)

From Stewart S, Fishbein MC, Snell GI, et al: Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung Transplant 26:1229–1242, 2007.

Acute Antibody-Mediated Rejection There is emerging evidence in support of a second form of acute rejection, mediated by donor-specific anti-HLA alloantibodies that develop de novo following transplantation.150,151 The clinical presentation can be indistinguishable from acute cellular rejection, with dyspnea, hypoxemia, and diffuse radiographic opacities. Hemoptysis should raise suspicion of this entity, but it is present in only 25% of cases.150 The suggested diagnostic criteria for acute antibody-mediated rejection are (1) presence of circulating donor-specific anti-HLA antibodies; (2) histopathologic evidence of capillaritis; and (3) detection of endothelial cell C4d deposition. Less than half of patients in the largest case series responded to corticosteroids alone; the addition of

106  •  Lung Transplantation 1845

plasmapheresis was beneficial in the majority of steroidrefractory cases.150 Intravenous immunoglobulin and antiCD20 monoclonal antibodies have also been used as adjunctive therapy.151

Bronchiolitis Obliterans Syndrome Bronchiolitis obliterans, presumed to represent the consequences of “chronic rejection,” stands as the major impediment to long-term graft and patient survival. Bronchiolitis obliterans is a fibroproliferative process characterized by submucosal inflammation and fibrosis of the bronchiolar walls, ultimately leading to complete obliteration of the airway lumen. The functional consequence of this process is progressive and largely irreversible airflow obstruction. Because the characteristic histology is difficult to demonstrate by transbronchial lung biopsy, the FEV1 has been adopted as an easily obtained diagnostic surrogate for histology, and the term bronchiolitis obliterans syndrome (BOS) has been applied to this functionally defined disorder (Table 106-7).152 Approximately 50% of transplant recipients develop BOS by 5 years and 75% by 10 years.1 As originally conceived, BOS was defined as an otherwise unexplained and sustained fall in FEV1 by at least 20% from posttransplant baseline. Concern that this definition might delay diagnosis beyond a stage amenable to treatment prompted

Table 106-7  Grading System for Bronchiolitis Obliterans Syndrome Stage

Spirometric Criteria

0

FEV1 >90% of baseline and FEF25%–75% >75% of baseline

0-potential

FEV1 81%–90% of baseline and/or FEF25%–75% ≤75% of baseline

1 2 3

FEV1 66%–80% of baseline FEV1 51%–65% of baseline FEV1 ≤50% of baseline

FEF25%–75%, mean forced expiratory flow between 25% and 75% of forced vital capacity; FEV1, forced expiratory volume in 1 second. From Estenne M, Maurer JR, Boehler A, et al: Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 21:297–310, 2002.

A

the more recent introduction of a BOS 0-potential (BOS 0-p) stage, defined as a decline in FEV1 by 10% to 19% or in mean forced expiratory flow between 25% and 75% of the forced vital capacity (FEF25%–75%) by at least 25%. The FEV1 criterion for BOS 0-p has proved to be a reasonable predictor of patients at risk for progression to more advanced BOS, with a positive predictive value of 60% for progression within 1 year and 80% for progression within 4 years.153,154 The positive predictive value of the FEV1 criterion is lower in SLT recipients with native lung emphysema, likely because of the confounding impact of native lung hyperinflation on lung function.154 Notably, the FEF25%–75% criterion suffers from a low positive predictive value in all recipient populations and is of questionable clinical utility.153,154 Acute cellular rejection and lymphocytic bronchiolitis have been consistently identified as major risk factors for development of BOS, supporting the view that BOS is a consequence of alloimmune injury.155,156 Whereas the risk of BOS appears to correlate with the severity and frequency of these immunologic insults, even minimal (A1) acute rejection is associated with an increased risk.149,157 Other possible immune-mediated risk factors include the presence of anti-HLA antibodies (particularly donor specific) and the development of anti–type V collagen antibodies.158,159 Nonimmune factors may also be important in initiating or perpetuating injury, suggesting that BOS may represent the end result of a wide array of insults to the airway epithelium. These factors include CMV pneumonitis, community respiratory viral infections, airway colonization with Aspergillus or Pseudomonas, primary graft dysfunction, and gastroesophageal reflux with occult aspiration.98,156,160-164 Although often viewed as a late complication, BOS pre­ sents within the first 2 years after transplant in one third to one half of cases (“early-onset BOS”).165,166 The decline in FEV1 that heralds the onset of BOS may be either insidious or abrupt. Dyspnea, weight loss, cough, and recurrent bouts of purulent tracheobronchitis, with recovery of P. aeruginosa from sputum cultures, are characteristic clinical features. Although chest radiographs are usually unremarkable, high-resolution CT commonly reveals air trapping (eFig. 106-3 and Videos 106-2 and 106-3), tree-in-bud opacities, and/or bronchiectasis (Fig. 106-5). The natural history of BOS is highly variable; those with early or abrupt

B

Figure 106-5  Radiographic features of bronchiolitis obliterans syndrome. A, High-resolution CT image obtained during expiration demonstrates a mosaic attenuation pattern consistent with air trapping. B, Image obtained from another patient with bronchiolitis obliterans syndrome demonstrates extensive bronchiectasis.

1846 PART 3  •  Clinical Respiratory Medicine

onset generally experience more rapid decline in lung function and higher mortality.165,166 Median survival from diagnosis is 1.5 years and 2.5 years for those with early- and late-onset BOS, respectively.165 A myriad of immunosuppressive strategies have been employed in the treatment of BOS, including use of conventional agents (e.g., pulse corticosteroids), inhaled cyclosporine, antilymphocyte antibodies, photopheresis, and total lymphoid irradiation, but consensus is lacking on the optimal approach.167,168 At best, immunosuppressive measures appear to slow the rate of decline rather than to arrest or reverse the process. More recently, azithromycin has emerged as a popular alternative, based on retrospective studies documenting short-term improvement in the FEV1 in approximately 30% to 40% of patients with BOS treated with this agent.169-172 In contrast to nonresponders, responders demonstrate higher pretreatment levels of BAL neutrophilia and a marked reduction in neutrophilia following initiation of therapy. This lends credence to the notion that the beneficial effects of macrolides relate in large part to their ability to suppress airway IL-8 production and neutrophil recruitment.170,171 Although still controversial, performance of surgical fundoplication to control gastroesophageal reflux has been associated with improvement in lung function in some patients with BOS.173 Adjuvant measures to mobilize respiratory secretions and control bacterial infection of the airways—including chest percussion, flutter or acapella valve, and inhaled and systemic antibiotics—may be of benefit in patients with accompanying bronchiectasis. At this time, the only definitive treatment for advanced BOS is retransplantation. The development of strategies to prevent BOS is an area of intense interest but, to date, little substantive progress. In recognition of the established link between acute rejection and BOS, most transplant centers routinely perform surveillance lung biopsies to detect and treat clinically silent acute rejection, but the impact of this strategy on risk of BOS remains uncertain.174 Early identification of recipients with gastroesophageal reflux and aggressive correction with fundoplication may delay or prevent onset of BOS, but this remains a controversial strategy.175 In a small randomized trial, the addition of inhaled cyclosporine to a conventional immunosuppressive regimen was associated with a dramatic reduction in the incidence of BOS, but a subsequent multicenter trial failed to demonstrate benefit.176,177 A small, single-center, randomized, placebo-controlled trial demonstrated that the prophylactic administration of azithromycin after transplantation improved BOS-free survival, but larger, multicenter studies will be required to corroborate these findings.178 Finally, some centers have employed a strategy to screen for donor-specific antibodies and, if detected, treat with intravenous immunoglobulin and rituximab in the hope of reducing the subsequent risk of developing BOS.179 Again, however, additional studies are required to assess the efficacy of this approach.

Other Forms of Chronic Lung Allograft Dysfunction Several other overlapping forms of CLAD that are distinct from BOS have recently been described. Variously termed “restrictive allograft syndrome,”180,181 “restrictive-CLAD,”182 and “acute fibrinoid organizing pneumonia,”183 these enti-

ties share in common a restrictive physiology and the presence of interstitial, alveolar, or ground-glass opacities on chest CT scans. The histologic findings vary among the published reports and include diffuse alveolar damage, interstitial fibrosis, and acute fibrinoid organizing pneumonia. There is remarkable agreement among the various reports on one point—survival of these patients is considerably worse than that of recipients with the more commonly encountered BOS.

POSTTRANSPLANTATION LYMPHOPROLIFERATIVE DISORDER Posttransplant lymphoproliferative disorder (PTLD) describes a spectrum of abnormal proliferative responses involving B cells in the majority of cases and ranging from benign polyclonal hyperplasia to malignant lymphomas. In approximately 90% of cases, Epstein-Barr virus (EBV) is the stimulus for B-cell proliferation, which proceeds in an unchecked fashion due to the muted cytotoxic T-cell response in the immunosuppressed host. EBV-naive recipients who acquire primary infection at the time of organ transplantation are at greatest risk of developing PTLD.184 A higher intensity of immunosuppression and, in particular, the use of antilymphocyte antibody preparations have also been implicated as risk factors. Among the myriad neoplasms that arise following lung transplantation, PTLD is second in frequency only to nonmelanoma skin cancers, with an incidence of approximately 5%.185 The risk of developing PTLD is greatest within the first posttransplantation year, though up to half of all cases are seen beyond this point. The majority of earlyonset cases involve the allograft, typically presenting as one or more pulmonary nodules that may be accompanied by mediastinal adenopathy (Fig. 106-6). In contrast, beyond the first year, intra-abdominal and disseminated forms of disease predominate.185 The diagnosis of PTLD is most firmly established by tissue biopsy, though fine-needle aspiration may occasionally

Figure 106-6  Posttransplantation lymphoproliferative disorder. CT scan demonstrates multiple nodules and masses, proven on biopsy to represent a high-grade B-cell lymphoma. In situ hybridization studies revealed the presence of Epstein-Barr virus RNA.

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yield sufficient material to make a cytologic diagnosis. Care must be exercised in interpreting transbronchial lung biopsies because the aggregates of lymphocytes associated with acute cellular rejection can appear similar to foci of PTLD on these small tissue specimens. Demonstration of the presence of EBV-infected cells by in situ hybridization or immunohistochemical staining can help to confirm a diagnosis in difficult cases. Determination of EBV viral load in the peripheral blood using DNA amplification techniques has been touted as an ancillary diagnostic tool. Preliminary studies involving adult lung transplant recipients suggest that an elevated viral load correlates with the presence of PTLD with a high degree of specificity (i.e., low false-positive rate), but the sensitivity is as low as 39%.186,187 Additional studies employing uniform assay techniques and threshold values for positive results are required before conclusions can be drawn about the clinical utility of this test. Initial treatment of PTLD involves reduction in the magnitude of immunosuppression to permit partial restoration of host cellular immunity against EBV. Regression of tumor is seen in up to two thirds of cases, but there is an attendant risk of precipitating acute or chronic rejection and patients must be monitored closely.188 For patients who fail to achieve a complete remission, cannot tolerate reduced immunosuppression, or have rapidly progressive disease, immunotherapy with anti-CD20 monoclonal antibodies (rituximab) has emerged as the preferred option. Use of this agent in the solid organ transplant population is generally well tolerated and associated with a complete response rate of 60%.189 In contrast, experience with standard chemotherapy has been poor, with up to one quarter of patients succumbing to treatment-related complications.189 There is no proven role for antiviral therapy in the setting of established PTLD, though there is suggestive evidence that the prophylactic use of antiviral agents may reduce the subsequent risk of developing PTLD.190

A

LUNG CANCER The development of lung cancer following lung transplantation has been reported almost exclusively in patients with underlying COPD or pulmonary fibrosis, the majority of whom have had significant prior smoking histories. The reported incidence of lung cancer following transplantation is 2% to 6% in patients with COPD and 3% to 4% in patients with pulmonary fibrosis.191-194 Data are conflicting on whether transplantation confers an increased likelihood of developing this form of cancer or whether the incidence is comparable with that of the general population with similar risk factors. Lung cancer most commonly arises in the native lung of SLT recipients. Less commonly, a previously unsuspected cancer may be incidentally detected in the explanted lung removed at the time of transplantation and may then recur in the allograft or in distant sites. A high rate of recurrence has also been documented in instances when lung transplantation has been performed as definitive treatment for underlying bronchioalveolar carcinoma.4 Finally, there are rare reports of lung cancer of donor origin transmitted to the recipient.195 Lung cancer in the transplant recipient often progresses at a rapid pace, potentially leading to initial confusion with an infectious process (Fig. 106-7).191 This aggressive behavior may reflect loss of antitumor immune surveillance in the immunosuppressed host or may be due to a more specific effect of cyclosporine in promoting tumor growth.196 Overall prognosis is poor but should not preclude attempts at curative resection in the rare instances in which earlystage disease is encountered.

RECURRENCE OF PRIMARY DISEASE A number of primary disorders have been documented to recur in the allograft following transplantation.197 Although

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Figure 106-7  Bronchogenic carcinoma arising in the native lung. The patient had undergone a left single-lung transplant for idiopathic pulmonary fibrosis (IPF). A, Chest radiograph demonstrates slight fullness in the infrahilar region of the native right lung (arrow). B, Repeat chest radiograph only 2 months later demonstrates marked enlargement of the right infrahilar mass, as well as an increase in adjacent interstitial opacities. This proved to be a right lower lobe squamous cell lung cancer with associated lymphangitic spread.

1848 PART 3  •  Clinical Respiratory Medicine

accurate figures are not available, sarcoidosis appears to have the greatest propensity to do so. Recurrence of sarcoidosis is typically asymptomatic and marked by incidental recovery of noncaseating granulomas on bronchoscopy and occasionally by the presence of micronodular opacities in the upper lobes on CT scan. Cases of recurrent lymphangioleiomyomatosis have also been reported. The abnormal smooth muscle cells found in the allograft are of recipient origin, suggesting that the mechanism of recurrence involves migration or metastasis from an extrapulmonary site.198 Other diseases for which recurrence has been reported include Langerhans cell histiocytosis, desquamative interstitial pneumonia, and diffuse panbronchiolitis. Recurrence of emphysema in the allograft was documented in a recipient 11 years after transplantation for alpha1-antitrypsin deficiency.199 The patient had resumed smoking and this was presumed to play a central role in accelerating the recurrence of disease. BAL fluid obtained after disease recurrence demonstrated free elastase activity, suggesting that the endogenous antiprotease defenses had been overwhelmed. These observations highlight the need for alpha1-antitrypsin-deficient transplant recipients to abstain from smoking but do not provide justification for the routine use of enzyme replacement therapy following transplantation. As previously mentioned, attempts to utilize lung transplantation as a definitive treatment for bronchioalveolar carcinoma resulted in recurrence rates of approximately 50%, leading the vast majority of centers to abandon this approach.4

RETRANSPLANTATION Retransplantation has been utilized as a salvage technique for refractory graft failure. Outcomes following early, emergent retransplantation for primary graft dysfunction are poor, and consequently, use of this intervention in this setting is discouraged.94,200 In contrast, retransplantation of carefully selected patients with chronic graft failure due to BOS results in survival rates that approach that of initial transplantation. The new allocation system introduced in the United States assigns a high priority to candidates with BOS, on par with that afforded to patients with IPF. This has led to shortened waiting times and to a doubling in number of retransplant procedures performed annually.94 Although the feasibility and reasonable success of retransplantation for BOS have been established, the issue of its appropriateness in the setting of severe organ shortages remains a vexing ethical dilemma.

FUTURE DIRECTIONS Since its introduction in 1963, lung transplantation has evolved from a heroic surgical therapy to a standard option for select patients with advanced lung disease. Nonetheless, major hurdles must yet be overcome in order to facilitate wider applicability of lung transplantation and more enduring results. The donor organ supply must be expanded to meet demand. More effective and less toxic immunosuppressive strategies must be developed to prevent graft loss

from chronic immunologic injury. An improved understanding of BOS and other forms of chronic allograft dysfunction is required in order to develop strategies to treat injuries of the transplanted lung in a targeted fashion. Increased utilization of ex vivo lung perfusion for assessment and treatment may offer a partial solution to enhancing the number, quality, and durability of lung allografts. The ultimate solution to many of the current impediments will likely come with advances in gene therapy, stem cell therapy, and tissue engineering. Advances in immunologic manipulation of the recipient and immunologic modulation of the organs to look more like “self ” will ultimately one day bring us closer to a state of immune tolerance (i.e., permanent graft acceptance in the absence of chronically administered immunosuppressive agents). It is only through these basic research initiatives that lung transplantation will truly fulfill its potential as a safe, effective, and durable treatment option.

Key Points Lung transplantation is a therapeutic option for a broad spectrum of advanced nonmalignant disorders of the airways, lung parenchyma, and pulmonary vasculature. The most common indications are COPD, idiopathic pulmonary fibrosis, and cystic fibrosis. ■ Single-lung and bilateral-lung transplants account for 97% of all procedures; heart-lung transplantation and living donor bilobar transplantation account for the rest. ■ The lung allocation system now utilized in the United States grants priority to patients with the greatest predicted “net transplant benefit”—the difference between predicted 1-year survival with versus without transplantation. ■ One-, 5-, and 10-year survival rates following transplantation are 82%, 55%, and 33%, respectively. ■ Common early complications include primary graft dysfunction due to ischemia-reperfusion injury, bronchial anastomotic stenosis, and bacterial pneumonias. ■ Infection rates among lung transplant recipients are several fold higher than among recipients of other solid organs, presumably due to exposure of the allograft to microorganisms via inhalation and aspiration and the higher level of immunosuppression in the lung transplant patients. ■ Acute cellular rejection, characterized by perivascular lymphocytic infiltration, is commonly encountered in the first year. It usually responds to high-dose corticosteroid therapy but is a major risk factor for subsequent development of bronchiolitis obliterans syndrome. ■ The major limitation to long-term allograft function and patient survival is bronchiolitis obliterans, characterized histologically by fibroproliferative obliteration of the small airways and physiologically by progressive airflow obstruction. ■ Newer approaches include ex vivo lung perfusion to assess lung function and perhaps to recondition lungs before transplantation and bridging recipients using extracorporeal artificial lungs, either with pumps or without, until transplantation. ■

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Complete reference list available at ExpertConsult.

Key Readings Cypel M, Yeung JC, Liu M, et al: Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med 364:1431–1440, 2011. Diamond JM, Lee JC, Kawut SM, et al: Clinical risk factors for primary graft dysfunction after lung transplantation. Am J Respir Crit Care Med 187:527–534, 2013. Egan TM, Murray S, Bustami RT, et al: Development of the new lung allocation system in the United States. Am J Transplant 6:1212–1227, 2006. Finlen Copeland CA, Snyder LD, et al: Survival after bronchiolitis obliterans syndrome among bilateral lung transplant recipients. Am J Respir Crit Care Med 182:784–789, 2010. Kotloff RM: Does lung transplantation confer a survival advantage? Curr Opin Organ Transplant 14:499–503, 2009.

Kotloff RM, Ahya VN: Medical complications of lung transplantation. Eur Respir J 23:334–342, 2004. Kreider ME, Hadjiliadis D, Kotloff RM: Candidate selection, timing of listing, and choice of procedure for lung transplantation. Clin Chest Med 32:199–211, 2011. Palmer SM, Limaye AP, Banks M, et al: Extended valganciclovir prophylaxis to prevent cytomegalovirus after lung transplantation: a randomized, controlled trial. Ann Intern Med 152:761–769, 2010. Yusen RD, Edwards LB, Kucheryavaya AY, et al: The Registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplantation report—2014. J Heart Lung Transplant 33:1009–1024, 2014.

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eFIGURE IMAGE GALLERY

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eFigure 106-1  Posttransplant ischemic anastomotic bronchostenosis. A–D, Axial chest dynamic expiratory CT (performed during a forced vital capacity maneuver) displayed in lung windows in a bilateral lung transplant recipient shows narrowing of the bronchus intermedius (arrow) associated with extensive hyperlucency and increased volume throughout the right lower lobe (arrowheads), reflecting air trapping in the lung subtended by the stenotic airway. (Courtesy Michael Gotway, MD.)

1849.e2 PART 3  •  Clinical Respiratory Medicine

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B eFigure 106-2  Acute cellular rejection in a lung transplant recipient: high-resolution chest CT findings. A and B, Axial high-resolution CT displayed in lung windows shows smooth interlobular septal thickening (arrowheads) in the transplanted right lung and right pleural effusion (*) detected at the time of diagnosis of biopsy-proven acute cellular rejection; these findings are markedly reduced following augmentation of immunosuppression (B). The findings of interlobular septal thickening, volume loss, and pleural effusion are not specific for acute cellular rejection, although that diagnosis is uncommon when these high-resolution CT findings are absent. (Courtesy Michael Gotway, MD.)

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eFigure 106-3  Bronchiolitis obliterans syndrome: high-resolution CT findings in a bilateral lung transplant recipient. A–C and Video 106-2, Axial inspiratory high-resolution CT shows minimal findings, with only slightly inhomogeneous lung opacity best seen in the bases (C). D–F and Video 106-3, Axial dynamic expiratory high-resolution CT (performed during a forced vital capacity maneuver) shows interval development of extensive, bilateral inhomogeneous lung opacity—the lighter regions reflect normal, collapsing lung at expiratory imaging, whereas the darker areas (arrowheads) represent air trapping due to small airway obstruction, reflecting bronchiolitis obliterans. (Courtesy Michael Gotway, MD.)

1849.e4 PART 3  •  Clinical Respiratory Medicine

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