108: Overview of Lung Transplantation with Anatomy and Pathophysiology

While there are numerous challenges that face the recipient and practitioner, the field of lung transplantation continues to improve and expand with technical, immunological, and donor-related advancements. The utility of thoracic organ transplantation for end-stage lung disease was not meaningfully realized until the development of cyclosporine in the 1980s. In the preceding decades (1963–1983), fewer than 50 lung transplants were performed worldwide, and no recipient survived for more than 10 months. Early lung transplants failed for four principal reasons: nonfunction of the primary graft, dehiscence of the bronchial anastomosis, acute lung rejection, and pneumonia. Developments in surgical technique, perioperative care, and immunosuppressive drugs culminated in the first successful long-term lung transplant, performed in 1983 in a patient with idiopathic pulmonary fibrosis.¹ The technical highlights of this operation included the concept of using an omental wrap around the bronchial anastomosis to restore bronchial artery circulation and prevent dehiscence, careful patient selection, and effective long-term immunosuppression with cyclosporine. Shortly thereafter, Patterson et al.² performed the first successful double-lung transplant in a patient with emphysema (Fig. 108-1).

As the discipline matured, the application of these surgeries changed based on disease-specific factors. Techniques were derived based on specific patient needs as the science progressed. While living-related lobar transplant is no longer in high demand, primarily because of the creation of the current Lung Allocation Score (LAS), it continues to be a vital tool for the occasional patient. Drs. Barr and Starnes have further defined this role in Chapter 110. Single- and double-lung transplantations are the current mainstays of treatment for end-stage pulmonary disease. The essence of these techniques has not changed much in the past decade; however, the choice of operation, sidedness, and advancements are discussed in detail by Drs. Bharat and Patterson in Chapter 109. Combined heart–bilateral lung transplantation for multiple-organ failure in patients with primary pulmonary disease was once a more common surgery until it was observed that transplanting lungs earlier rather than later in these patients could prevent cardiac failure.

The advent of better therapies for pulmonary hypertension, closer monitoring of right heart function, and a better understanding of secondary pulmonary hypertension have had a significant impact on the need for combined heart–lung transplant. Heart–bilateral lung transplantation is now reserved for patients with other coexisting primary pulmonary and cardiac diseases, primarily of a congenital nature. The number of heart–lung transplantation procedures has declined over the years; however, new indications continue to arise for selected patients.

Some of the most exciting areas of advancement are in the mechanical means of supporting both the recipient and the donor lung, as well as a heightened awareness of the immunology of the lung transplant patient. Ex vivo evaluation and resuscitation of the donor lung is no longer a dream and is in full clinical trials in the United States. Our center has been working with ex vivo lung perfusion for nearly a decade, which has the potential to significantly improve the size of acceptable donors in the lung pool.³ Management of the acutely ill candidate has new options with the expanded use of extracorporeal life support devices including the practical application of “walking ECMO” and the work on artificial lung technology. Drs. Martin, Hoopes, Diaz-Guzman, and Zwischenberger help define this issue in Chapter 113. Despite the overall and improving feasibility of thoracic organ transplantation, its use continues to be limited by the number of available donor organs, the morbidity of mandatory lifelong immunosuppression, and the as yet apparent biologic incompatibility of host and allograft.

Lung transplantation entails the replacement of a native diseased lung with a cadaver lung (see Chapter 109) or lobar transplant from a living-related donor(s) (see Chapter 110). All adult lung transplants are orthotopic procedures. For most septic diseases and certain pulmonary hypertensive disorders, the extent of disease mandates a bilateral lung transplant. In 2004, 1188 lung transplants were performed in the United States. With improved techniques and improved donor management that number had increased to 1830 for the year ending 2011. While the number of double-lung transplants was virtually equal to single-lung transplants in 2000, it has continued to increase annually and now is double the rate of single-lung transplant.^4,5 Single- and bilateral lung transplants now account for 29.9% (548) and 70.1% (1282) of the total number of transplants, respectively. During this same interval, heart–bilateral lung transplants numbers dropped from 31 to 17 with a peak of 41 in 2010.^4,5

Lung transplantation surgery involves three major anastomoses: (1) bronchial, (2) pulmonary artery, and (3) atrial. The bronchial anastomosis is associated with the highest complication rate (3%–6%)⁶ compared with atrial and arterial anastomoses (<1%). Complications of bronchial anastomosis include dehiscence and stricture. If there is breakdown of the anastomosis, it usually occurs within several weeks of transplantation. Airway obstruction secondary to stricture or malacia manifests within several months. A common area for additional stricture is the postanastomotic donor bronchus. The tissue here is relatively ischemic and remains so for several weeks. Short donor bronchi and overlapping donor/recipient bronchi are techniques used to lessen this area of ischemic injury.

It is interesting to note that certain pulmonary structures (e.g., bronchial and lymphatic vessels) are not routinely reanastomosed after implantation. The bronchial circulation has marked interconnections with the pulmonary arterial circulation.⁷ These interconnections result in modest retrograde perfusion of most of the major portions of the airway, with the exception of a “watershed” region in the mid-mainstem bronchus (proximal donor). Attempts to reanastomose the bronchial circulation are technically feasible but have not demonstrated a significant clinical benefit if the watershed region in the mid-mainstem bronchus is excised.⁸ No significant difference has been demonstrated in airway healing with intact versus divided bronchial circulation. Similarly, there is no significant difference in the frequency of chronic rejection (bronchiolitis obliterans).

Division of the pulmonary lymphatics does have significance for early posttransplant management. In the normal lung, Starling forces cause 2% of the pulmonary blood flow to be filtered in excess of reabsorption. This excess fluid volume typically is drained by the pulmonary lymphatic system. After lung transplantation, this excess fluid can lead to progressive pulmonary edema, which degrades graft function and must be managed properly. The initial stages of submucosal lymphatic regeneration are not detected until approximately 3 weeks after transplantation.

Immunosuppression

The lung is a mediator of many immunologic processes, serving as an interface between the exogenous and endogenous environments. Consequently, lung transplant patients have required higher levels of immunosuppression than recipients of kidney, heart, or liver. The immunosuppression strategy can be conceptualized as two overlapping phases: (1) induction and (2) maintenance. While there are some variations in the medications used at different lung transplant programs, the approach to immunosuppression is fairly similar. The general concepts are discussed here but are better defined in Chapter 111 by Drs. Goldberg and Camp.

The goal of induction therapy in lung transplantation is to deplete or inactivate the host T cells. The original goal of early aggressive immunosuppression was simply to induce a state of immunologic unresponsiveness or tolerance. In most cases, polyclonal antibodies (e.g., antilymphocyte globulin and antithymocyte globulin) or monoclonal antibodies (e.g., anti-CD3, OKT3, and anti-interleukin 2 receptor) were used to inactivate (or bind) T-lymphocyte antigens. The ability of induction agents to achieve immunologic unresponsiveness, however, proved to be very disappointing. Nonetheless, there remains a practical use for induction therapy in lung transplantation. Because the lungs are relatively edematous after transplantation, aggressive diuresis is commonly used in the postoperative lung transplant recipient to maintain effective gas exchange. In this setting, induction therapy permits potentially nephrotoxic maintenance therapies, such as cyclosporine or tacrolimus, to be minimized during the first postoperative week. Further, during this time following ischemic insult to the donor lungs, the ability of the immune system to multiply the inflammatory result is blunted.

The general approach to maintenance immunosuppression is based on a multiagent regimen composed of calcineurin inhibitors (e.g., cyclosporin A or tacrolimus), cell cycle inhibitors (e.g., azathioprine or mycophenolate), and steroids (Table 108-1). The regimen generally is started at a relatively high dose and tapered over the first 3 months after transplantation. The rate at which the dose of maintenance therapy is tapered depends on the presence and severity of acute rejection episodes experienced by the patient.

Acute rejection generally is treated with high-dose steroids. A typical episode of acute rejection is treated with 1 g/day of IV steroids (Solu-Medrol) × 3 doses, followed by a modest taper of oral prednisone to baseline levels.

Acute Rejection

The immune-mediated destruction of the transplanted lung occurs both acutely and chronically. Acute rejection in the lung is often characterized by hypoxemia, fever, and radiographic infiltrates. The presentation of acute rejection can be virtually indistinguishable from acute infection. In contrast, chronic rejection is associated with a slow and progressive decline in pulmonary function.

Acute rejection is an inflammatory reaction initially confined to the perivascular zones. Untreated, the acute rejection will progress to involve not only blood vessels but also airways and interstitium. This pathophysiologic process is reflected in the generally accepted classification of lung allograft rejection (Table 108-2).⁹

Because the signs and symptoms of acute rejection are nonspecific, the diagnosis is often triggered by clinical suspicion and requires histologic confirmation. Many transplant teams use surveillance bronchoscopy, bronchoalveolar lavage, and transbronchial biopsy to evaluate the lung parenchyma and environment. In addition to signs of acute rejection, the lung tissue is evaluated for other sources of inflammation. For example, cytologic inclusion bodies suggest a viral infection, polymorphonuclear leukocytes indicate a possible bacterial infection, and necrosis or hyphae are suggestive of fungal infection.

What has become clear in the past 5 to 10 years is the fact that acute rejection is a much more complex and diverse set of immunologic processes that are both cellular and noncellular mediated and are poorly understood. The recognition of subtle states of rejection has become a very hotly debated topic and which therapeutic modalities, and when, are not yet clearly understood. This topic is of keen interest as there are strong associations between the number and severity of acute rejection episodes, and the development of bronchiolitis obliterans syndrome (BOS) (see below), the common pathologic endpoint of chronic rejection. Early use of newer therapies beyond pulsed doses of maintenance medications are more commonly used including targeted immunolytic therapies (Antithymocyte, anti-IL2 receptor, anti-CD3), and extracorporeal photopheresis (ECP) to name a few.

Chronic Rejection

Ongoing immune destruction of the lung leads to scarring of the terminal airways, a process known as bronchiolitis obliterans. This end-stage process is characterized by the presence of intraluminal polypoid plugs of granulation tissue in the terminal and respiratory bronchioles that cause partial or total obliteration of the lumen of the airway. BOS is the irreversible and final common pathway of a number of lung diseases.

Chronic airway inflammation may be owing to a combination of effects. In some cases, the acute rejection is superimposed on an underlying bronchiolitis obliterans. The ongoing destruction of the airways promotes frequent colonization by bacteria and fungi, and thus a component of inflammatory response actually may reflect infection.

Confirmation of BOS by histologic examination of a transbronchial biopsy is relatively insensitive (60%). However, the histologic severity of bronchiolitis obliterans correlates strongly with airflow obstruction measured by spirometry. Hence the classification system for BOS is based on spirometry (Table 108-3).¹⁰ Patients with bronchiolitis obliterans have a characteristic “scooped” expiratory flow histogram with a marked absolute reduction in forced expiratory volume in 1 second (FEV₁) (Fig. 108-2). Chest radiographs may show hyperinflation secondary to chronic small airway obstruction (Fig. 108-3), and CT scan can show signs of delay in airspace emptying.

Approximately one-third of patients develop histologic evidence of bronchiolitis obliterans within 12 months of lung transplant. Although the coincidence of bronchiolitis and chronic infection complicates the analysis, approximately two-thirds of patients ultimately experience a progressive and unrelenting loss of pulmonary function owing to chronic rejection. Multiple therapies are used to arrest or slow this process with varied success. Bronchiolitis obliterans remains the primary obstacle to widespread long-term graft function and survival.

The transplant experience varies depending on approach (single vs. double, heart vs. bilateral lung, cadaver vs. living donor), makeup of the regional transplant recipient/donor pool, and preference and expertise of a particular transplant team. Excellent results can be achieved with differing surgical philosophies, and it can be informative to compare the experience of divergent centers.

The indications for lung transplantation include pulmonary diseases that affect the host lung but will not recur in the transplanted lung. Worldwide, nearly 85% of current candidates for lung transplant have emphysema-related diseases, cystic fibrosis, idiopathic pulmonary fibrosis, or pulmonary hypertension (Fig. 108-4).

The contraindications to lung transplantation include coexisting uncorrectable cardiac disease or other significant extrapulmonary organ dysfunction. Other absolute contraindications for lung transplantation include an active malignancy, HIV infection, hepatitis B antigen positivity, and hepatitis C with histologic evidence of active disease. Patients with active substance abuse, including current smokers, are also contraindicated for lung transplantation.

Relative contraindications to lung transplantation include poor nutritional status (body mass index <17.0 or >35.0), symptomatic osteoporosis, continuous high-dose prednisone, and colonization with panresistant bacteria, fungus, or atypical mycobacteria. Other relative contraindications include the requirement for invasive ventilation as well as psychosocial problems likely to increase postoperative mortality.¹¹

Surgical contraindications include the relative concerns related to hemorrhage on cardiopulmonary bypass (CPB) and healing of the airway anastomosis. Patients requiring CPB who have obliterative pleural disease, mediastinal fibrosis, or calcific atria face a markedly elevated risk of perioperative hemorrhage. Patients with a history of mediastinal irradiation may have an increased risk of postoperative airway dehiscence. Right ventricular dysfunction is a relative contraindication to lung transplantation. Pasque and colleagues have shown, however, that some patients with early right-sided heart failure experience improved right ventricular function after transplant.¹² The aforementioned factors are applicable to all transplants, whether the donor organ is from a cadaver or from a living-related donor. Indications unique to the living-related donor are discussed in Chapter 110.

In the past 15 years, the 1-year lung transplant survival rate has increased from approximately 70% to 85% as a result of improvements in donor management, airway anastomotic technique, and perioperative recipient management (Table 108-4).^4,5 In contrast, mortality rates after 1 year have remained largely unchanged. These results suggest that the major challenge in lung transplantation is the issue of biologic incompatibility between the donor and recipient and the persistent effect of inflammation in its many forms.

In the first year after lung transplantation, infections are the leading cause of death. Recipients are at high risk for bacterial, fungal, viral, and protozoan infections. Acute infection is rarely seen after the first year. The cause of death after the first year is frequently coexisting chronic rejection (i.e., BOS), infection, and other comorbid diseases.

The functional consequences of lung transplantation vary with the underlying recipient disease and disability. Roughly 80% of patients, however, are able to resume an active lifestyle, including returning to work, and 90% report improved quality of life.

Most patients referred for lung transplantation are younger than 55 to 60 years of age. While age, per se, is not a prognostic factor, it is associated with a rising incidence of comorbid disease. As age advances, recipients are meticulously evaluated to rule out conditions that in and of themselves may preclude transplantation.

The timing of the referral for lung transplant evaluation is guided by measurable parameters of the underlying disease (Table 108-5). Additional considerations include the life expectancy of the patient. The waiting period for a donor organ to become available for transplant varies depending on the geographic region, but it is directly related to each patient's LAS.^4,5 The LAS is a fairly complex mathematical model that is used to rank all candidates based on several factors. Unlike previous models that were based solely on the patient's time on the list, the current model compares patients by numerous factors, including (1) severity of disease, (2) the disease process (each disease has a variable time course), (3) the probability that the recipient will not survive an additional year without transplant, and (4) the likelihood that the candidate will survive a year with transplant. The mortality for patients on the waiting list was once approximately 15%. The LAS appears to be improving this process, but long-term evaluation is warranted.

Although at any given moment approximately 2400 people in this country are actively waiting for a suitable donor organ, only 7% to 22% of multiorgan donors are suitable for lung donation.¹³ In many instances, the donor has been compromised by chest trauma, aspiration pneumonia, ventilator-associated pneumonia, or their own native lung disease. There is hope that ex vivo lung perfusion techniques will be able to help evaluate or resuscitate many currently unusable lungs to improve this very low conversion rate.

Potential recipients for a donor lung are identified initially by ABO blood group compatibility. The size of the donor lungs is estimated using standard reference values derived from age, gender, race, and height.¹⁴ Potential recipient–donor matches should be within 15% to 20% of estimated lung volumes. Donor lungs that are larger, particularly in the setting of double-lung transplantation, may result in cardiac compression with chest closure. Small lungs can function in a larger recipient. Size mismatch is avoided because it disproportionately disadvantages smaller recipients.

We prefer to use organs from donors with a clear chest radiograph, minimal shunt as determined by arterial oxygen (PaO₂ ≥300 mm Hg), no recent aspiration, and no significant smoking history (<20 pack-years). A history of chest trauma or purulent sputum suggests the utility of bronchoscopy to evaluate the airways for blood or evidence of established infection. However, there is a growing movement nationally to extend the criteria for donor acceptability in part because of the dramatic shortage of usable donor lungs. This is a point of considerable academic debate, and the definition of suitable will be in flux for some time to come.

It is important to obtain microbiologic cultures of the donor airway to focus the early antibiotic therapy. Prolonged antibiotic use in the setting of aggressive immunosuppression can give rise to opportunistic infections in the early postoperative course.

Donor viral serology is also important for perioperative management. Most transplant programs exclude donors with positive hepatitis C serology because of the risk of hepatitis transmission. In contrast, many donors are CMV positive. CMV causes a complex bidirectional interaction between the donor lung and the recipient. CMV has been associated with acute viral pneumonitis as well as both acute and chronic rejection.¹⁵ When both the donor and recipient are CMV negative, survival is better than any other serologic combination.^4,5 Finally, Epstein–Barr virus (EBV) serology is relevant to later recipient management. EBV-positive donor lungs in an EBV-negative recipient confer a greater risk for posttransplant lymphoproliferative disorders (PTLDs). Each center has a preferred approach to donor assessment. Special considerations apply to the living-related donor and/or heart–bilateral lung cadaver, and these are reviewed in Chapters 109 and 110.

At Brigham and Women's Hospital, we use a standard posterolateral thoracotomy incision placed in the fifth intercostal space for single-lung transplantation. Double or bilateral sequential lung transplants can be performed through a median sternotomy; however, we typically use a transverse thoracotomy. Double-lung transplants generally require CPB to ensure adequate exposure to the left hilum. Techniques for exposure (e.g., bilateral, anterolateral, and clamshell) and preoperative preparation are described in Chapters 109 and 110.

The most important technical aspect of the bronchial anastomosis is the resection of the ischemic portion of the mainstem bronchus. The recipient bronchus is divided at the level of the mediastinal pleura, and the donor bronchus is transected no more than two cartilaginous rings proximal to the lobar carina. If the ischemic mainstem bronchus is resected, the anastomosis should heal properly, regardless of whether a telescoping or end-to-end suture technique is used.

We use a running monofilament suture along the membranous airway to create the bronchial anastomosis. The membranous bronchus is well perfused and is rarely a site of dehiscence or stricture unless there is undue tension of the membranous portion. The tissue is quite thin, and overt tension or poor tissue overlap may place this area at increased risk. In contrast, the medial cartilaginous–membranous junction is the region of airway located farthest from the retrograde pulmonary blood flow and the most likely site of anastomotic separation. Consequently, in this region we use an invaginating or evaginating monofilament mattress suture. Traditionally, the donor bronchus is invaginated into the recipient bronchus. We have recently begun to place the smaller bronchus into the larger bronchus based on best size matching. The technique allows for the least amount of airway narrowing and in the setting of recipient within donor excludes the most ischemic airway outside the well-perfused recipient stump. Our suture technique facilitates (1) a telescoping anastomosis, (2) accommodation of size mismatch, and (3) tight apposition at the area of greatest risk. The anastomosis at the cartilaginous rings generally heals well. We use interrupted absorbable sutures or a continuation of the running monofilament mattress suture.

The completed anastomosis should be airtight. Most patients will require mechanical ventilation for hours to days postoperatively. In addition to complicating the ventilatory management, an anastomotic air leak will contribute to the risk of pleural space infection.

Because of the potential for anastomotic dehiscence, periairway abscess, and the risk of bronchovascular fistula, we recommend interposing donor pericardium, intercostal muscle pedicle, or other vascularized tissue between the pulmonary artery and the bronchial anastomosis. Typically, adequate donor pericardium can be mobilized so that not only are the structures separated, but the bronchial stump also can be wrapped circumferentially.

Mucociliary clearance is impaired in lung transplant patients. Turbulent airflow at the anastomotic transition and mucociliary impairment are among the many potential explanations. To minimize the contribution of suture material to impaired clearance, we ensure that no knots are placed on the intraluminal side of the anastomosis.

The pulmonary artery anastomosis generally is performed using running monofilament suture (e.g., 5-0). The technical issue is to avoid “purse stringing” of the anastomosis. This is typically associated with a large size mismatch, as seen in patients with pulmonary hypertension. Rarely, if the lung donor artery is left too long, it will lead to kinking of the intrapleural portion of the artery. Careful attention to this detail is critical.

The venous anastomosis is constructed last and is more prone to technical complications than the pulmonary artery anastomosis. A short donor atrial cuff and a large size mismatch can lead to torsion-related obstruction of the segmental pulmonary veins. When the atrial anastomosis is even slightly rotated relative to venous inflow, it can lead to increased resistance at the orifice of the pulmonary veins. Even a gradient difficult to quantify by transesophageal echocardiogram can lead to pulmonary edema. Since many patients develop pulmonary edema independent of the atrial anastomotic technique, the surgeon must be confident of the atrial anastomosis before leaving the OR.

As a rule, pulmonary edema that develops in the OR is related to a technical complication. Pulmonary edema that develops 4 hours after the operation generally is attributable to an implantation response. Two aspects of our program to lower the incidence of this lung reperfusion injury are initiation of induction therapy prior to beginning the implantation and controlled perfusion of the first lung during a double-lung transplant, which may help lessen the tissue injury during and following the technical aspects of the implant. Alternative techniques for exposure, bronchial anastomosis, atrial anastomosis, and pulmonary anastomosis are discussed in Chapters 109 and 110.

The incidence of early graft failure has declined steadily since the first successful long-term lung transplant in 1983.¹⁶ Although many factors likely contribute to this trend, an important element is management of the donor lung. Prior to procurement, the lungs are treated with a pulse of system steroids and 500 μg of prostaglandin just preceding the flush with the chosen perfusate. Donor lungs are routinely anterograde and retrograde flushed in situ to eliminate neutrophils (a source of oxygen-free radicals and inflammatory mediators) and debris, including subclinical pulmonary emboli, fat emboli, and poorly flushed blood. The lungs are inflated with 100% oxygen and stored at 4°C to minimize ischemic injury. Ischemic time has been linked directly to outcome. Hence highly coordinated communication with all surgical teams and transporting agencies minimizes ischemic time and lowers the risk for ischemia–reperfusion injury.

Another trend is the increasing use of CPB during double-lung transplantation. The use of CPB serves three major purposes. It may minimize reperfusion pulmonary edema, which occurs commonly in the first implanted lung during a sequential transplant. Although the etiology is unclear, progressive pulmonary edema occurs in approximately 20% of patients after lung transplantation. This is commonly referred to as the implantation response, and patients generally are responsive to diuretics, with the condition resolving within the first 48 to 72 hours.¹⁷ The implantation response can be life-threatening when the pulmonary edema and associated hypoxic vasoconstriction lead to right ventricular dysfunction. Once right-sided heart failure occurs, treatment is limited to extracorporeal membrane oxygenation. The secondary advantage of CPB is time. Patients undergoing lung transplant are often fairly unstable and tolerate manipulation poorly. Initiation of CPB permits maintenance of stable oxygenation and perfusion while allowing for efficient surgical implantation. Third, the maintenance of stable perfusion pressure and metabolite delivery helps to ensure that secondary organ function is preserved, which may improve the stability of the posttransplant course.

Posttransplant pulmonary edema can progress rapidly over the first 4 hours. At Brigham and Women's Hospital, to minimize transplant pulmonary edema, we use aggressive diuretic therapy in the first several hours in the setting of increased filling pressures, poor oxygenation, or evidence of early pulmonary dysfunction, such as ischemia–reperfusion injury. The severity of the implantation response is assessed empirically.

Although nitric oxide (NO) has been used widely in most adult patients, the results have been somewhat disappointing if not inconsistent. The initial use of prophylactic NO to lower the incidence of ischemia–reperfusion injury has not demonstrated a predictable result and often delays the time to initial extubation. However, the postoperative pulmonary hypertension and hypoxemia, when observed in lung transplant recipients, can be ameliorated with NO-mediated treatments, and this should be considered in that clinical setting. The current cost of inhaled NO is very substantial so the use of inhaled prostaglandins has been successfully introduced with a lower cost for the same effect.

Mechanical ventilation is minimized to improve airway clearance and reduce the risk of ventilator-associated pneumonia. Mechanical ventilation is a particular challenge in patients undergoing single-lung transplantation for emphysema. The hypercompliant native lung and the relatively noncompliant transplanted lung yield two distinct mechanical compartments. In this setting, mechanical ventilation may result in hyperinflation of the native lung with suboptimal distending pressures of the transplanted lung. While using a double-lumen tube with two different ventilation pressures is appealing conceptually, it is difficult in practice. The differential mechanical ventilation is hard to synchronize, the double-lumen endotracheal tube position is difficult to maintain, and bronchoscopic airway access is limited to a pediatric bronchoscope. As a result, a more reliable strategy is to optimize the function of the transplanted lung and discontinue mechanical ventilation as soon as possible.

The long-term surgical complications of lung transplantation that arise more than 6 weeks after surgery are bronchial stricture and malacia. In both cases, these complications are rare if airway length is minimized. A lung donor bronchus is associated with cartilage that is frequently necrotic and colonized with Aspergillus. Although anatomic dehiscence may not occur, the healing of this cartilage may be associated with excessive granulation tissue and stricture. Alternatively, the cartilage may lose its structural integrity, and the bronchial malacia may result in poor airway clearance. The clinical course associated with both stricture and malacia is characterized by recurrent infections resulting in bacterial pneumonias that are progressively resistant to antibiotics. Airway strictures can be treated with dilation, laser ablation, or mechanical stents. These measures have variable impact on airway clearance.

Similarly, chronic rejection is frequently associated with chronic infection. The late stages of bronchiolitis obliterans are commonly associated with bronchiectasis, a productive cough, and airway colonization with Pseudomonas spp.

Chronic renal insufficiency is a late complication of prolonged calcineurin inhibitor therapy. Both CSA and FK-506 are associated with a progressive decline in glomerular filtration rates.¹⁸

Chronic immunosuppression is associated with PTLD. Most commonly associated with EBV infection, PTLD can be either polyclonal or monoclonal. Polyclonal PTLD is a relatively benign B-cell proliferative disorder that responds to a reduction in immunosuppression. In contrast, monoclonal proliferative disorders are cytologically indistinguishable from immunoblastic lymphoma. These monoclonal immunoblastic lymphomas rarely respond to even the most aggressive cytotoxic chemotherapy. A thorough review of systemic complications of lung transplantation is provided in Chapter 112.

Recent clinical outcome studies of sufficient statistical power have been published to aid the physician–surgeon transplant specialist to manage the supply and demand of a finite number of donor organs. These studies enhance our ability to predict clinical outcome, refine characteristics for patient selection, manage complications, and maximize organ allocation.

While there is general consensus that lung transplantation conveys a survival benefit and improved quality of life for patients with end-stage pulmonary disease,¹⁹ whether this benefit is equal for all diagnostic groups or independent of type of procedure (single-lung transplant vs. double-lung transplant vs. heart–lung transplant) is still being investigated. Over the past 5 years, there has been a significant change in patterns, with double-lung transplantation becoming the most common transplant. Preliminary data seem to support a survival advantage for many patients less than 55 years of age for several disease processes. Mason et al. evaluated outcomes for patients with a higher-risk diagnosis of pulmonary fibrosis. While they noted that survival after lung transplantation for idiopathic pulmonary fibrosis (IPF) is worse than after other indications for transplantation, survival may be improved by double-lung transplant.²⁰ Chang et al. have been more liberal and found that despite longer median allograft ischemic times, as well as greater patient acuity, as determined by listing diagnosis, overall early and midterm patient survival has remained higher than nationally reported figures. Bilateral lung transplantation in eligible patients is the procedure of choice.²¹

One area of change has been the extended age criteria not only for donors but also for recipients. Traditionally, lung transplant was limited to those younger than 60 years of age, with double-lung transplant being restricted to those younger than 55 years of age. The United Network for Organ Sharing (UNOS) registry currently lists candidates as old as 75 years of age actively awaiting transplant. Not only are age limits being extended but also the role of single- versus double-lung transplant is being evaluated. Nwakanma et al. have examined this issue in the United States. They reviewed UNOS data from 1998 to 2004 and noted that 1656 lung transplant recipients were 60 years of age or older (mean 62.7 ± 2.4 years, median 62 years). Of these, 28% had bilateral and 78% had single-lung transplantation. Survival was not statistically different between the two groups. In the multivariate analysis, bilateral versus single-lung transplantation was not a predictor of mortality. IPF and a donor tobacco history of more than 20 pack-years were significantly associated with mortality.²² There is a very interesting if not problematic trend in lung transplantation based on the current version of the LAS. The modeling currently has significantly increased the percent of older (>65) patients and those with the complex family of interstitial fibrotic lung diseases that are undergoing lung transplantation in the United States. While the rate of patient deaths on the waiting list has improved, there appears to be a suggestion that early postoperative survival may be adversely impacted. We await the final analysis.

The goal of keeping patients alive after referral to the transplant waiting list has generated a series of studies designed explicitly to determine disease-specific survival in the context of organ allocation. One of the pivotal changes in lung transplantation organ allocation in the past several years has been the creation and adoption of the LAS for the ranking of listed lung transplant candidates. Previous methods were based on time on list and did not address the nature of specific disease processes, or the acuity of individual patients. In May 2005, the LAS was implemented to improve the mortality rate for individuals on the waiting list for transplantation, as well as to define a potential best use for this rare resource. A number of key variables have been identified (Table 108-6) as predictive of outcome and are being used to calculate a score that, in essence, does four things: It identifies (1) the specific disease process, each of which has different patterns and clinical risks, (2) the severity of the specific patient's clinical condition, (3) the likelihood of mortality within 1 year based on the individual's current status and medical conditions, and (4) the likelihood of 1-year posttransplant survival given those same factors.

Use of the LAS has been instrumental in lowering the mortality rate on the waiting list but as noted above has been associated with a higher acuity at the time of transplant. While there was a hope of lower early mortality following transplant, the midterm analysis appears to find some concerns although has not been fully completed. McCue et al.²³ did a small review and found a small but significant 1-year survival advantage among post-LAS implementation patients; however, this was largely due to decreased early mortality in comparison with the control cohort.

Acute and chronic allograft rejection (i.e., bronchiolitis obliterans) remains the major rate-limiting factor for long-term survival after lung transplantation. In a systematic review of published studies from 1990 to 2002, Sharples and colleagues compared the reported risk factors for bronchiolitis obliterans from all transplant centers reporting more than 25 patients. Their work supported the view that bronchiolitis obliterans is an alloimmunologic injury characterized by serial acute rejection episodes that are in some manner mediated by other inflammatory processes (e.g., viral infection or ischemic injury). Burton et al.²⁴ have demonstrated that the development and progression of chronic allograft rejection after lung transplantation (BOS grades 2 and 3) are associated with a threefold increase in the risk of death at each stage irrespective of whether BOS developed early or late. In general, there are many studies aimed at defining the root causes of BOS, with a common theme being processes related to inflammation. These include pseudomonas infections,²⁵ use of induction protocols,²⁶ incidence and severity of viral infections following transplant,²⁷ the presence of specific inflammatory cell types within the transplant graft,²⁸ and the presence of gastroesophageal reflux.²⁹ The association between gastroesophageal reflux and end-stage lung disease is established in patients with IPF. It is reasonable to infer that gastroesophageal reflux disease would have a negative impact on the recipient's posttransplant health and hasten the development of bronchiolitis obliterans.³⁰ In a retrospective analysis of patients treated at Brigham and Women's Hospital, Linden et al.³¹ examined the benefit of performing laparoscopic Nissen fundoplication in patients waiting for lung transplantation. This retrospective analysis revealed 19 of 149 active waiting list recipients with a history of active severe reflux disease who underwent laparoscopic Nissen fundoplication between 2001 and 2005. The technique was shown to be safe and to stabilize oxygen requirements in this subgroup of patients with IPF (n = 14). Control patients with IPF who did not undergo the procedure (n = 31) had a statistically significant deterioration in oxygen requirements. BOS continues to be the Achilles heel of long-term survival.

In recent years, the indications for recipients have broadened, placing more pressure on the already limited pool of donor organs. As a means of counteracting this shortage, the feasibility of using marginal donor organs has been investigated. In this regard, the Toronto Lung Transplant Group conducted a retrospective review of all their transplant recipients between 1997 and 2000 to compare clinical outcome in standard donors and standard recipients versus marginal donors and extended recipients. Donors were defined as extended if they met one or more of the following criteria: age more than 55 years, smoking history longer than 20 pack-years, presence of infiltrate on chest plain film radiograph, PaO₂ of less than 300 mm Hg, and purulent secretion on bronchoscopy. Through the efforts of early studies such as this, it was recognized that suitable donor organs that could impart significant survival benefit likely existed outside the fairly rigid guidelines that directed organ donation. It also has been noted that many donors do not achieve suitable donor status for lung transplantation (17% nationally for all donors) because aggressive early management is not implemented routinely. The notion of reducing waiting list mortality by performing intervening procedures to improve recipient health and chances for long-term graft survival is being actively pursued. Angel and colleagues have shown that a simple algorithm-based protocol was associated with a significant increase in the number of lung donors and transplant procedures without compromising pulmonary function, length of stay, or survival of the recipients.³² At the national level, the Breakthrough Collaborative for Organ Donation, run by the HRSA, has been championing these and other efforts to improve the pool of suitable donors and improve outcomes in lung transplantation by the use of best practices.

Limited availability of donor organs, as well as morbidity secondary to lifelong immunosuppression and chronic graft rejection, has prompted serious investigation of ways to optimize and extend graft allocation and survival. Literature review and outcomes analysis, as described earlier, provide insight into the purpose and utility of lung transplantation.

Clinicians and scientists continue to explore the possibility of xenotransplantation, which would provide an unlimited supply of thoracic organs that could be supplied, essentially, on demand.³³ The main barrier to xenotransplantation is immunologic. None of the four distinct immunologic reactions, that is, hyperacute rejection, acute vascular rejection, acute cellular rejection, and chronic rejection, has been conquered in the laboratory. Nonhuman primates (e.g., baboon) and mammals (e.g., pig) present the most promising models; however, societal factors and risk of transferred viral infection preclude the use of organs from nonhuman primates. The pig appears to be the more suitable and acceptable option. Consequently, current guidelines published by the ISHLT focus on the pig model and detail the specific immunologic barriers to overcome. Other options are being explored to extend the role and effectiveness of lung transplantation. Additional novel models of immune suppression are being trialed with early success. The concept often raised by several researchers, including pioneers such as Dr. Thomas Starzl, is the possible development of immune tolerance. Clearly, there are patients who develop tolerance of their grafts and go on to need little or no chronic immune suppression. The process of how to induce such a symbiotic state is the subject of entire books but does raise the exciting idea that chronic immune suppression and the long list of complications associated with it could be eliminated.^34,35

Lung transplantation is a lifesaving treatment but is complicated and does not yet impart the same durable outcomes offered by other solid-organ transplants. There have been substantial improvements in the past decade in patient management and understanding of immunology that are making strides towards improved patient outcomes. It serves a clear role in patients with severe, medically maximized lung disease and offers a markedly improved quality of life. Limiting factors for this treatment modality include a limited resource pool and multiple complications that markedly affect the broad and prolonged application of this intervention. Current work is improving the effectiveness of this therapy dramatically, and advanced technique and growing experience allow broader availability to the population as a whole.

Since the first successful single-lung transplant on November 7, 1983, there has been significant progress in the technical aspects of lung transplantation. Early deaths from acute graft failure and anastomotic dehiscence are now rare complications in the postoperative period. The major barrier to lung transplantation is no longer technical, but rather biologic. The fundamental nature of this barrier is illustrated by the remarkably similar survival curves reported by different transplant groups around the world. The next major advance in lung transplantation will need to address this biologic barrier with the development of new targeted, and possibly lung-specific, immunoregulation.