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.