CLINICAL STATUS OF LUNG TRANSPLANTATION

During the past two decades, lung transplantation has become a viable option for end-stage pulmonary disease. Advances in surgical techniques and immunosuppression and standardization of preoperative and postoperative care have contributed to improved survival and quality of life. Chronic rejection and limited allograft availability remain the two most important issues to resolve in the coming years.

As indicated in Figure 1, from approximately 1985 until 1994, the number of lung transplants (single and double) from cadaveric donors increased. Yet, by 1994, the rate of increase in the annual number of transplants appeared to slow, despite increased numbers of patients with end-stage lung disease listed and waiting for lung transplantation. This trend has persisted despite the use of increasingly older donors and the initiation of living donor transplants. As of April 2001, 76,124 people are awaiting solid organ transplantation in the United States. Of this number, 3748 are awaiting lung transplantation and 215 are awaiting heart-lung transplants (United Network Organ Sharing Critical Data, http://www.unos.org).

Figure 1: International statistics regarding the number of lung transplants performed since 1985. The numbers increased until 1994, at which time the rate of increase appears to have reached a plateau. (From ISHLT Registry Report 2000, http://www.ishlt.org, accessed April 15, 2001.)

The majority of single lung transplants are performed for individuals with end-stage chronic obstructive pulmonary disease; cystic fibrosis accounts for the majority of bilateral/double lung transplants. Improvements in the management of selected patients with emphysema via lung volume reduction surgery, the antibiotic management of patients with cystic fibrosis, and the use of long-term prostacyclin therapy in patients with pulmonary hypertension may alter organ allocation trends in the future.

RECIPIENT SELECTION

Referral and listing of potential candidates for lung transplantation must consider a waiting period of 1 to 2 years after the completion of screening. During this waiting time, it is imperative that patients maintain adequate nutrition and conditioning. Guidelines for referral timing consider the rate of progression of specific diseases, but each patient must be considered individually. These guideline are listed in Table 1⁽¹⁾.

Table 1: Disease-specific guidelines for adult lung transplantation

The use of standardized criteria is essential to the selection of candidates for lung transplantation. Age criteria include limits of 55 years for heart-lung transplantation candidates, 60 years for candidates for bilateral lung transplantation, and 65 years for candidates for single lung transplantation. The relative contraindications have changed as management of the lung transplantation patients has improved over time. For example, corticosteroid usage, once an absolute contraindication, is not necessarily prohibitive at moderate doses. Coronary disease, if treated, is no longer an absolute contraindication, especially if left ventricular function is preserved ⁽²⁾. Osteoporosis and fractures are common in both the preoperative and postoperative settings and remain a relative concern, mandating aggressive management before transplantation ^(3,4). A history of active malignancy of any organ is considered an absolute contraindication for lung transplantation. Of note, lung transplantation for bronchioalveolar carcinoma has been performed, but tumor recurrence in the donor lung occurred in four of seven patients within 10 to 48 months posttransplantation ⁽⁵⁾. Guidelines for listing for transplantation are included in Table 2⁽¹⁾.

Table 2: Indications and contraindications for lung transplantation

One actively debated issue relevant to disease-specific considerations for lung transplantation has been the transplantation of patients with multiple or pan-resistant bacterial organisms. International guidelines suggest that the presence of pan-resistant bacteria is not an absolute contraindication, but multiple centers limit offering lung transplantation to patients with cystic fibrosis with Burkholderia cepacia^(6,7). The management issues associated with this organism have been reviewed ⁽⁸⁾. One group has suggested that triple antimicrobial therapy can be bactericidal when B cepacia has a multi-resistant profile ⁽⁹⁾. The presence of B cepacia has been associated with higher mortality before and after transplantation in individuals with cystic fibrosis. Yet, some suggest that alterations in medical management after transplantation may improve outcomes for this subgroup ⁽¹⁰⁾. B cepacia species represent distinct genomic categories named genomovars, with the majority of the genomovar types being II or III ⁽¹¹⁾. To date, seven genomovars have been identified ⁽¹²⁾. Ultimately, the decision to transplant patients with B cepacia is made by individual centers. Hopefully, in the future this decision will be aided by knowing more about the genetic epidemiology of the genomovars and their association with short- and long-term outcomes.

DONOR SELECTION

Before brain death and organ procurement, the lung may be exposed to injury from gastric aspiration or bacterial infection, potentially limiting organ use. These injuries may be compounded by the trauma of mechanical ventilation, further compromising the suitability for lung donation without compromising donation of other solid organs. Suitable allografts are generally characterized by Pao₂ greater than 300 mmHg while mechanically ventilated with an Fio₂ of 1.0 and positive end-expiratory pressure of 5 cm of water. Unilateral pneumonia or trauma does not preclude donation of the contralateral lung. Guidelines suggest that donor age should be less than 60 years, with a smoking history of no greater than 20 to 30 pack-years. Age and smoking criteria may be more flexible, however, when a waiting recipient’s survival is precarious. Liberalized smoking criteria have resulted in comparable outcomes ^(13–15). In this setting, the potential benefit outweighs the risk from the use of “marginal” or “extended” donors. In addition to more flexible criteria for age, smoking history, and gas exchange, the use of lungs from non–heart beating donors may help reduce the donor shortages ^(14–16). Successful transplantation of organs from non–heart beating donors has been described ⁽¹⁷⁾. One group suggests that careful in situ preservation techniques will protect the anatomic and physiologic attributes of these cadaveric lungs as they are prepared for implantation ⁽¹⁸⁾. In rodent and porcine models of non–heart beating cadaveric donors, research has demonstrated healing of the bronchial anastomosis without parenchymal abnormalities and with acceptable function ^(19–22).

Consideration must be given to the proinflammatory gene activation that occurs in solid organs as a consequence of brain death and the idea that long-term organ dysfunction might be programmed even before allografting ⁽²³⁾. As such, cytokine profiling represents a significant advance for identification of organs suitable for transplantation. The inflammatory cascade and the consequent pulmonary dysfunction associated with massive irreversible brain injury and brain death have been implicated as preventing approximately 75% of potential organs from ever being considered for lung donation ⁽²⁴⁾. One group has demonstrated an increase in interleukin 8 in the lungs of potential organ donors after brain death. Donor lungs with high interleukin 8 levels had decreased graft oxygenation and early graft failure; these patients had shorter survival times ⁽²⁵⁾. Cytokine profiles should be considered during donor selection given the relevance to short- and long-term outcomes.

SURGICAL CONSIDERATIONS: PRESERVATION ISSUES

The vascular endothelium of the lung is most susceptible to ischemic injury, potentially leading to an increase in permeability with resultant pulmonary edema. Hypothermic flush perfusion of the pulmonary vasculature (with Euro-Collin’s solution or University of Wisconsin Solution) is most commonly used to prevent this problem. A number of studies have been performed on potential additives that enhance the efficacy of flush solutions. Nitroprusside, dimethylurea, and pentoxifylline have been tested as agents to improve preservation and limit pulmonary edema in the early postoperative state ^(26,27). An alternative solution of low-potassium dextran has been found to decrease both severity and incidence of reperfusion injury and to improve survival and graft function. The administration of prostanoids into the pulmonary circulation improves lung preservation by dilating the pulmonary vasculature and decreasing leukocyte adhesiveness, thus facilitating more extensive distribution of solution.

Relevant to the development of ischemic injury is the eventuality of reperfusion injury. Leukocyte adhesion to the endothelium and production of oxygen-derived free radicals contribute to this response. Prostanoid use and infusion of donor leukocytes and inhaled nitric oxide use and inclusion of superoxide dismutase or catalase as free radical scavengers may help diminish some reperfusion injury ^(28–31).

As research in the field of lung preservation continues, it should be underscored that graft ischemic time may be an independent predictor of survival, with the negative effects being most pronounced after 5 hr ⁽³²⁾. As such, transportation of patients and organization of surgical and medical staff should be coordinated closely once donor organs become available. Once procured, the lung poorly tolerates more than 6 hr of ischemic time, which limits cross-matching of HLA antigens and geography of organ donation. However, a recent study suggests viable extension of approved ischemic time to 5 to 8 hr from 4 to 5 hr without change in short-term outcomes ⁽³³⁾. One study reports that it is not graft time alone that portends a poor survival after transplantation, but the interaction between donor age and ischemic time. This is especially true if donor age exceeds 55 years and ischemic time exceeds 6 to 7 hr ⁽³⁴⁾.

SINGLE LUNG TRANSPLANTATION

Single lung transplantation is most commonly used for non-septic lung diseases. The lung to be extracted is determined preoperatively as that having the poorest pulmonary function. This is typically delineated via ventilation/perfusion scanning. The use of only one lung optimizes allograft availability, providing a lung for a second recipient.

In patients with pulmonary hypertension, there has been some concern over the use of single lung transplantation, secondary to preferential perfusion of the allograft in the setting of high-native vascular resistance and perfusion of the cardiac output almost fully through the allograft. However, no difference has been found perioperatively, and postoperative survival is similar with either double versus single lung transplantation ⁽³⁵⁾. There are some accounts that the use of extracorporeal membrane oxygenation, intraoperatively and into the postoperative setting, may reduce some of the reperfusion injury encountered in single lung transplantation for pulmonary hypertension ⁽³⁶⁾.

Single lung transplantation is an option in patients with end-stage emphysema. Occasionally, selective lung ventilation has been used to manage overinflation of the native lung after transplant ⁽³⁷⁾. However, a recent review notes that despite radiographic evidence of native lung hyperinflation, there is little compromise of the allograft in most patients. These data suggest that routine lung volume reduction, isolated lung ventilation, or bilateral transplant is not necessary, despite the risk for native lung hyperinflation ⁽³⁸⁾. In some cases, however, native lung hyperinflation may result in severe allograft compromise, acutely and chronically, secondary to compressive atelectasis. Hyperinflation of the native lung may occur many months postoperatively and, in this setting, native lung volume reduction has been used to preserve allograft volume and function ^(39–41). As a way in which to limit this potentially preventable cause of allograft compromise, measurements of patients’ static lung compliance have been advocated as a screening technique to select patients who might benefit from lung volume reduction surgery after transplantation ⁽⁴²⁾.

BILATERAL LUNG TRANSPLANTATION

Bilateral sequential lung transplantation has surpassed en bloc resection and implantation as the procedure of choice for septic lung disease and other diseases in which bilateral transplantation is preferred. Advantages of the sequential procedure include a lower incidence of bronchial anastomotic complications and less technical difficulty to perform. Cardiopulmonary bypass is not always necessary in the sequential procedure because selective lung ventilation may adequately preserve oxygenation and ventilation. Indications for adult lung transplantation by procedure are provided in Figure 2.

Figure 2: Indications for adult lung transplantation. Emphysema is the predominating indication for single lung transplantation, with cystic fibrosis as the predominating indication for double lung transplantation. (From ISHLT Registry Report 2000, http://www.ishlt.org, accessed April 15, 2001.)

HEART-LUNG TRANSPLANTATION

As isolated lung transplantation has evolved and more diseases have been successfully treated with this technique, the number of heart-lung transplants has decreased. The number of centers that perform this operation decreased from 62 in 1993 to 30 in 1998 ⁽⁴³⁾. Right ventricular function typically improves after isolated lung transplantation, and the presence of cor pulmonale is neither an absolute exclusion criteria for lung transplantation nor an indication necessarily for heart-lung transplantation ^(44–46). Presently, heart-lung transplantation is best reserved for patients with end-stage pulmonary disease with concomitant irreversible cardiac failure.

LIVING-DONOR LOBAR TRANSPLANTATION

Living-donor lobar transplantation is now a realistic option for carefully selected patients. As of December 2000, 139 living-donor lobar transplants have been performed in the United States (United Network Organ Sharing Critical Data, http://www.unos.org). Blood group compatibility is the only matching performed; HLA matching is not a prerequisite. In adults, outcomes have been similar to cadaveric transplantation. However, results have been reported to be superior to cadaveric lung transplants in children ⁽⁴⁷⁾. Improved function and less obliterative bronchiolitis have been noted in pediatric recipients of lobar donation ⁽⁴⁸⁾. In both children and adults, the procedure has been considered safe for the donor; donation of a lobe was associated with only a 15% decrease in lung volume without change in functional capacity ⁽⁴⁹⁾. However, one group has noted that 61.3% of living donors had postoperative complications, including pleural effusions, bronchial stump fistulas, phrenic nerve injury, and bronchial stricture ⁽⁵⁰⁾. Morbidity and mortality data that concern living donors should continue to be monitored closely in the coming years.

COMPLICATIONS OF LUNG TRANSPLANTATION

Complications of lung transplantation include complications secondary to the surgery itself; hyperacute, acute, and chronic rejection; and complications of the immunosuppressive agents.

Reimplantation Response

The morbidity and mortality in the first weeks after single or double lung transplant are due mainly to the reimplantation response and airway anastomotic complications. The reimplantation response manifests as worsening gas exchange in the hours to days after transplant. There is decreased lung compliance, and there are also perihilar infiltrates. This diagnosis should be considered after the exclusion of volume overload, rejection, pneumonia, or vascular compromise. A recent retrospective study found that pulmonary reimplantation response occurred 57% of the time after lung transplantation. In this series, there was no association with a prolonged ischemic time, pulmonary hypertension, age, gender, type of lung transplant, or underlying pulmonary disease. However, cardiopulmonary bypass was associated with an increased incidence and severity of the reimplantation response ⁽⁵¹⁾.

In 15% of lung transplantation recipients, severe lung injury may develop, which is attributable to the reperfusion injury and lymphatic disruption associated with the perioperative period ⁽⁵²⁾. Development of this pattern of lung injury, if unilateral, may dictate the need for selective lung ventilation; nitric oxide or extracorporeal membrane oxygenation also may be considered ^(31,53,54).

On a clinical continuum with the reimplantation response is acute graft dysfunction, in which early abnormalities of lung function and lung compliance after implantation are associated with pulmonary hypertension and rapidly progressive pulmonary edema. Aspiration, contusion, or inadequate lung preservation may account for acute graft dysfunction. Acute graft dysfunction is associated with a mortality up to 60%, although some patients who have survived have gained adequate graft function ^(53,55).

Airway Complications

Airway complications have decreased, as the years of successful lung transplantation accumulate. Graft failure, secondary to bronchial dehiscence, occurred early in the transplant experience. Telescoping of the donor bronchus into that of the recipient has promoted long-term integrity of the donor-recipient airway connection. This technique diminished allograft failure secondary to dehiscence but resulted in a higher incidence of anastomotic stenosis and postoperative pneumonia when compared to end-to-end anastomosis ^(56–60). Anastomotic stenosis is now the most common large airway complication; rates of anastomotic complications vary with technique and center ^(58,60–64). Anastomotic complications are diagnosed with direct visualization with bronchoscopy or by suggestive decrements in spirometry ^(65–67). Symptoms include dyspnea with chest tightness and wheezing. The narrowing because of strictures may be managed with balloon dilation or with stent placement; granulation tissue may be removed via surgical or laser ablation ⁽⁶⁸⁾.

Rejection

Immunosuppression remains the key to successful solid organ transplantation. Hyperacute rejection is an uncommon cause of lung allograft dysfunction. Although current immunosuppressive combinations may control acute rejection, chronic rejection still accounts for the majority of long-term morbidity and mortality.

Hyperacute Rejection

Preformed antibodies against allograft antigens, including HLA and ABO blood group antigens, target the donor vascular endothelium and may lead to hyperacute rejection within minutes to hours after transplantation. The antibodies bind to the vascular endothelium, activate inflammatory and coagulation cascades, thus causing extensive thrombosis of graft vessels and graft failure. Clinically, hyperacute rejection in the pulmonary allograft has been associated with a positive T-cell cross-match and diffuse alveolar damage ⁽⁶⁹⁾. Another case of hyperacute rejection is described as characterized by interstitial neutrophilic infiltration, with platelet and fibrin thrombi and antibody deposition on the endothelial surface and vessel walls ⁽⁷⁰⁾. Hyperacute rejection, which is extremely rare, must be distinguished clinically from ischemia-reperfusion injury, which is likely present in most lung transplant recipients. Fulminant hyperacute rejection is almost uniformly fatal and reinforces the importance of ongoing research in graft preservation and cross-matching to help attenuate this contribution to mortality.

Acute Rejection

Acute rejection typically occurs in the first 3 to 6 months after transplantation. Most recipients have at least one episode. The risk remains after this time, and later episodes of rejection are not uncommon. The acute rejection response includes both a cellular response and soluble mediators, whereas hyperacute rejection is considered primarily a humoral response. The degree of HLA mismatching, especially at HLA-DR and HLA-B loci, appears to be a risk factor for acute rejection ^(71,72).

Transbronchial biopsy has been of use in the asymptomatic patients with rejection, in which routine surveillance biopsies have revealed histologic evidence of minimal to mild grade rejection. Not infrequently, radiography is unrevealing ⁽⁷³⁾. When rejection is symptomatic, patients may complain of fever, cough, dyspnea, or anorexia. Spirometry is a useful adjunct; declines in home spirometry of 10% to 15% usually prompt a search for acute rejection. A decrease in FEV₁, vital capacity, and diffusion capacity have a sensitivity of greater than 80% to detect acute rejection or infection episodes ⁽⁷⁴⁾. However, specificity is low because deterioration in pulmonary function parameters does not point to an etiology of pulmonary dysfunction ⁽⁷⁵⁾. Bronchoscopy with biopsy aids in the diagnosis of rejection. The key histologic finding is perivascular lymphocytic infiltrates, which may be in association with lymphocytic bronchitis or bronchiolitis. Eosinophilic alveolitis has been associated with allograft rejection ⁽⁷⁶⁾. Despite characteristic pathology and spirometry suggestive of acute rejection, infection and rejection do not infrequently occur together.

Infection should be excluded before an augmentation of immunosuppression. Competitive reverse transcription–polymerase chain reactions of cytotoxic lymphocyte effector molecules such as perforin, granzyme B, granulysin, and Fas ligand are being investigated as tools to assist differential diagnosis of graft dysfunction. A recent report suggests that the transcription of cytotoxic lymphocyte effector molecules is increased in both rejection and infection, but it is highest in infection with cytomegalovirus. Novel noninvasive methods for diagnosing acute rejection have been suggested, but they remain experimental. For example, exhaled nitric oxide levels reportedly correlate with acute lung rejection and may serve as a future noninvasive way to monitor allograft function and rejection ⁽⁷⁷⁾. Tumor necrosis factor levels, gamma interferon levels, and soluble interleukin-2 receptor levels are also elevated during episodes of acute rejection, but they lack sensitivity and specificity.

Treatment of acute rejection usually includes a brief course of high-dose corticosteroids (methylprednisolone 7–15 mg/kg daily for 3 days). Ganciclovir prophylaxis is indicated preemptively during the steroid therapy for patients at risk for cytomegalovirus. Symptomatic improvement usually occurs within 48 hr of steroid initiation, although surveillance biopsies may demonstrate persistent rejection in one third of patients who symptomatically respond to treatment ^(78,79). After the pulse of steroids, a higher dose is maintained for several weeks. If symptoms persist, a second pulse of steroids may be indicated. If a response does not occur, cytolytic therapy should be considered. Total lymphoid irradiation has been used in cases of refractory acute rejection ⁽⁸⁰⁾. Persistent symptoms and spirometric decline should prompt a search for an alternative diagnosis such as airway stenosis, infection, or chronic rejection.

Chronic Rejection

Chronic rejection usually occurs 6 months to 1 year after transplantation. It is characterized as graft dysfunction secondary to airflow limitations. It may be present in up to 40% of patients at 2 years ^(6,81) and in 60% to 70% of patients who survive for 5 years ⁽⁸²⁾. The target of the immune response in chronic rejection is the bronchial epithelium, manifested histologically as obliterative bronchiolitis. Airway injury stimulates fibroproliferation in the small airways, leading to narrowing and ultimately luminal obliteration. Graft dysfunction may develop more than 3 months posttransplant, with a mean time to formal diagnosis of 16 to 20 months ^(83,84).

For diagnosis, transbronchial biopsy has a sensitivity of only 17% in some series ⁽⁸⁵⁾. Home spirometry helps detect a bronchiolitis syndrome (suggested by a sustained decrease in the FEV₁ by 20% upon consecutive measures) ⁽⁸⁶⁾ and may do so before it is revealed by laboratory testing ⁽⁸⁷⁾. Similar to acute rejection, symptoms are nonspecific and include insidious onset of cough and dyspnea, although dyspnea is a later symptom and may portend more extensive disease ⁽⁸⁸⁾. Chest radiographic findings are nonspecific and may include volume loss, subsegmental atelectasis, linear opacities, and bronchiectasis ^(89,90). Air trapping and bronchial wall thickening on high-resolution computed tomography scanning can help support the diagnosis, and, in one study, they were the most sensitive and specific findings for obliterative bronchiolitis ⁽⁹¹⁾.

The etiology of chronic rejection is obscure, but prior acute rejection, cytomegalovirus infection, airway ischemia, and HLA mismatching have all been implicated ^(82,92–95). One group found that late acute rejection, lymphocytic bronchitis, or bronchiolitis and decreased immunosuppression were all risk factors for bronchiolitis obliterans syndrome ⁽⁹⁶⁾. Another group has found that ongoing neutrophilic inflammation, as reflected by increased polymorphonuclear cells in bronchoalveolar lavage, was a significant predictor for mortality ⁽⁹⁷⁾. Cytokines and adhesion molecules have been a focus of investigation in the realm of obliterative bronchiolitis, yet it is unclear if these factors are a causal contributor or a response to chronic rejection. There are some data that suggest neutrophilia and consequent interleukin-8 elevations antedate the development of obliterative bronchiolitis ⁽⁹⁸⁾. These data also suggest that the level of elevation may correlate with the severity and rapidity of the development of obliterative bronchiolitis. Transforming growth factor (TGF)-β has been demonstrated to localize to the airway and lung parenchyma in patients with obliterative bronchiolitis, with expression greater in patients with bronchiolitis obliterans syndrome as opposed to those without. TGF-β positivity in tissue preceded the diagnosis of bronchiolitis obliterans by 6 to 18 months and increased expression was associated with its development ^(99,100).

Corticosteroid therapy, inhaled cyclosporine, cytolytic therapy, tacrolimus, and mycophenolate mofetil have all been used in the management of bronchiolitis obliterans. Extracorporeal photopheresis has been applied by some groups to manage refractory rejection ^(101,102). In the majority of patients, the problem is difficult to resolve, and the mortality rate at 3 years after diagnosis is 40% or higher. Treatments may slow, but not terminate, functional decline ^(103,104). Late-stage management is largely palliative. Retransplantation has been performed for some patients with bronchiolitis obliterans. Early results were notable for an increased morbidity and mortality when compared to first time transplantation ⁽¹⁰⁵⁾. However, more recent experience suggests that retransplantation outcomes approximate those of initial transplantation ⁽¹⁰⁶⁾. Future research must focus upon the etiology of chronic rejection given the progressive and often fatal nature of its course. Understanding the genesis of bronchiolitis obliterans, with a goal of prevention, is key.

Immunosuppression

Induction of an immunosuppressed state is critical to the success of solid organ transplants. Extensive reviews of immunosuppression regimens for the lung transplant patient have been published ^(107,108). At most centers, a triple-drug regimen is standard and includes steroids, cyclosporine, and azathioprine. Despite aggressive multi-drug therapy, acute rejection is still common in the first weeks to months after transplantation. In this setting, tacrolimus and mycophenolate mofetil are sometimes substituted for cyclosporine and azathioprine, respectively. A prospective randomized study of tacrolimus versus cyclosporine demonstrated that acute rejection occurred less frequently in the tacrolimus group (89% vs. 100% in the cyclosporine group) ⁽¹⁰⁹⁾. Another prospective trial reported a reduced incidence of biopsy-proven obliterative bronchiolitis in the group that had received tacrolimus versus cyclosporine (21.7% vs. 38%) ⁽¹¹⁰⁾. Although tacrolimus use has been associated with lower rates of rejection, with similar infection rates, a higher incidence of new onset diabetes has been observed ⁽¹¹¹⁾. Tacrolimus has been demonstrated as efficacious in reversing refractory rejection ⁽¹¹²⁾. Tacrolimus has been used as a rescue therapy in bronchiolitis obliterans, in which patients treated with tacrolimus have a slowed rate of decline ⁽¹⁰⁴⁾. Some have suggested the use of tacrolimus as a primary immunosuppressant after lung transplantation ⁽¹¹³⁾. Guidelines have been published for the use of tacrolimus ⁽¹¹⁴⁾.

Antilymphocyte preparations are the mainstay of induction therapy in some centers. They were introduced initially, in part, to help avoid steroids in the early perioperative period. Cytolytic therapy is also used in steroid-resistant rejection. Polyclonal antilymphocyte globulin, antithymocyte globulin, and murine monoclonal antibody to CD3 (OKT3) all have been used in these circumstances. A recent, randomized prospective study in 44 lung recipients found that induction with rabbit antithymocyte globulin reduced the incidence of acute allograft rejection ⁽¹¹⁵⁾.

Others have suggested that the use of OKT3 is as safe and effective as induction immunosuppressive regimen. When used as such, it is associated with a lower incidence of acute rejection in the immediate postoperative period and, potentially, a decreased incidence of obliterative bronchiolitis in the long term ⁽¹¹⁶⁾.

Infection

Immunosuppressive agents necessary to prevent and treat rejection diminish host defenses and predispose to infection. The rate of infectious complications is higher in lung transplant patients as compared to recipients of other solid organs ^(117,118). In the perioperative period, donor airway intubation and ventilation expose the allograft to airway colonization and aspiration, and recipient airway intubation after transplantation can be prolonged. Impairment of the cough reflex and mucociliary clearance further limit the lung defense mechanisms ^(119,120).

In the first 2 months after transplantation, bacterial pneumonia is the most common infection. Gram-negative bacilli are the most common organisms, and these organisms also are associated with late infections in patients with obliterative bronchiolitis ⁽¹²¹⁾. Evaluation of infiltrates and rapid identification of organisms is imperative for directing antimicrobial therapy.

Viral diseases may lead to poor outcomes in the lung transplant patient; the Epstein-Barr virus has been implicated in posttransplant lymphoproliferative disorder, and the respiratory syncytial virus and adenovirus have been associated with severe disease and mortality in lung transplant recipients ^(122,123). Cytomegalovirus remains a common pathogen after lung transplantation and may be associated with progression to chronic rejection.

Cytomegalovirus

Cytomegalovirus is the predominant viral process in lung transplant recipients. Most infections are thought to be reactivation events ⁽¹²⁴⁾. Alternatively, infection may be a new primary infection that is secondary to donor tissue infection. Primary infection frequently occurs in recipients negative for cytomegalovirus who receive lungs from a cytomegalovirus-positive donor. Cytomegalovirus is associated with more severe disease and higher mortality rates in this subgroup ^(125,126).

The symptoms of cytomegalovirus are nonspecific and may be accompanied by leukopenia; more than 3% of atypical lymphocytes may be viewed on peripheral smear as well ⁽¹²⁷⁾. The most devastating manifestation of cytomegalovirus is pneumonitis. Rapid diagnosis of cytomegalovirus is facilitated by finding early antigen in bronchoalveolar lavage fluid and urine. Yet, patients may have evidence of infection without having disease. The presence of early antigen is suggestive of active replication ⁽¹²⁸⁾. Serum tests for cytomegalovirus antigens in the peripheral blood likewise provide rapid diagnosis, with plasma cytomegalovirus polymerase chain reaction quantitation shown to correlate with disease stage ⁽¹²⁹⁾. Because cytomegalovirus infection may be asymptomatic, biopsy of the lung may be critical for demonstrating active disease ⁽¹²¹⁾.

Cytomegalovirus infections are frequently treated with ganciclovir, although resistance may occur. Many centers have adopted prophylaxis regimens after transplant, with some studies suggesting that this may delay the onset of a less severe infection. In the absence of ganciclovir prophylaxis, the incidence of cytomegalovirus pneumonia is between 17% and 27%^(130,126). Although the prevalence of obliterative bronchiolitis syndrome is not altered, prophylaxis against cytomegalovirus has been reported to delay its onset ^(131,132). As clinical experience grows, the appropriate course of therapy, as well as the role of oral ganciclovir and cytomegalovirus immune globulin, will be elucidated. This will allow for optimization of management and prevention of this important complication.

Fungal Infection

Fungal infection in the lung transplant patient is associated with a higher morbidity and mortality, with a peak incidence in the first 2 months after transplantation and initiation of immunosuppression ⁽¹³³⁾. In a series by Cahill et al., 69 of 151 patients (46%) had positive fungal cultures at some time postoperatively ⁽¹³⁴⁾. Invasive disease with Aspergillus fumigatus occurred in 5 patients during the 6 months posttransplantation. A fumigatus is the most common cause of fungal infection in this setting, and although it may colonize the airways after transplant, it is usually without clinical relevance. A fumigatus may form ulcerations and pseudomembranes; tracheobronchitis and infection around the anastomosis may be aggressive and symptomatic or asymptotic and lead to diagnosis of infection once disease is already disseminated ⁽¹³⁵⁾. Invasive A fumigatus should be treated with amphotericin followed by itraconazole therapy for 12 weeks. Prophylactic therapy has been suggested, with regimens varying from fluconazole, itraconazole, or systemic and inhaled amphotericin. One group describes no cases of fungal infection in 52 patients treated with both fluconazole and aerosolized amphotericin ⁽¹³³⁾.

Mycobacterial Infection

Mycobacterial infections have been documented with variable frequency after lung transplantation. Although a screening tuberculin test is standard as part of the transplantation workup, a positive test is not a contraindication for transplantation. Chronic lung disease and immunosuppression each are risk factors for mycobacterial infection, and several groups have investigated the incidence of mycobacterial infections in lung transplant recipients ^(136–138). One group retrospectively reviewed 261 lung and heart-lung transplant recipients during a 12-year period. The incidence of mycobacterial infections was 9%, with most classified as Mycobacterium avium complex. In that series, the range between transplant and diagnosis of infection was broad, between 2 and 3086 days. Another group performed a retrospective review in 219 transplant patients and noted a 3.8% incidence of infection, with no deaths as a result of mycobacterial infection of any subtype ⁽¹³⁹⁾. Most complications associated with mycobacterial infection have been secondary to drug toxicity.

Malignancy

Immunosuppression has been associated with increased risks of neoplasms, including non-Hodgkin’s lymphoma, squamous cell cancers of the skin and lip, Kaposi’s sarcoma ⁽¹⁴⁰⁾, carcinoma of the vulva and perineum, and kidney and hepatobiliary tumors ⁽¹⁴¹⁾. Posttransplant myelogenous leukemia has been described in a patient 9 months after double lung transplantation for emphysema ⁽¹⁴²⁾. B-cell lymphoproliferative disorders have been associated with substantial morbidity and mortality in lung transplant recipients, with some older series recounting posttransplant lymphoproliferative disorder (PTLD) as the third leading cause of death outside the perioperative time frame ⁽¹⁴³⁾. PTLD is associated with the Epstein-Barr virus, but it may be of B- or T-cell proliferation. The proliferation is not limited to the lungs, lymph nodes, or bone marrow; one case describes presentation of PTLD of the gallbladder with acute cholecystitis ⁽¹⁴⁴⁾. Older series report an incidence of PTLD of 7.9% after lung transplantation ⁽¹⁴³⁾. Another series reported a 1.8% incidence in 109 consecutive lung transplant patients ⁽¹⁴⁵⁾. Others have described an incidence in the 20% range ⁽¹⁴⁶⁾; the true incidence is most likely between the lower and higher observed rates. Some have noted a higher incidence of PTLD in the pediatric patients who were transplanted for cystic fibrosis ⁽¹⁴⁷⁾. In these patients, the only risk for PTLD was two or more episodes of acute rejection within 3 months posttransplant. Epstein-Barr virus or cytomegalovirus serologies, age, and the use of antithymocyte and antilymphocyte globulins were not risk factors. The first line of treatment is to decrease immunosuppression. Anecdotal experience suggests a role for intravenous immunoglobulin. Extracorporeal photochemotherapy has been tried in this setting ⁽¹⁴⁸⁾. Monoclonal antibodies directed against CD20 are available and have been used for the treatment of PTLD in lung transplantation patients ⁽¹⁴⁹⁾.

SURVIVAL

International statistics convey 1-year, 3-year, and 5-year survivals of 74%, 58%, and 47%, respectively, for lung transplant recipients, although survival statistics will vary by transplant center. There remain survival differences between double versus single lung recipients, which seem to diverge between the third and fourth year after transplantation (Fig. 3).

Figure 3: Adult lung transplantation survival statistics. (From ISHLT Registry Report 2000, http://www.ishlt.org, accessed April 15, 2001.)

One study evaluated survival benefits of lung transplantation among patients with cystic fibrosis, interstitial fibrosis, and emphysema. The data demonstrate that transplantation conferred a survival benefit when compared with waiting time for cystic fibrosis and pulmonary fibrosis; there was no survival benefit for patients with emphysema ⁽¹⁵⁰⁾. This lack of survival benefit is an important consideration given that emphysema is the most common reason for single lung transplant. There are a high number of individuals with emphysema on the waiting list with a low attrition rate. Bilateral lung transplant for emphysema has been associated with improved lung function and a trend for improved survival at the cost of decreased organ availability for other waiting patients ⁽¹⁵¹⁾.

The benefits of transplant versus medical therapy must be addressed continually as medical treatments for end-stage lung disease are refined. One example of this is the use of prostacyclin in patients with pulmonary hypertension; improved exercise capacity to 27 months has been observed in a cohort of patients with primary pulmonary hypertension. If this trend continues beyond 3 years, then the benefit of transplantation in patients with pulmonary hypertension may not persist ⁽¹⁵²⁾.

EXERCISE CAPACITY

The majority of patients who undergo lung transplantation have a marked improvement in functional capacity and quality of life. By the end of the first year, most patients report no restriction in activity, and 6-minute walk results are at least twice the preoperative value ^(153,154). Results of formal cardiopulmonary exercise testing reveal submaximal exercise capacity for age-matched controls ^(155–159). One group found that at approximately 2 months after transplantation, maximum oxygen uptakes ranged from 22% to 71% of the predicted uptake. Work capacity, tidal volumes, and peak minute ventilation were not statistically different between single or double lung transplant or heart-lung transplant recipients, although a persistent limitation in aerobic capacity and work rate was observed ⁽¹⁶⁰⁾. Another group demonstrated expiratory and lower limb muscle weakness but preserved inspiratory muscle function when compared to age-matched controls. This suggests, in part, that muscle groups are effected variably by the myopathic side effects of immunosuppressant regimens and deconditioning ⁽¹⁶¹⁾. Note that the finding of respiratory muscle weakness has been not consistently observed, leading one group to postulate that most of the work capacity reduction is secondary to limb muscle deconditioning ⁽¹⁶²⁾. This group also found no difference between those patients who did or did not undergo postoperative exercise training. The findings suggest that pretransplant rehabilitation may actually provide the most benefit after transplantation.

The presence of a low anaerobic threshold with a suggestion of impaired muscle use of oxygen suggests mitochondrial dysfunction, potentially secondary to cyclosporine ^(163–165). Lower mitochondrial ATP production and lower activity of mitochondrial glutamate dehydrogenase, citrate synthase, 2-oxogluterate dehydrogenase, and 3-hydroxyacyl-CoA-dehydrogenase all have been noted after transplantation. These mitochondrial enzyme reductions were found in conjunction with a lower proportion of type 1 muscle fibers and higher lactate and inosine monophosphate content, suggestive of anaerobic metabolism. This also suggests that reduced type 1 fiber proportion, along with reduced oxidative capacity, may play a role in exercise limitations after transplant ⁽¹⁶⁶⁾. A recent summary of skeletal muscle dysfunction after lung transplantation has been published ⁽¹⁶⁷⁾.

QUALITY OF LIFE

Quality of life is improved after transplantation. TenVergert et al. found that lung transplantation improves quality of life secondary to improved mobility and energy, improved sleep, diminished dyspnea, and increased ability to accomplish activities of daily living ⁽¹⁶⁸⁾. Other reports have suggested marked improvement in quality-of-life indices within the first year ^(169,170). Yet this trend reverses with the development of the bronchiolitis obliterans syndrome, which is associated with a decrement in quality of life ⁽¹⁷¹⁾. In one cross-sectional study, patients with bronchiolitis obliterans syndrome reported restrictions of energy and physical mobility without effect on pain, sleep, social interactions, and emotional parameters. Nonetheless, most recipients who survive beyond 5 years remained active despite the development of bronchiolitis obliterans ⁽¹⁷²⁾.

CONSIDERATIONS FOR THE 21ST CENTURY

Twenty-eight years have elapsed since the first human lung transplant was performed by Dr. James Hardy at the University of Mississippi. Since that time, lung transplantation has emerged as a viable therapeutic option for people with advanced lung disease. However, obstacles remain, thus limiting graft availability and function and prolonged survival. Further experience with living lobar transplant may hold promise in the setting of limited allograft availability. Further research in lung preservation may allow for more time to do tissue typing and cross-matching. Refinements in organ procurement and preservation will lead to a gradual improvement in survival, but new modalities of donor organ evaluation and immunosuppression are likely to lead to the most significant strides. Blockade of specific T-cell costimulatory pathways is under investigation as a way to promote graft tolerance without systemic immunosuppression. These advances, together with standardized guidelines for the training of physicians in the care of patients, should help carry lung transplantation forth into the 21st century. In the future, a more detailed understanding of immune mechanisms of tolerance may allow for successful xenotransplantation, and research in pulmonary organogenesis may someday provide an alternative to allografting.