Abstract
Indications for pediatric lung transplantation vary by age, with some conditions leading to transplant throughout childhood (e.g., pulmonary hypertension) and others predominating in younger (e.g., surfactant disorders) or older (e.g., cystic fibrosis) children. The use of the “Lung Allocation System” has resulted in shorter waiting list times and also in sicker children proceeding to lung transplant. The number of absolute contraindications to transplant has diminished as centers develop greater expertise. Strategies such as extracorporeal membrane oxygenation (ECMO) are being used as a “bridge” to transplant in some patients with severe lung disease. Patients who undergo lung transplant require lifetime immunosuppression, which increases their ongoing risk of infection. Acute rejection can occur in the period immediately following transplant. Medication side effects, particularly renal dysfunction, become increasingly common over the years following transplant. Malignancies are relatively uncommon as a complication of transplant, but posttransplant lymphoproliferative disorder (PTLD), a form of lymphoma often associated with Epstein-Barr virus (EBV), can occur months or years following transplant. Complications such as chronic lung allograft dysfunction (CLAD) become increasingly common in the years following transplant. Treatment for CLAD is challenging, and this complication limits long-term allograft survival. Average survival in pediatric lung transplantation is just over five years. Extending patient survival and improving organ supply will be vital to the future of the field.
Keywords
lung transplantation, pediatrics, cystic fibrosis, interstitial lung disease, pulmonary hypertension
Introduction
With reports of successful heart-lung and lung transplantation in adults in the early 1980s, the application of lung transplantation to the pediatric population became an appealing prospect. Early reports of success in children undergoing lung transplantation led to a marked increase in such procedures beginning in the early 1990s. Between January 1986 and June 2014, more than 2000 lung and almost 700 heart-lung transplantations in patients less than 18 years old have been reported to the Registry for the International Society for Heart and Lung Transplantation (ISHLT). The number of lung transplant procedures performed annually from 2006 to 2015 has varied between approximately 95 and 140. Historically, heart-lung transplant was considered for patients with end-stage lung disease, with the relatively healthy native recipient heart considered for use in a “domino” transplant. Heart-lung transplant was also considered in patients with right ventricular failure associated with severe pulmonary hypertension. However, in the current era, heart-lung transplant is typically reserved for cases associated with left ventricular failure or congenital heart disease not amenable to surgical repair. Thus the number of heart-lung transplants performed has dropped to approximately 10 per year worldwide.
Typically, 40–45 centers report pediatric lung transplants, yielding a statistical average of 2–3 transplants per center annually. In reality, a few centers perform the majority of these procedures, and most centers perform very few. The number of lung transplants performed yearly is far below the number of other solid-organ transplants such as heart, liver, and kidney transplantation. This relative paucity is likely due to multiple factors, including lower prevalence of end-stage pulmonary diseases in children, improved therapies for cystic fibrosis (CF) and pulmonary hypertension, the significantly lower procurement rate of donor lungs compared with other organs, and the small number of pediatric lung transplant centers in the United States and worldwide. Notwithstanding changes in the allocation of lung allografts (discussed later), the mortality rate for pediatric candidates aged 1–11 years awaiting lung transplantation remains higher than that in adults, underscoring the need to expand the potential donor pool and perhaps the number of centers performing this procedure.
Indications and Timing
Indications for lung transplantation in children have undergone considerable change in the past three decades as experience with this procedure has grown. Lung transplantation has been performed successfully even in young infants with distinctly uncommon problems such as surfactant protein B deficiency and alveolar capillary dysplasia. The most common diagnoses for which children are transplanted are listed in Fig. 67.1 according to the age in years at time of transplantation. In children younger than 1 year, the most common indications are pulmonary hypertension, usually associated with congenital heart disease, other pulmonary vascular diseases, primarily pulmonary vein stenosis, and rarely alveolar capillary dysplasia; disorders of surfactant metabolism, including surfactant protein B and C deficiencies and ABCA3 transporter mutations; and a spectrum of “fibrotic” lung diseases. Less common indications include interstitial lung disease, bronchopulmonary dysplasia, and pulmonary hypoplasia. In patients 6–17 years of age, CF is the most common indication, and in the 12- to 17-year group, nearly 70% of pediatric lung transplants are performed in CF patients. In the 1- to 5-year age group, disorders leading to pulmonary hypertension remain a common indication. The relative percentage of children with primary pulmonary hypertension coming to lung transplant has diminished significantly during the past two decades, largely because of the introduction of effective medical therapies, including prostaglandins (epoprostenol), phosphodiesterase (PDE) inhibitors (bosentan), and sildenafil (see Chapter 35 ). Surprisingly, despite a steady increase in the median survival for CF, the relative percentage of children with CF receiving lung transplants has not changed appreciably in recent years. Historically, timing of referral for lung transplant has been predicated on matching predictions of mortality with the anticipated waiting time for donor lungs. For example, studies in CF led to recommendations for referral for lung transplantation once the forced expiratory volume in 1 second (FEV 1 ) declined below 30% predicted. Although more recent studies have attempted to add to these criteria, none have improved significantly on the ability to predict waiting list mortality. Even in the best model, the positive predictive value is less than 50%. In other diseases leading to lung transplant, criteria are less clear. Given absent or imperfect disease-specific criteria, before committing a child to lung transplant, most pediatric centers carefully consider multiple factors beyond lung function, including growth and nutritional status, frequency of hospitalizations, and potential for improvement in overall quality of life.
During the past 10 years, listing practices for children >12 years of age and adults have been affected by the adoption in 2005 of the “Lung Allocation System” (LAS) in the United States by the Organ Procurement and Transplantation Network (OPTN). Based on models of waiting list mortality and posttransplant survival, this new system attempts to allocate donor lungs to maximize the 1-year transplant survival benefit. The survival models are based on diagnosis and other factors including age, height and weight, need for supplemental oxygen, pulmonary artery pressures, 6-minute walk distance, and lung function. Since adoption of the LAS, waiting time and waiting list mortality have decreased in the United States. Nevertheless, an increased number of sicker patients are undergoing transplant—and a significant proportion of those patients (primarily those requiring mechanical ventilation) have had poorer overall survival than historical lung transplant cohorts—because the contribution of the waiting list mortality to the LAS is twice that of posttransplant survival :
LAS = posttransplant survival − 2 × waiting list survival , normalized to a 0 − 100 scale .
An important aspect of the LAS is the potential for serially collected data from patients listed for lung transplant to be used for refinement of the underlying models that generate the priority score. For children younger than 12 years of age, in an effort to reduce waiting list mortality for these candidates, lung allocation was modified in the fall of 2010 to create two urgency tiers, similar to the status 1 and 2 in heart transplant allocation. Current changes in allocation involve the broader geographic sharing of pediatric donor lungs with pediatric recipients, which has been predicted to improve access for pediatric patients without adversely affecting adult ones. It is difficult to predict the long-term benefits of these policy modifications.
There are numerous unsolved challenges in pediatric lung allocation, and a root problem is the relative scarcity of organs. Some usable organs are probably not being transplanted: among children whose families have agreed to donate at least one organ, less than 5% of 11-year-old-and-younger donors are providing lungs. Extending pretransplant survival with lung bypass technologies, as well as salvaging suboptimal lung allografts (e.g., with ex vivo lung perfusion, [EVLP] discussed later in this chapter), have the potential to marginally increase the numbers of available donor lungs at a given time.
Contraindications
As experience with pediatric lung transplant has grown, the number of absolute contraindications has declined, with most considered relative contraindications based on each transplant center’s experience and expertise ( Table 67.1 ). Common absolute contraindications to pediatric lung transplantation include systemic disease affecting other organ systems, such as malignancy, HIV, hepatitis B or C, tuberculosis, and liver, renal, or left ventricular failure. However, in some transplant centers, multiorgan transplantation (e.g., liver-lung transplantation) may be an option in selected patients with failure of an organ other than the lung. In CF patients, Burkholderia cepacia complex (BCC) organisms are often a concern. Initially, all BCC organisms were thought to lead to poor outcome after lung transplantation, but more recent analyses have suggested that only colonization with B. cenocepacia (formerly BCC, Genomovar III), and a related organism, B. gladioli, carries significant risk. B. cenocepacia colonization remains an absolute contraindication to lung transplant at a significant percentage of pediatric centers. Infection or colonization with Aspergillus, atypical mycobacteria (particularly Mycobacterium abscessus ), or multiresistant organisms is a relative but not absolute contraindication in patients with CF. It is not uncommon for lung transplant candidates to present unique and complex challenges to the transplant center, including malnutrition, diabetes, osteoporosis or osteopenia, vertebral compression fractures, and the use of systemic corticosteroids. These are considered relative, but not absolute, contraindications. Prior pleurodesis, either chemical or surgical, although not a contraindication to transplant, may prolong the ischemic time because of excessive bleeding from the parietal pleura, particularly when cardiopulmonary bypass and attendant heparinization are used, and is associated with higher mortality.
| Absolute | Relative |
|---|---|
| Active malignancy within 2 years a | Pleurodesis |
| Sepsis | Renal insufficiency |
| Active tuberculosis | Markedly abnormal body mass index |
| Severe neuromuscular disease | Mechanical ventilation |
| Documented, refractory nonadherence | Scoliosis |
| Multiple organ dysfunction b | Poorly controlled diabetes mellitus |
| Acquired Immunodeficiency Syndrome | Osteoporosis |
| Hepatitis C with histologic liver disease | Chronic airway infection with multiply resistant organisms c |
| — | Fungal infection/colonization |
| — | Hepatitis B surface antigen positive |
a Some centers prefer a disease-free interval of 5 years.
b Consider heart-lung transplant with concomitant left ventricular insufficiency or irreparable congenital heart disease, liver-lung transplant with concomitant hepatic failure.
c For some transplant centers, infection with Burkholderia cepacia complex organisms, particularly genomovar III (B. cenocepacia), is an absolute contraindication.
Finally, psychosocial concerns for children, particularly nonadherence, can be particularly challenging, especially when the responsibility for adherence is shared between separated parents. Decisions about how to handle such cases—without creating the perception that the parent’s misbehavior led to the child being denied the opportunity for transplant—must be an individualized, shared responsibility of both the referring and transplant centers. In families where nonadherence to a recommended treatment regimen is recognized, some centers recommend formulation of a contract between the referring physician and family that outlines the need for strict adherence to a treatment program over a 3- to 6-month period prior to evaluation/listing for lung transplant. In general, adherence concerns become an absolute contraindication only in combination with other medical risk factors or after persistent failure on the part of the child and family to meet a set of agreed upon expectations for care and follow-up. In contrast, a significant psychiatric or mental health disorder in either the primary caregiver or the patient is considered an absolute contraindication to transplant.
Surgical Technique
Potential donor lungs are evaluated using arterial blood gases, chest radiographs, airway cultures, and airway examination by bronchoscopy. The donor history is reviewed for signs/symptoms of acute viral infection. In addition, the donor is routinely screened for hepatitis A, B, and C, HIV, varicella-zoster, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and herpes virus.
One response to organ scarcity has been to explore the feasibility of longer-term lung bypass technologies. Extracorporeal membrane oxygenation (ECMO) is now being used as a “bridge to transplant” in some patients with end-stage disease. Patients who undergo short pretransplant ECMO runs may spend a longer intraoperative period on cardiopulmonary bypass, but they do not have worse survival. This approach to bridging is now being extended to include “ambulatory ECMO,” which allows for intensive physical rehabilitation for patients on the waiting list. Most pediatric patients undergoing ambulatory ECMO have had only short ECMO courses, but an evaluation of outcomes in these cases will help to determine whether extended courses of ECMO could be used to augment the quality and quantity of pretransplant survival. Paracorporeal lung assist devices, which remove and oxygenate blood from the pulmonary artery, subsequently returning it to the left atrium, have been used as a longer-term bridge (e.g., greater than 2 months). Nevertheless, these bypass technologies put patients at elevated risk of bleeding or infectious complications.
Another promising perioperative approach to organ scarcity is EVLP, which entails organ procurement followed by ex vivo diagnostics and organ reconditioning. Antibiotics can be used to perfuse the organ, thereby reducing bacterial load, and clots can be washed from the pulmonary circulation. Outcomes to date with EVLP lungs have been similar to non-EVLP lungs, and there is hope that this technology could be used to capture “marginal donor lungs” that would otherwise go unused.
In most pediatric transplant procedures, cardiopulmonary bypass with heparinization has traditionally been used for the implantation procedure, but ECMO has become an increasingly common alternative. The surgical approach is via a bilateral anterolateral transsternal incision (the “clamshell” incision), which optimizes visualization and access to both pleural spaces. The clear majority of children undergo bilateral sequential lung transplantation with telescoped bronchial-to-bronchial anastomoses. Pericardial or peribronchial lymphatic tissue from the donor and recipient is used to cover the anastomosis. This improves the blood supply to the anastomosis and may reduce the exposure of adjacent vascular structures to infection, in the event of airway infection and subsequent dehiscence. In patients with CF, careful attention to maintaining sterility of the donor allograft requires vigorous washing of the recipient trachea and bronchial stumps with an antibiotic solution prior to implantation.
Heart-lung transplantation is rarely used in children in the United States at this time. Even in the presence of marked right ventricular hypertrophy associated with pulmonary hypertension, successful bilateral lung transplantation is generally associated with resolution of right ventricular dysfunction. In patients with pulmonary hypertension caused by a congenital heart defect, intracardiac repair of the anatomic defect may take place at the time of bilateral lung transplant, obviating the need for heart-lung transplantation. Single lung transplantation is used infrequently among children, and much less than in adults.
Success with living donor lobar lung transplantation was first reported by Starnes in 1994. In this procedure, a right lower lobe from one healthy donor and a left lower lobe from another (generally family members) are implanted in the recipient. Typically, this technique has been used in both adults and children in the setting of rapidly progressive respiratory failure where cadaveric lung allografts were judged unlikely to be available or where further deterioration in clinical status would make the patient ineligible for deceased donor transplantation. Although living donor lung transplant has virtually disappeared in the United States since the introduction of the LAS, it is still used in Japan, where access to donor organs suitable for children has been restricted. Other strategies for increased availability of organs for children and other smaller recipients include donor downsizing using linear stapling devices or lobectomy and lobar transplant.
Posttransplant Management
Immunosuppressive Regimen
In the immediate preoperative period, triple drug immunosuppression and directed antimicrobial therapy is begun. In virtually all circumstances, immunosuppression consists of a calcineurin inhibitor (CNI; either tacrolimus or cyclosporine A [CSA]), a cell cycle inhibitor (azathioprine or mycophenolate mofetil [MMF]), and corticosteroids. Based on studies suggesting marginally better efficacy, there has been a trend in recent years toward the use of tacrolimus and MMF over CSA and azathioprine. Nearly all pediatric lung transplant recipients are on tacrolimus and more than 80% are on MMF at the end of the first year. Because lung transplant recipients have a higher risk for rejection episodes than other solid organ transplant recipients, more intense immunosuppression regimens have been developed. For example, the initial targets for trough levels for tacrolimus and CSA are typically maintained in a range of 10–20 mg/mL and 300–500 mg/mL, respectively. Initial dosing for prednisone is typically 0.5–1.0 mg/kg per day with the goal of 0.25–0.5 mg/kg per day by 3–4 months after transplant, depending on the clinical course. Nearly all patients remain on prednisone at 1 and 5 years posttransplant. In addition, the use of induction immunotherapy at the time of transplant remains widely used in pediatric lung transplantation; recent data indicate that almost 70% of patients receive either a polyclonal agent (antilymphocyte or antithrombocyte globulin) or, more commonly, an interleukin-2 (IL-2) receptor antagonist (daclizumab or basiliximab).
Antimicrobial Regimen
Most patients receive intravenous (IV) antibiotics before and after lung transplantation, based on the most likely potential infecting organisms. Cultures from the donor may allow precise choices of antibiotics. In patients without CF, a single antibiotic with broad gram-positive and gram-negative coverage is typically used for 7–10 days posttransplant. In recipients with CF, their pretransplant sputum cultures help guide therapy; typically, such antimicrobial therapy is directed against gram-negative organisms, commonly Pseudomonas aeruginosa and occasionally Achromobacter spp. Vancomycin is often included to cover methicillin-resistant Staphylococcus aureus (MRSA), which is being found increasingly in children with CF and advanced lung disease. In CF patients in whom Aspergillus fumigatus has been found, many transplant centers use voriconazole or anidulofungin postoperatively and, in some circumstances, aerosolized amphotericin, oral itraconazole, or oral voriconazole. Prophylaxis against Pneumocystis jiroveci is begun shortly after transplant with trimethoprim/sulfamethoxazole (TMP/SMX) administered three times weekly. In patients unable to tolerate TMP/SMX, nebulized pentamidine, oral atovaquone, or dapsone are alternatives. Oral nystatin is begun in the early posttransplant period to reduce the likelihood of candida infection.
Although the availability of ganciclovir has reduced the significance of CMV in lung transplant recipients, CMV remains a serious potential complication associated with an increased risk of mortality. The approach to CMV prophylaxis in the pediatric lung transplant recipient is controversial, varying considerably among transplant centers. In most instances, CMV prophylaxis is not administered when both recipient and donor are CMV seronegative. If either the donor or recipient is seropositive for CMV, ganciclovir or valganciclovir are administered for 4–12 weeks posttransplant. More recent studies have suggested a potential benefit to extending the duration of prophylaxis (with IV ganciclovir or oral valganciclovir) to 6 months or longer. Some pediatric centers administer CMV hyperimmune globulin (CMVIg) in conjunction with ganciclovir based on reports of improved outcomes with CMV disease in adult patients. However, the long-term benefit of CMVIg remains unclear.
Management Issues Unique to Pediatrics
Although guided by the strategies used in adult lung transplant recipients, several significant differences exist in therapy and monitoring for pediatric lung transplant recipients, most importantly related to the ability to diagnose chronic lung allograft dysfunction (CLAD; defined later in this chapter).
Although spirometry is essential for the clinical diagnosis of CLAD, it is generally not reliable until children reach 6 years old. Using thoracoabdominal compression techniques, infant pulmonary function testing (PFT) can identify the presence of airflow obstruction, but this testing requires specialized equipment and experience. Moreover, such tests cannot be performed as frequently as conventional spirometry because they require sedation or anesthesia. Infant PFT has not been used in recent chronic allograft dysfunction diagnostic criteria.
An additional limitation for infants and toddlers relates to transbronchial biopsies (TBBx). Although TBBx forceps small enough to fit through the suction channels of endoscopes used for bronchoscopy in young children became available in the 1990s, the smaller forceps typically yield much smaller pieces of tissue. Therefore obtaining tissue for the diagnosis of rejection in infants may be technically challenging.
Therapeutic challenges also exist. Newer immunosuppressant and antiinfective agents often are not available in the liquid forms required for young children. Management of liquid forms can be difficult for patients and families, as they usually must be compounded by local pharmacies and may have a short shelf life. In addition, the use of liquid forms may be problematic for transplant centers because dosing decisions must often be made when appropriate absorption and pharmacokinetic data for infants and children are not available.
Complications
Complications following lung transplantation occur in predictable timelines: a few weeks after transplant, when the most common complications are related to the condition of the donor organs and the surgical procedure; an early phase, 1–6 months after transplant, when infectious and acute immunologic complications become more prevalent; and a late phase, >6 months after transplantation when chronic immunologic complications such as bronchiolitis obliterans (BO) and malignancies are observed more frequently ( Fig. 67.2 ).
Immediate Posttransplant Phase
Because pediatric lung transplant procedures are performed with cardiopulmonary bypass or ECMO, postoperative bleeding, particularly in the pleural space or at the site of the vascular anastomoses, is a common concern. Other complications of the surgical procedure include injury of the phrenic or recurrent laryngeal nerve, causing diaphragmatic or vocal cord dysfunction. Dehiscence at either the vascular or the bronchial anastomoses may require prompt surgical attention and an early return to the operating room. Most transplant centers perform flexible bronchoscopy within 24–48 hours of transplantation to obtain cultures from the lower airways and to assess the integrity of the airway anastomosis. Fortunately, dehiscence of the airway anastomosis has become rare since the development of techniques to cover the anastomosis with vascularized tissue. However, other airway complications occur at a frequency comparable to that seen in adult lung transplant recipients, including fibrotic strictures, excessive granulation tissue, and airway collapse at the site of the anastomosis. In the event of the development of stenosis of the airway lumen, balloon dilatation or stent placement by bronchoscopy may be necessary. Mechanisms invoked to explain the development of anastomotic narrowing include donor airway ischemia, impaired airway healing, and barotrauma if prolonged ventilation is needed after transplantation.
Rejection
Lung allograft rejection remains problematic, representing an important obstacle to long-term success of transplantation, particularly in comparison to other solid organ transplant procedures. A variety of mechanisms have been proposed to explain this discrepancy, including the richness of immune effector cells resident in the pulmonary vasculature and lymphatic system, the ongoing daily exposure of the vast epithelial surface of the lung allograft to potential environmental irritants, toxins, and pathogens, and the fact that the lungs are exposed to the entire cardiac output.
Hyperacute rejection within hours of transplant is a rare, potentially catastrophic complication in the immediate posttransplant period associated with circulating recipient antibodies that bind to donor human leukocyte antigen (HLA) molecules on vascular endothelium, leading to significant graft ischemia. It can be prevented by screening the recipient for anti-HLA antibodies and avoiding donors with related antigens. However, because the logistics of organ allocation often preclude HLA information being available at the time of organ offer, this approach is typically reserved for patients with antibodies to a significant percentage of HLA types. Alternatively, patients with a low percentage of antibodies reactive to the spectrum of HLA antigens undergo cross-matching at the time of transplant. Patients with positive cross-matches are usually treated with plasmapheresis to prevent hyperacute rejection, and even highly sensitized patients can undergo transplant.
The most frequent problem that occurs in the first posttransplant week is primary graft dysfunction (PGD) related to reimplantation lung injury. PGD is associated with the procurement procedure and duration of ischemia prior to implantation; the generation of hydroxyl radicals and proinflammatory cytokines during ischemia may be causative factors. Complications related to graft dysfunction vary from mild, noncardiogenic pulmonary edema to a picture of acute respiratory distress syndrome histologically characterized as diffuse alveolar damage. Patients generally have marked hypoxemia and diffuse infiltrates. Treatment is supportive with careful fluid management and ventilatory support ; ECMO support has also been used in selected cases. Although early retransplantation may be considered, outcomes in this setting are generally poor.
Acute rejection is much more common than hyperacute rejection: most patients undergo at least one episode. Acute rejection can occur as early as 1 week after transplantation or as long as 2–3 years later. Most commonly, episodes of acute rejection occur 2–12 weeks after transplantation. Nonspecific signs and symptoms of acute rejection include cough, fever, dyspnea, hypoxemia, and radiographic changes. Lung function studies, if available, tend to show an obstructive pattern. Chest examination may show tachypnea and crackles on auscultation. Since these findings are not specific for rejection and are difficult to differentiate from infection, evaluation by bronchoscopy with bronchoalveolar lavage (BAL) and TBBx is generally indicated, particularly for patients presenting in the first 3 months after transplant. Histologically, biopsy specimens in acute rejection show perivascular lymphocytic infiltrates with or without airway inflammation. They are classified according to a standardized scoring system. Because patients with acute rejection may be asymptomatic, many transplant centers advocate surveillance bronchoscopy with TBBx on a scheduled basis (e.g., at 2 weeks, 1, 2, and 3 months after transplant, quarterly intervals for the rest of the first year, and semiannually thereafter). Some transplant centers perform bronchoscopy and biopsies only when symptoms of lower respiratory tract disease become manifest, arguing that long-term outcomes are unaffected with this approach. Performance of screening biopsies during the first posttransplant year has increased following publication of data suggesting that a single episode of minimal acute rejection is an independent risk factor for chronic rejection. However, this finding was not confirmed in a multicenter analysis of pediatric lung transplant recipients.
Treatment of acute rejection consists of 10 mg/kg of IV methylprednisolone daily for 3 days. For persistent or recurrent acute rejection, lympholytic therapy with, for example, antithymocyte globulin may be initiated or the daily immunosuppressive regimen may be altered or enhanced. Although episodes of acute rejection are common after lung transplantation (perhaps even expected), there are data suggesting that younger transplant recipients (<3 years of age) have fewer episodes of acute rejection than older children or adults.
Infection
Sources of increased risk of infection in the immediate posttransplant period and beyond are multifactorial. These include organisms present in the donor at the time of procurement, the intensity of immunosuppression, the loss of a normal cough reflex because of postoperative pain and the disruption of afferent and efferent nerves responsible for coordinating the cough response, impairment of mucociliary transport, and alteration in trafficking of immune effector cells to regional lymph nodes. Despite the use of prophylactic antibiotics in the perioperative period, recipient factors (particularly in patients with CF) and donor factors (e.g., active viral infection) may lead to significant infectious complications early in the postoperative period. Younger children appear to be at greatest risk for early viral infections, perhaps because they are less likely to have developed immunity. In CF transplant recipients, the chronically infected lungs may cause seeding of the blood or mediastinum with recipient airway flora during explantation. Furthermore, chronic sinus disease typical of CF is a potential source of infection to the allograft and has led some transplant centers to advocate pretransplant sinus surgery coupled with antibiotic washing of the sinuses. However, a recent retrospective analysis of sinus surgery in patients with CF undergoing transplant at a major transplant center showed no survival benefit associated with pretransplant sinus surgery.
Early Phase (1–6 Months)
Rejection
In addition to acute rejection, which has peak incidence during this period, it has become clear that the posttransplant development of donor specific anti-HLA antibodies (i.e., allo antibody response) can lead to antibody-mediated rejection (AMR). AMR can also develop in response to circulating self-antigens (i.e., auto antibody response) such as collagen V and K-alpha 1 tubulin. The clinical manifestations of humoral lung allograft rejection are difficult to differentiate from infection or acute cellular rejection. Patients present with dyspnea, pulmonary infiltrates, and decreased lung function. Although there is no “gold standard” for diagnosis, the presence of circulating donor specific antibodies (identified using solid phase flow cytometry techniques), alveolar capillary complement (C4d) deposition, and capillaritis in the setting of allograft dysfunction is usually considered sufficient evidence. Diagnosis is complicated by disagreement regarding the meaning of laboratory testing: many laboratories report a mean fluorescence intensity (MFI) value, which—although it represents some amount of bound antibody to a single antigen bead—cannot be interpreted as a true titer. Treatment of humoral rejection is also controversial. Most centers use some combination of steroids, plasmapheresis, IV immunoglobulin, and B-cell reduction (Cytoxan or rituximab). The role of newer agents such as bortezomib, a proteosome inhibitor targeted at plasma cells, or complement inhibitors such as eculizumab remains to be elucidated.
Infection
During this period, the risk of infectious complications is typically highest, especially in patients who have received an induction agent. The initial concern is for organisms carried with the donor organs during implantation or (primarily in the case of CF) harbored in the upper airways of the recipient. Subsequently, community and nosocomial organisms may cause infection, as may opportunistic (pneumocystis, candida) pathogens. Patients who are seropositive for CMV or who are seronegative and receive lungs from a CMV-positive donor are at risk for CMV disease during this early phase because most prophylactic regimens against CMV are completed during this period.
Clinical manifestations of CMV infection vary from a febrile, viral syndrome associated with leukopenia to invasive disease with viremia affecting, most commonly, the lung but also other organs, particularly the gastrointestinal (GI) tract. In CMV pneumonitis, patients may develop a constellation of signs and symptoms, including cough, fever, chills, respiratory distress, crackles, and diffuse interstitial infiltrates. Isolation of CMV by BAL or TBBx in the setting of a typical clinical picture is strongly suggestive of CMV pneumonia, although it is worth noting that asymptomatic shedding of CMV occurs. Treatment for CMV includes IV ganciclovir for 2–6 weeks and, in some centers, adjunctive therapy with CMV hyperimmune globulin. Oral valganciclovir may be administered for 2–3 months after completion of the IV ganciclovir course.
In the preganciclovir era the incidence of CMV disease in mismatched recipients reached 75% or higher in the first 6 months after transplant, and CMV pneumonitis was a risk factor for the subsequent development of BO. With the availability of ganciclovir for prophylaxis and treatment, the frequency of CMV pneumonitis has decreased and the significance of CMV disease in the lung transplant population has been reduced.
P. jiroveci was a frequent problem in lung transplant recipients in the early phase after transplant before routine administration of TMP/SMX began in the late 1980s. As with other solid organ recipients, TMP/SMX prophylaxis has resulted in a marked decline in disease attributable to this fungus in lung transplant recipients. Patients ill with Pneumocystis present with acute onset of fever, respiratory distress, hypoxemia, and interstitial infiltrates. Silver or fluorescent staining of BAL specimens will demonstrate organisms with a typical morphology and is diagnostic of disease. IV TMP/SMX is the treatment of choice.
Viral infections can be particularly problematic during this period. Adenovirus and paramyxoviruses including parainfluenza and respiratory syncytial virus (RSV) can cause significant lung injury or mortality. Many centers treat these viruses aggressively with cidofovir and ribavirin, respectively. Moreover, fungal infections also pose significant risk.
Medication Side Effects
Triple drug immunosuppressive therapy has offered a therapeutic approach that allows long-term success in solid organ transplantation. However, the side effects of these medications can be troublesome enough in some patients to ultimately affect functional outcome and quality of life. The degree of immunosuppression is a delicate balance between too much, with risks for the development of opportunistic infections, and too little, with its attendant risks of allograft rejection.
CSA and tacrolimus are both associated with hypertension and nephropathy, although these may be less severe with tacrolimus. The risks of renal dysfunction with CSA or tacrolimus are compounded by the frequent use of other nephrotoxic drugs, such as aminoglycosides, ganciclovir, or amphotericin. One year after lung transplantation, 41% of patients have hypertension and 9% have renal dysfunction; this rises to 68% and 30%, respectively, 5 years after transplant. Hirsutism and gingival hyperplasia appear to occur more frequently in CSA-based immunosuppression. CNIs also cause neurologic toxicity, and seizures, headache, and sleep disturbance are common problems in the first months after transplant. In patients with CF, inconsistent and erratic metabolism and absorption of CNI can occur and underscores the need for close monitoring of blood levels. Routine blood counts are necessary for patients receiving azathioprine or MMF because of their effects on white blood cell counts. Systemic and oral corticosteroids have the potential to cause a host of well-known side effects. For example, daily use of oral corticosteroids may lead to glucose intolerance and diabetes, particularly in patients with CF, with prevalence rates of more than 35% in long-term survivors of lung transplantation. Patients receiving tacrolimus have a higher risk of developing diabetes than those receiving CSA.
Late Phase (>6 Months)
Ongoing complications in the late phase include those related to infection, drug toxicity, acute cellular and humoral rejection, and airway anastomotic narrowing. Posttransplant lymphoproliferative disease (PTLD) and CLAD, two very serious complications, also become apparent.
Posttransplant Lymphoproliferative Disease
The incidence of malignancy after lung transplantation in children is 5% 1 year after transplant and rises to 10% at 5 years; PTLD is by far the most common malignancy. PTLD is generally an EBV-driven lymphoma in an immunosuppressed patient and appears to occur more commonly in lung transplant recipients (as compared with other solid organ transplant recipients), in patients with CF, and in children as compared with adults. These findings are probably explained by the intensity of immunosuppression in lung transplant recipients and the fact that many pediatric patients are EBV seronegative at the time of transplantation.
Manifestations of PTLD are protean, often vague, and often confusing. A high index of suspicion is required because early diagnosis and treatment improves the likelihood of resolution of disease. In the first posttransplant year, the most common site of PTLD involvement in lung transplant patients is the allograft. Although PTLD can be asymptomatic, symptoms of cough, fever, and dyspnea are typical. The typical radiographic finding is single or multiple round or ovoid pulmonary nodules. Involvement of lymph nodes draining the chest is not uncommon. After the first year, the incidence of extrapulmonary PTLD increases. Other sites of involvement in PTLD include the GI tract, the skin, and other lymphatic tissue including lymph nodes and the nasopharynx. Elevated quantitative measurement of EBV by polymerase chain reaction (PCR) has been shown to be a sensitive and somewhat specific marker for PTLD; most centers monitor this test on a regular basis. In addition, positron emission tomography can be a sensitive and specific test that is often performed when EBV PCR or other clinical indicators raise suspicion for PTLD. After a suspicious lesion is identified, histologic diagnosis is important for prognostic purposes. CD20-positive tumors may be more amenable to antibody therapy. A monomorphous histologic pattern has a worse prognosis.
If PTLD is identified early, the mainstay of treatment is reduction in immunosuppression alone. Although some adult centers reduce immunosuppression based only on the presence of elevated EBV PCR, a study suggests caution should be taken with this approach in children. Although reduced immunosuppression can be successful in some patients, in many cases additional therapy is needed. Most centers now use therapy modeled after a Children’s Oncology Group protocol that includes rituximab, an anti-CD20 monoclonal antibody shown to be effective in non-Hodgkin’s lymphoma, low-dose cyclophosphamide, and prednisone. This approach has been promising in pediatric solid organ transplant recipients with PTLD.
Chronic Lung Allograft Dysfunction
Chronic allograft dysfunction, most commonly BO, is the greatest obstacle to long-term success of adult and pediatric lung transplantation. By 6 years after lung transplantation in children, only 40% of survivors are free of BO, a worrisome figure because BO is the leading cause of death after the first year posttransplant. Histologic analyses of lesions of BO show progressive and irreversible stenosis of the bronchiolar lumen, eventually resulting in fibrosis and near occlusion of the airway lumen with collagen.
BO is generally equated with chronic lung allograft rejection, although the immunologic basis of BO remains poorly understood. As diagnosis of BO from tissue obtained by TBBx may be difficult because of the patchy and uneven distribution of the disease, a clinical correlate, bronchiolitis obliterans syndrome (BOS) was described. Among the criteria used to establish a diagnosis of BOS is an otherwise unexplained fall in FEV 1 of greater than 20% from the best previous baseline studies. BOS was previously considered the clinical manifestation of BO, but it is now known that BOS is not specific for BO and that chronic rejection can occur without evident changes in tissue pathology. Due to the variety of disease presentations of chronic rejection, the term “chronic lung allograft dysfunction” is now used to describe persistent lung function decline in transplant patients. Although BOS is associated with obstructive PFTs (i.e., FEV 1 decline), it is now recognized that some patients with chronic rejection develop progressively restrictive PFT changes (i.e., decline in total lung capacity) and have a worse prognosis—a clinical entity that has come to be known as “restrictive allograft syndrome” (RAS).
A variety of risk factors for the development of CLAD have been proposed, most based on single-center studies. A comprehensive review of these reports identified acute rejection as the only consistent risk factor with acute rejection episodes occurring more than 3 months posttransplant carrying the greatest significance. The presence of lymphocytic bronchitis or bronchiolitis (“B-grade” rejection) was also significant, particularly when observed beyond 6 months after transplant. The role of CMV (based on donor or recipient serology, CMV “infection,” or CMV pneumonitis) as a risk factor was deemed inconclusive, likely due in part to the use of ganciclovir prophylaxis and treatment. More recently the presence of anti-HLA antibodies, as well as autoantibodies to structural proteins such as K-alpha 1 tubulin and collagen V, have been identified as risk factors. In addition, gastroesophageal reflux has been identified as a risk factor, with some evidence that fundoplication can reduce the incidence of BO. An association between community-acquired respiratory viruses (paramyxoviruses, influenza, and adenovirus) has been suggested. Finally, nonadherence with the immunosuppressive regimen can also result in BO. In contrast, there are center-specific data showing that younger children and patients receiving living related lobar transplantation are at lower risk for developing BOS. Currently, the most prevalent hypothesis is that CLAD represents a final common pathway resulting from the immune response to an airway injury induced by one or more of these above risk factors leading to chronic airway epithelial damage and eventually severe airway obstruction. The consistent identification of acute rejection as a risk factor for BO reinforces the importance of routine surveillance bronchoscopy to detect and treat subclinical acute rejection. As noted previously, this issue is further complicated by reports that episodes of minimal acute rejection (grade A1) were a risk factor for early-onset BO. Although the consensus approach to grade A1 rejection in asymptomatic patients has been observation, to reduce the risk for early development of BO, the possibility of altering or enhancing immunosuppression in this setting has been entertained.
Treatment of CLAD is problematic at best, with augmented immunosuppression the general recommendation. Some transplant centers have endorsed changing the immunosuppressive regimen from CSA to tacrolimus, with anecdotal reports of success (though most pediatric centers no longer use CSA as their primary CNI). The use of azithromycin 3 times weekly as an antiinflammatory agent appears to benefit a subset of patients, typically those with airway neutrophilia, leading to the suggestion that BO has at least one phenotype based on azithromycin responsiveness. Treatment is complicated by the phenotypic variability of what is known as chronic rejection. Antilymphocyte agents such as antithymocyte globulin or OKT3 may be effective adjunctive therapy in some patients. Recently, treatment with photopheresis has shown some benefit, although not all CLAD patients will show equal response to therapy. As with PTLD, early identification and treatment is most likely to be effective. However, in many patients, progression of disease is inexorable and often complicated by infection with bacterial or viral pathogens. The goal of therapy is to ameliorate the chronic rejection, reduce the risk of infectious complications, and prevent further deterioration in lung function. Many centers consider retransplantation as an option in patients with progressive decline in lung function.
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