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1 Department of Pediatrics, Washington University, St. Louis, Missouri
Correspondence and requests for reprints should be addressed to Stuart C. Sweet, M.D., Ph.D., Division of Allergy/Pulmonary Medicine, Washington University, One Children's Place, Campus Box 8116-NWT, St. Louis, MO 63110. E-mail: sweet{at}kids.wustl.edu
ABSTRACT
Pediatric lung and heart-lung transplantation are viable therapeutic interventions for end stage pulmonary parenchymal or pulmonary vascular diseases. Issues specific to pediatrics include unique diagnoses and increased need for mechanical ventilation before transplant and increased complications related to infection both before and after transplant. Although outcomes for children as a group are similar to those for adults, young children often fare better, perhaps in part due to reduced incidence of acute and chronic rejection. As in other solid organs, long-term outcomes in adolescents are poor. Increased focus on improving adherence in this age group will be important. Similar to adults, bronchiolitis obliterans remains the major late complication. Uniform treatment protocols and multicenter pediatric studies will be required to ultimately overcome this pervasive problem and improve pediatric lung transplant outcomes.
Key Words: lung transplantation • pediatrics • cystic fibrosis • pulmonary hypertension • surfactant disorders
Although the first human lung transplantation was performed by Hardy in 1963, challenges related to rejection and healing of the airway anastomoses prevented successful application of this therapy until the early 1980s (1, 2). As with other forms of transplantation, reports of successful lung and heart-lung transplantation in adults kindled interest in offering such potential life-saving interventions to children. The first reported pediatric lung transplantation was performed at the University of Toronto in 1987 in a 16-year-old boy with familial pulmonary fibrosis (3). Since that time, these procedures have become accepted therapies for end-stage pulmonary disease in adults and children. According to the most recent pediatric lung and heart-lung transplantation registry report from the International Society for Heart and Lung Transplantation (ISHLT), through 2007 nearly one thousand pediatric lung and more than 200 pediatric heart-lung transplants have been performed (4). In contrast to adult lung transplant, however, the number of pediatric lung transplants in the United States or internationally has remained relatively unchanged (Figure 1). After peaking at over 80 transplants per year in the late 1990s, over the past several years the number of pediatric lung transplants has remained stable at between 65 and 75 per year (4, 5).
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INDICATIONS/CONTRAINDICATIONS
In contrast to adults, in whom the primary diagnoses leading to transplant are chronic obstructive pulmonary disease (COPD) or interstitial lung diseases including idiopathic pulmonary fibrosis (IPF) (5), the primary diagnoses leading to lung transplantation in the pediatric age group are cystic fibrosis (CF), making up more than 50% of pediatric lung transplant candidates, and pulmonary hypertension, either idiopathic or related to congenital heart disease (4). In addition, there are several disease processes unique to children that are amenable to transplantation. Many of these fall under the rubric of the pediatric interstitial lung disease (chILD) syndrome (6, 7) including diseases of surfactant metabolism, such as disorders of surfactant protein B and C and the ABCA3 transporter (8–10). Other indications for transplant unique to children include congenital cardiac diseases that involve the pulmonary vasculature (e.g., Tetralogy of Fallot with absent pulmonary arteries), primarily pulmonary vascular abnormalities (such as alveolar capillary dysplasia or pulmonary vein stenosis) or combinations of pulmonary parenchymal and pulmonary vascular diseases such as pulmonary hypertension/hypoplasia associated with congenital diaphragmatic hernia.
In general, contraindications for lung transplantation in children parallel those in adults and are well described elsewhere (11). Areas of particular challenge for pediatricians include mechanical ventilation, Burkholderia cepacia complex (BCC) colonization, and psychosocial considerations. Children, particularly infants, are more likely than adults to require mechanical ventilation at referral or before lung transplantation. Although mechanical ventilation is a significant risk factor for morbidity and mortality in adults and older children (5, 12), the impact on infants is less clear (S. C. Sweet, unpublished data). Therefore, ventilator use is generally not considered a contraindication in infants and older children unless associated with systemic infection.
Because the majority of children referred for lung transplant have CF as their underlying diagnosis, concerns about BCC organisms will likely play a significant role in a pediatric lung transplant center. Although initially all patients with BCC organisms were thought to be at increased risk, more recent analyses have suggested that only colonization with B. cenocepacia (formerly BCC, Genomovar III), and a related organism, B. gladioli, carries significant risk (13–15). B. cenocepacia colonization remains an absolute contraindication to lung transplant at a significant percentage of pediatric centers.
Finally, psychosocial concerns for children, particularly nonadherence, can be particularly challenging, especially when the responsibility for adherence is shared with the child's parents. Decisions about how to handle such cases without creating the perception that the child is denied the opportunity for transplant because of the missteps of his or her parents must be individualized. In the author's center, psychosocial concerns only become a significant contraindication in combination with other medical risk factors or after failure over time on the part of the child and family to meet a set of agreed-upon expectations for care and follow-up.
Once evaluated, perhaps the most difficult decision for pediatric lung transplant physicians is determining the appropriate time to accept organs. Although in some cases, such as surfactant protein B deficiency or alveolar capillary dysplasia, it is generally clear that the child will not survive without transplant, in other cases, such as surfactant protein C deficiency, the unpredictable natural history of the disease process makes determining when transplant will confer benefit a challenge (Table 1). Even in the case of CF, for which the natural history of the disease process in children has been modeled (16, 17), many factors, including the improvement in care of this population in recent years, have led to questions about the survival benefit of transplant in this population (18, 19). Thus, the limited predictive data, variable course, and unique diagnoses lead most pediatric centers to carefully consider multiple factors, including waiting list survival estimates (when available), growth and nutrition status, frequency of hospitalizations, and potential for improvement in overall quality of life before committing a child to lung transplant.
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Timing of transplantation is also influenced by the underlying allocation system. One of the byproducts of the success of lung transplantation has been a steady increase in the number of adults undergoing lung transplantation (5, 20). Thus children are facing increased competition with adults for organs; this may explain why the ratio of transplants to waiting list deaths in pediatric candidates remains higher than that in adults (21). Because the principles for allocation of organs include a directive to "recognize the differences in health and in organ transplantation issues between children and adults throughout the system and adopt criteria, polices, and procedures that address the unique health care needs of children," and because end-stage organ dysfunction has a significant impact on growth and development, priority has been given to children in U.S. transplant allocation systems (22). In 2005, when the allocation of lungs in the United States was modified to incorporate allocation to candidates over 12 years of age based on a combination of transplant benefit and medical urgency (23), these principles led to including preferential allocation of lungs from pediatric donors to pediatric recipients. However, this system provides limited benefit to children under 12. Because the diversity in diagnoses and small numbers of young pediatric patients was felt to preclude development of accurate models of lung transplant waiting list outcomes, lung transplant candidates under 12 years old were not included in the new algorithm and continue to receive organs only on the basis of waiting time. A mechanism to stratify younger patients based on medical urgency is on the horizon, however. Recognizing that infants carry the highest waiting list mortality rate among all transplant candidates, the OPTN board recently approved a series of proposals to direct organs from donors under 11 years old to younger children first (24–26). The proposal for lung transplant candidates prioritizes children under 12 awaiting lung transplant based on objective medical urgency criteria, and distributes organs from donors under 12 over a much greater distance before offering them to older children or adults (25). These proposals are currently scheduled to be programmed into the OPTN computer system in 2009 and will hopefully reduce waiting list mortality for infants and young children.
SURGICAL PROCEDURE AND COMPLICATIONS
Technically, the lung and heart-lung transplant procedure are essentially the same as the procedures used in adults (27). The main difference relates to the increased use of bypass. Although controversial, there is some evidence that cardiopulmonary bypass (CPB) is an independent or contributing factor for primary graft dysfunction (PGD) (28). Therefore most adult bilateral lung transplant centers perform lung transplantation using single-lung ventilation through dual-lumen endotracheal tubes. However, such tubes are not widely available or used in pediatrics. Thus, most pediatric lung transplants are performed using cardiopulmonary bypass. A large single-center comparison of the incidence of PGD in pediatric and adult lung transplant found no difference (29), suggesting that CBP does not carry additional risk in children.
The choice between lung and heart-lung transplantation is generally dictated by whether irreversible left ventricular failure is present. Even in the case of congenital heart disease, lung transplantation with concomitant repair can be considered to limit the potential for complications related to a heart allograft (30).
Because of their size, pediatric candidates are more likely to be considered for technical lung transplant variants than adults. Two approaches have been used. The first involves two living donors, each providing a lower lobe to the recipient (31). This living donor lobar transplant (LDLT) procedure has been often been used to provide organs rapidly to children with CF who underwent an unexpected rapid progression of their disease. Although outcomes can be comparable to deceased donor transplant (32, 33) and there is some evidence to suggest that the incidence of bronchiolitis obliterans is lower in LDLT recipients (34, 35), the procedure is resource intensive and the donor lobectomy is not without risk (36, 37). The use of LDLT in the United States has declined significantly in recent years, most likely as a result of increased access to organs for critically ill patients provided by the new lung allocation system (23), but continues to be used in Japan (33) and offered at experienced pediatric transplant programs in the United States.
The second area of technical variation involves reducing the size of lungs procured from deceased donors. Options include lobectomy (most commonly involving the right middle lobe or lingula), wedge resection using a linear stapler, single lobe transplant, or split lung "bipartitioned" transplant (in which two smaller "lungs" are created from a single deceased donor lung) (38). Although case series in adults suggest that outcomes in recipients of reduced-size organs can be comparable to recipients of full-sized grafts (39, 40), and has anecdotally been effective in the author's pediatric experience, these approaches have not been systematically studied in children.
In terms of surgical complications, although the smaller airways and vasculature might theoretically be expected to lead to increased frequency of anastomotic complications, this has not been documented. A systematic review of airway complications at the author's center revealed similar frequencies of complications across the entire pediatric age group (41).
MANAGEMENT CHALLENGES
Although therapy and monitoring for children is guided by the strategies used in adult lung transplant recipients, several important differences exist. Perhaps the most important relates to the ability to diagnose chronic allograft dysfunction or bronchiolitis obliterans syndrome (BOS).
The measurements of FEV1 and FEF25–75 by spirometry are essential for the clinical diagnosis of BOS, yet spirometry is generally not possible in children under 4 years of age and not reliable until children reach 6 years of age. Infant pulmonary function testing, using thoracoabdominal compression techniques (42, 43), can provide information regarding the presence of airflow obstruction, but requires specialized equipment and experience. In addition, such tests cannot be performed with the same frequency as conventional spirometry because they require anesthesia. Moreover, BOS criteria do not exist for parameters obtained using infant pulmonary function testing. Spirometry can be performed in older children, but results may be variable. Also, because spirometric parameters are proportional to height, the most recent revision of the BOS grading scheme includes a recommendation that percent predicted values, rather than absolute measurements, be used for calculating the BOS score. However, this approach has not been validated. Because reliable pulmonary function data is not always available, many pediatric centers use surveillance bronchoscopy and transbronchial biopsy to ensure early diagnosis of acute rejection. Similarly, for pediatric recipients, it is difficult to rely solely on spirometry and BOS criteria to guide decisions about when to consider therapy for chronic allograft dysfunction.
An additional limitation for infants and toddlers relates to transbronchial biopsies. Although transbronchial biopsy forceps small enough to fit in 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. This makes obtaining adequate alveolar tissue for the diagnosis of acute rejection somewhat challenging. More importantly, adequate airway tissue is rarely present to allow assessment of "B" grade airway inflammation or "C" grade chronic allograft dysfunction (44, 45). Thus, evaluation for histologic evidence of chronic lung allograft dysfunction in infants and young children often requires open lung biopsy (OLB). Because of the invasive nature of OLB, timing is often guided by other measures to assess airflow obstruction such as ventilation/perfusion scanning and inspiratory/expiratory high-resolution CT scanning (46).
In addition to diagnostic challenges, therapeutic challenges also exist. Newer medications, including immunosuppressant and anti-infective agents, often do not include liquid forms required for young children. Such liquid preparations must be compounded by local pharmacies and may have a short shelf life, making them difficult to manage for patients not residing near a pediatric medical center. Moreover, absorption and pharmacokinetic data for infants and children often do not exist, often making dosing decisions in drugs that may have narrow therapeutic windows challenging.
Children are often immunologically naïve to infectious agents, particularly respiratory pathogens. This increases their risk for significant complications from such organisms. Viral organisms (including parainfluenza) and adenoviral infections (47, 48), as well as fungal infections (49), have been shown to have significant morbidity and mortality in pediatric lung transplant recipients.. Moreover, the incidence of post-transplant lymphoproliferative disease in pediatric lung transplant recipients is higher than that in adults (50, 51), presumably because children are more likely to be naïve to Epstein-Barr viral infection before transplant. Most centers now monitor for EBV and other viral infections using qualitative and/or quantitative PCR techniques. Developing effective strategies for the use of PCR data, such as identifying the appropriate time to preemptively reduce immunosuppression in the face of increasing EBV viral load, will be crucial to improved outcomes in pediatric lung transplantation.
OUTCOMES
In spite of these challenges, survival after pediatric transplantation is comparable to that in adults, with median survival in the most recent ISHLT registry report of 4.3 years. As in adults, the most common cause of late mortality is bronchiolitis obliterans (4). When age subgroups are considered, however, children in the 1- to 10-year-old age groups have long-term outcomes better than those of infants or adolescents (21). This may be due in part to the observation that infants and toddlers appear to be more immunologically tolerant of the allograft. The incidence of both acute rejection and chronic allograft dysfunction in this population is lower than in older children and adults (52). Outcomes for infants may be limited by a relatively higher incidence of early death.
The poor long-term outcomes in adolescents may be one reason more pediatric lung transplants are not being performed. Most commonly it is ascribed to the propensity for poor adherence in the teenage population, though other mechanisms, including the impact of hormonal changes associated with puberty, have not been fully explored. Nonetheless, adherence is a significant concern, both as a component of the assessment of candidates before transplant and as a potential contributor to poor outcome, particularly in adolescent patients. Most pediatric transplant practitioners can relate anecdotes about adolescents who chose to stop taking their immunosuppressant medications with catastrophic results. However, literature regarding objective assessment of adherence, systematic evaluation of risk factors for poor adherence, and techniques for preventing or reversing nonadherence is limited (53). One area for potential focus relates to transitions in care. Within the medical environment, transplant candidates and recipients undergo several transitions: the first set occurs as the process of diagnosing the underlying disease leading to transplant often involves new care providers. Then, referral to the transplant center introduces another care team. Because there are relatively few pediatric lung transplant centers, most patients must relocate to the transplant center to await transplant. If all goes well, patients return home a few months after transplant, often requiring visits to additional pediatric subspecialty care providers. For adolescents, additional transitions occur as they mature and gain increased independence, particularly when attending college. As parental oversight diminishes, this maturation process places increased responsibility for adherence on the adolescent/young adult patient. Finally, at some point after attaining adulthood, transition of care to an "adult" transplant center occurs, often with expectations for minimal parental involvement in the care process. There is some evidence that the latter transitions can be associated with reduced adherence (54). More research is needed to assess whether care transitions have the potential to negatively impact outcomes and, if so, interventions focused on better preparing patients and their families for these transitions.
GROWTH
Reversing growth and developmental delay is a significant goal of pediatric solid organ transplantation (55). Thus, growth is an important outcome measure unique to pediatrics. Although catch-up growth occurs after transplant, most recipients have some delay due to the suppressive effect of immunosuppressant medications, primarily corticosteroids. For this reason, most transplant programs attempt to reduce dosage of immunosuppressant medications, particularly corticosteroids, as soon as possible after transplant. Growth hormone can be used after transplant, but there are theoretical concerns about the risk of triggering rejection. Steroid-free immunosuppression regimens are being explored with some success in kidney, liver, and heart transplantation (56–58). Limited data exist regarding growth after pediatric lung transplantation. In a single-center review of somatic growth, the overall rate of somatic growth was roughly 64% of the predicted values (59). At the author's center, several infants transplanted at SLCH who are doing well more than 4 years after transplant have achieved growth parameters in the normal range. Thus, with careful reduction in immunosuppression, adequate growth can occur.
Another unique outcome measure for pediatric lung transplantation is growth of the transplanted lungs. Unfortunately, in humans, assessment for lung growth is difficult. Although spirometry measurements (i.e., FEV1 and FVC) after lung transplant may be in the normal range in infants (60) and older children (59), these measurements may reflect increased volume of each alveolar unit rather than alveolar tissue growth or increased surface area for gas exchange. The limited evidence regarding lung growth is mixed. Immature animals receiving lung transplants showed lung tissue growth (61, 62). Airway growth, as measured by serial imaging studies, was demonstrated in a small retrospective study (63). However, a single center study of the diffusing capacity of carbon monoxide (DLCO) in pediatric recipients of cadaveric and living donor transplants did not show an appreciable increase in DLCO (64). DLCO provides a better estimate of gas exchange surface area, but is not readily measurable in infants. Thus, whether lungs grow in pediatric lung transplant recipients requires further study.
TRANSPLANT BENEFIT/QUALITY OF LIFE
Although the primary goal of organ transplantation is to prolong life, and clinical (and more recently allocation decisions) regarding the timing of transplantation are generally based on estimates of survival benefit, a recent provocative paper, "Lung transplantation and survival in children with cystic fibrosis" (18), has challenged the ability of the lung transplant system in the United States to achieve that goal. The study findings are contrary to prior findings from a group in the United Kingdom (65), were biased against transplantation because covariates were obtained well before the time of transplant (when predicted survival was good), and estimated benefit on the basis of factors that had the potential to change between listing and transplant. Nonetheless, an important observation in the study by Liou and coworkers relates to waiting list mortality (18). The paper estimated that 57% of the children listed in the United States had a predicted survival of 5 years or greater (18). Though review of the data suggests that this is an overestimate (a large number of patients died on the waiting list), it reinforces perhaps the most relevant implication for the study: the waiting time–based system in the United States may have led to patients being listed well before transplant would have provided a survival benefit. Though the new lung allocation system may have mitigated this concern somewhat, better predictors of waiting list mortality for pediatric lung transplant candidates remain a priority.
The study by Liou and colleagues also reinforced the concept that in decisions regarding benefit of transplantation, measurement of benefit must include objective assessment of quality of life (QoL). Unfortunately, comprehensive objective measures of QoL either before or after pediatric lung transplant do not exist. Although two studies of medium- and long-term adult lung transplant survivors found improved QoL (66, 67), extrapolation to children and adolescents must be done with caution. Moreover, measures of childhood development must also be included. To date, published research investigating QoL in pediatric lung transplant recipients has largely been descriptive and contains limitations regarding study design and methodology (68). Although in the most recent ISHLT registry report 80 percent of children surviving 7 years after lung transplantation had no activity limitation (4), early data suggest that children may experience psychological difficulties and an impaired QoL (69).
Based on these issues, a critique of the study by Liou and coworkers by an international group of pediatric lung transplant physicians (19) proposed a research agenda for pediatric lung transplantation that focuses on developing strategies to continually reassess and maximize the potential for lung transplantation to provide QoL and survival benefit.
FUTURE CONSIDERATIONS
In summary, although presenting unique challenges related to pediatrics, lung transplant is a viable alternative for infants, children, and adolescents with end-stage pulmonary parenchymal and vascular disease. Although survival after pediatric lung transplantation has improved over the past decade (4), long-term survival rates remain well below heart and other solid organ transplants, and as alluded to above, ongoing challenges remain regarding optimization of patient selection and allocation policies to ensure that pediatric lung transplantation confers survival and/or QoL benefit.
As survival continues to improve, there will be appropriately increased focus on growth and development in pediatric lung transplant recipients. Understanding how to minimize the effects of transplantation and immunosuppression on these critical processes in children is paramount. Moreover, identifying the etiologies responsible for and addressing the poor outcomes in the adolescent population will remain an important area for study.
Finally, bronchiolitis obliterans remains the key obstacle limiting long-term survival. Further understanding of the risk factors for bronchiolitis obliterans in children, as well as identification of markers to facilitate earlier diagnosis, will require uniform treatment strategies and multicenter collaborations, as few centers perform enough transplants each year to adequately power such studies. Understanding the immunologic mechanisms behind the reduced incidence of rejection and bronchiolitis obliterans in the naïve but developing immune system of infants (52) appears to provide a key research opportunity.
The pediatric lung transplant community must move beyond anecdotal medicine, single-center retrospective studies, and reliance on studies performed in adults for guidance on new therapies. If accomplished, such efforts will make pediatric lung transplantation less of a palliative therapy and more of a cure for fatal lung disease in children.
FOOTNOTES
Conflict of Interest Statement: S.C.S. received $47,100 in 2006, 2007, and 2008 as a research grant for participating in a multi-center study sponsored by Expression Diagnostics, Inc.
(Received in original form August 26, 2008; accepted in final form September 11, 2008)
REFERENCES
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