Special Considerations for Immunosuppression in Children

The admonition that “children are not small adults” is well justified in the immunosuppressive management of children after liver transplantation. When compared with adults, several key differences are apparent when considering immunosuppression for children:

Children are more immunoresponsive than adults.
The incidence of rejection varies with age.
Exposure to immunosuppression may span many decades in transplanted children.
The risk for recurrent disease, as well as the attendant immunosuppressive modifications required, is very low in children in comparison to adults.
The pharmacokinetics of immunosuppressive drugs is different in children.
Children are at increased risk for complications from primary infections with common viral pathogens.
Vaccination practices require modification in immunosuppressed children.
Children are uniquely susceptible to the toxicities of immunosuppressive drugs that might affect growth, development, and cognitive function.
Noncompliance in adolescent patients is an important cause of immunological graft failure and patient death.
Young children, especially the very young, are often excluded from studies of new immunosuppressive drugs.

These unique characteristics of children require consideration in the context of recent changes in the philosophy of immunosuppression after liver transplantation. Over the past 4 decades our approach to immunosuppression has taken several dramatic turns. The 1970s were marked by very high graft and patient loss secondary to rejection, which inspired efforts to find effective immunosuppressive drugs. This was achieved with the advent of cyclosporine. The 1980s were characterized by learning how to use cyclosporine and treat resistant rejection with powerful monoclonal antibodies. In the 1990s there was a surge in the availability of new immunosuppressive drugs, including tacrolimus, as potential substitutes for cyclosporine. New immunosuppressive protocols strove for the least amount of rejection possible. By 2000 the fearsome implications of long-term immunosuppression were increasingly apparent. In addition, the realization came, at least for liver recipients, that not all rejection was harmful and some may even be beneficial. Individualization of immunosuppression with combinations of new drugs designed to decrease toxicity became a worthy goal. End points of clinical trials of immunosuppressive drugs moved away from emphasizing that the lowest achievable incidence of rejection was the most desirable goal. Pediatric induction protocols designed to safely minimize immunosuppression emerged, and the push to stop all immunosuppression, either empirically or through protocols that might induce tolerance, is driving many protocols now proposed.

These new approaches to immunosuppression are particularly relevant to children because unlike adults, the effects of long-term immunosuppression are an important cause of both late graft and patient loss. If tolerance is achievable, children will stand to gain the greatest benefit from decades of immunosuppression-free life.

This chapter highlights the important characteristics of children that provide the rationale for the clinical management of immunosuppression after pediatric liver transplantation. The mechanism of action of immunosuppressive drugs and new immunosuppressive agents in development are described in Chapter 91, Chapter 94 .

Increased Immunoresponsiveness of Children

Physicians experienced in the care of both adults and children after solid organ transplantation share a common impression that rejection in pediatric patients is more frequent and often more difficult to treat than rejection in adult patients.

Immunological studies of the differences in immune response between adults and children are rare. Higher CD4 counts in children characterize lymphocyte subset differences between healthy children and adults. Moreover, children show increased antibody formation after blood transfusions. Ettenger et al noted that before renal transplantation, children 5 years or younger had an increased absolute number of T cells and an increased T helper–to–T cytotoxic suppressor ratio. The rate of spontaneous blastogenesis, a nonspecific measure of the alloreactivity of T cells, was also increased. In support of this evidence, Kimball et al reported that pediatric kidney recipients showed stronger panel- and donor-specific mixed lymphocyte responses and a greater response to T-cell mitogens than adults did. Several observations indirectly support the belief that children are more immunoresponsive than adults after liver transplantation. Before the use of tacrolimus and the microemulsion formulation of cyclosporine (Neoral), Sokal et al reported a high incidence of steroid-resistant rejection in children younger than 1 year undergoing liver transplantation, and in another study, children treated with OKT3 for steroid-resistant rejection had a 59% complete response rate versus the 75% to 80% success rate reported in adult studies. Furthermore, anti-OKT3 antibodies developed in 65% of children versus an expected incidence from adult studies of 20% to 40%.

Few studies of immunoresponsiveness of pediatric liver recipients have been performed. In a comparison study of a small number of children and adults before and after liver transplantation, suppressor/cytotoxic cells were decreased in adults in comparison to children before transplantation, but after transplantation, the same subset was increased in children in comparison to adults. However, this finding did not correlate with the occurrence of rejection in the two groups. This study described only the phenotypic characteristics of circulating T cells and did not address T-cell function.

Although it is accepted that immunoresponsiveness is depressed at the extremes of age, it is still debated whether very young solid organ transplant recipients are relatively hyporesponsive in comparison to older children. Woodle et al reported that children transplanted when younger than 3 months still had a 42% incidence of rejection—comparable to that in older children. In contrast, Murphy et al found a lower incidence of rejection in younger children. In the Studies of Pediatric Liver Transplantation (SPLIT) registry, the 12-month probability of rejection incrementally increased with age and ranged from 43.8% in infants younger than 6 months up to 57.9% in children older than 13 years. In contrast, in the North American Pediatric Renal Transplant Cooperative Study database, the incidence of rejection decreased with age, and in children younger than 1 year, rejection carried a worse prognosis. A similar finding of more lethal rejection in infants was reported in pediatric heart recipients, although in another study, surveillance heart biopsies in young children showed that neonates (<30 days of age) had an incidence of rejection similar to that of children younger than 24 months.

Taken together, these data do not suggest that less immunosuppression should be given to young children after transplantation.

Immunosuppression for Pediatric Liver Recipients: Current Practices, Rejection, and Changing Ideas

Changing Trends in Immunosuppression

Calcineurin Inhibitors

The use of a calcineurin inhibitor (CNI), either cyclosporine or tacrolimus, still forms the basis of initial immunosuppression after pediatric liver transplantation. Tacrolimus is usually combined only with low-dose steroids, whereas cyclosporine-based protocols generally incorporate a third agent such as azathioprine or mycophenolate mofetil (MMF). The SPLIT database provides some insight into current immunosuppressive practices in pediatric liver transplantation in the United States and Canada. Of 1092 first liver transplant recipients, 33% were initiated on cyclosporine versus 55% on tacrolimus. Twelve months after liver transplantation, 29% were receiving cyclosporine as compared with 65.5% receiving tacrolimus.

Only about a third of children (34.5%) received triple therapy initially. Induction therapy with either monoclonal or polyclonal antibodies was unusual; only 11% of children received this modality for initial induction. Whereas almost all children receive steroids at transplantation, by 24 months the percentage was down to 46.9%.

Although neither cyclosporine- nor tacrolimus-based regimens have ever shown superiority over the other in either patient or graft survival in controlled trials, evidence is increasing that tacrolimus-based therapy may decrease both the overall incidence of rejection and steroid-resistant rejection when compared with cyclosporine therapy in children. The first evidence of the superiority of tacrolimus in reducing rejection was reported in the initial randomized multicenter trial of tacrolimus versus cyclosporine in 1995. However, a valid criticism of this study was that tacrolimus was compared with the older formulation of cyclosporine rather than the newer microemulsion form (Neoral). In a recently presented large multicenter European randomized trial of pediatric liver recipients receiving either Neoral, azathioprine, and steroids or tacrolimus and steroids, freedom from rejection (55.5% versus 40.2%) or steroid-resistant rejection (94.0% versus 70.4%) was significantly higher in the tacrolimus-treated children. In the extensive Pittsburgh experience in which outcomes of tacrolimus- and cyclosporine-treated children were compared over a 20-year period, both patient and graft survival was improved with tacrolimus immunosuppression; however, this result may have been a reflection of other factors related to changes in clinical practice over time. The same authors also reported less rejection, more freedom from steroids, and less hypertension in tacrolimus-treated children, a finding confirmed by others. The efficacy of tacrolimus in preventing and treating rejection has resulted in increased use of tacrolimus as the primary immunosuppressive drug after pediatric liver transplantation.

This change in practice is also reflected in the SPLIT database, in which it was documented that 65% of children received cyclosporine in 1996 for initial immunosuppression versus 18.6% in 2001 ( Fig. 92-1 ).

FIGURE 92-1, Primary immunosuppression in patients with a first transplant by year of transplantation.

Steroids

Steroid use after pediatric liver transplantation is also changing. The well-known adverse effects of steroids, most particularly their association with poor growth after pediatric liver transplantation, have prompted most pediatric programs to practice some form of steroid withdrawal or minimization. Early studies, only one of which was randomized and controlled, reported that steroid withdrawal was safe and had a beneficial impact on growth. In a study with a historical control group it was noted that steroid withdrawal was more often successful in children treated with tacrolimus compared to cyclosporine. However, in the only randomized trial testing this claim, no difference was noted between successful steroid withdrawal at 3 months in adults treated with either tacrolimus or cyclosporine.

The current practice of steroid withdrawal in children is quite variable. Some programs withdraw steroids as early as 3 months, whereas others start weaning at 3 months or delay weaning to 12 months or later. Adult studies have demonstrated the efficacy of ultrashort courses of steroids, such as 24 hours, 14 days, or complete steroid avoidance, but few studies—and no prospective randomized controlled trials—have tested these approaches in children. As discussed later, most studies of steroid minimization or avoidance in children have been in conjunction with monoclonal or polyclonal induction therapy.

It is also not established which patients should not be weaned from steroids. The clearest contraindication appears to be children transplanted for autoimmune hepatitis, who have a high incidence of recurrent disease. It is unclear whether a previous history of rejection, a recent rejection episode, multiple episodes of rejection, or steroid-resistant rejection is important in deciding whether and when steroids should be weaned.

Triple-Drug Therapy

The efficacy of triple-drug therapy versus dual therapy for either induction or maintenance immunosuppression has not been studied in randomized controlled trials in children after liver transplantation. SPLIT data from 1995 to 2002 ( Fig. 92-2 ) show that in induction regimens, MMF is usually combined with cyclosporine and steroids and is less frequently used with tacrolimus and that azathioprine use is decreasing. One anticipated benefit of adding MMF would be to permit systematic lowering of tacrolimus or cyclosporine levels, with an attendant reduction in their toxicities. This concept is of particular relevance in managing CNI-induced nephrotoxicity or neurotoxicity. Evans et al reported that 48 children with a median baseline calculated glomerular filtration rate (cGFR) of 54 mL/min/1.73 m ² at a median of 4 years after orthotopic liver transplantation had a significant increase in cGFR by 2 months after being transferred to MMF monotherapy or MMF combined with low-dose CNIs.

FIGURE 92-2, Use of triple immunosuppression over time. AZA , Azathioprine; CsA , cyclosporin A; MMF , mycophenolate mofetil; Tac , tacrolimus.

Monoclonal or Polyclonal Antibody Induction Therapy

The inclusion of monoclonal or polyclonal antibodies in induction protocols after pediatric liver transplantation largely fell out of favor in the late 1980s after trials of the anti-CD3 monoclonal antibody OKT3 failed to show any long-term benefit in either the overall incidence of rejection or cyclosporine-induced renal toxicity.

There has been a resurgence of interest with development of the chimeric and humanized interleukin-2 receptor (IL-2R) monoclonal antibodies basiliximab and daclizumab, which have a long half-life and do not induce either a cytokine release syndrome or an antimonoclonal human antibody response. Both of these monoclonal antibodies target the IL-2R α chain expressed only on activated T cells and have primarily been studied in protocols to avoid or minimize the use of steroids, discussed in detail later. Antibody induction therapy has also been used in at attempt to delay the initiation of tacrolimus. A decreased incidence of acute rejection was reported in children after a single dose of daclizumab combined with MMF and prednisone for induction, and introduction of tacrolimus at day 7. This approach is of particular benefit in children with renal impairment and has been demonstrated to potentiate the recovery of renal function.

A promising new strategy for induction is costimulation blockade using monoclonal antibodies. Belatacept, a monoclonal antibody that binds to the B7 ligands that prevent the engagement of CD28 on T cells, was recently approved for use in adult kidney transplant recipients. It still requires combination with CNIs but at lower doses with a consequent benefit in renal function. A higher than expected incidence of posttransplantation lymphoproliferative disorder (PTLD) and serious central nervous system infection has limited this drug for use in pediatric solid organ transplantation.

Sirolimus

The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus showed early promise in adult liver recipients as potent immunosuppressant drugs without the nephrotoxicity and neurotoxicity associated with the CNIs. Early protocols using sirolimus as primary therapy focused on the reduction or elimination of CNIs.

However, the use of mTOR inhibitors in pediatric liver transplant patients has been limited after a large multicenter randomized controlled European study using sirolimus as primary immunosuppression in adults was discontinued because of an increased risk for hepatic artery thrombosis in the sirolimus group.

Despite an earlier study in a small number of pediatric liver transplant recipients that did not show an increased incidence of thrombotic events when sirolimus was introduced within the first 3 to 4 weeks after antithymocyte globulin induction, the use of these drugs in children has subsequently focused on their use as rescue agents for acute and chronic rejection and to ameliorate tacrolimus-associated side effects. In 12 children with chronic graft dysfunction the addition of everolimus resulted in improved liver function in 8, with 4 children showing complete normalization of liver test results. Harnessing the important antiproliferative effects of the mTOR inhibitors has been shown to be beneficial in preventing tumor recurrence in adult patients transplanted for hepatocellular carcinoma. Small pilot studies in pediatric liver transplant recipients suggest some benefit in the management of PTLD and hepatoblastoma. In another center’s experience sirolimus was substituted for tacrolimus in 11 children with PTLD with 10 of 11 showing resolution. This use of sirolimus might be an important adjunct to the management of B cell–driven PTLD and related to evidence that sirolimus causes programmed cell death in B lymphoma cells.

The mTor inhibitors have serious side effects that can limit their use. The most common are hyperlipemia, occurring in as many as 50% of patients, bone marrow suppression inducing both thrombocytopenia and less often leucopenia, and delayed wound healing. An uncommon but serious side effect is interstitial pneumonitis. Dosing recommendations and therapeutic drug monitoring are largely extrapolated from adult studies, although the pharmacokinetics of sirolimus in children are substantially different as compared to adults (see later).

Rejection

An analysis of rejection in 1902 first pediatric liver transplant recipients from the SPLIT registry showed that rejection occurred most often in the first 3 months. The cumulative rejection rates were 0.45 at 3 months, and they increased only modestly to 0.59 at 24 months ( Fig. 92-3 ). The median time to first rejection was 16 days, the average number of rejection episodes per patient per year was 0.51, more than one rejection episode occurred in 18.5% of children, and steroid-resistant rejection was relatively unusual and occurred in 11.2% of children. High-dose steroids were the most common treatment of rejection. Antilymphocyte preparations such as polyclonal antithymocyte globulin or anti-CD3 monoclonal antibodies such as OKT3 were used as initial treatment in 8.3% of first rejection episodes and 3.8% of second rejection episodes but increased to 11.4% if patients experienced more than three rejection episodes. When Kaplan-Meier probabilities of rejection over time were examined for various factors, there was a trend toward less rejection in children younger than 6 months and in recipients of living donor grafts, findings also reported by other investigators. In a multivariate analysis, initiation of immunosuppression with tacrolimus as opposed to cyclosporine was the only factor that showed a significantly lower probability of rejection at 6 months, 51% versus 64% ( P =.01). At the time of last follow-up, however, no difference in patient or graft survival was noted in those who underwent tacrolimus or cyclosporine induction.

Somewhat surprisingly, the incidence of rejection in pediatric recipients of living related grafts has not been consistently shown to be statistically less frequent than in recipients of deceased donor grafts despite better HLA compatability However, in one study the severity of rejection was less in living donor grafts compared to deceased donor grafts. Therefore, in general, pediatric transplant programs do not alter their immunosuppressive protocols for recipients of living donor as compared to deceased donor grafts.

The prognosis of late acute rejection is different than that of early rejection. It is frequently associated with low levels of immunosuppression, which are often related to noncompliance. The diagnosis may be delayed and the liver biopsy specimen more difficult to interpret because of features of hepatitis and centrilobular venulitis and necrosis. In addition, the response to steroids can be suboptimal, and some authors have reported an increased risk for progression to chronic rejection.

Chronic rejection appears to be increasingly rare, and some investigators attribute this decline in chronic rejection to the increasing use of tacrolimus in pediatric liver transplantation. In reviewing the extensive use of tacrolimus in Pittsburgh, Jain et al reported that chronic rejection, defined histologically as vanishing bile duct syndrome, occurred in 3.1% of 1048 tacrolimus-treated patients and was virtually absent in pediatric recipients. A study of risk factors for chronic rejection in 385 pediatric liver recipients at the University of Chicago found that recipients of deceased donor organs, African Americans, patients with two or more episodes of rejection, patients with PTLD and cytomegalovirus (CMV) disease, and those with autoimmune hepatitis as the indication for transplantation had a significantly higher risk for chronic rejection.

Understanding the consequences of rejection may be a more important subject for study than the incidence of rejection. In contrast to kidney and heart allografts, a liver allograft is often described as an immunologically privileged organ. Evidence continues to accumulate that rejection, particularly if steroid sensitive and occurring early after transplantation, appears to have no long-term adverse effects on either graft function or survival. As noted earlier, no prospective randomized trial that investigated a new immunosuppressive drug for use after liver transplantation has shown a significant improvement in patient or graft survival despite significant improvements in rejection and even steroid-resistant rejection. In fact, a few adult studies and one pediatric study purport that rejection itself may have a beneficial effect on patient survival. Wiesner et al showed that one episode of rejection resulted in a small but statistically significant improvement in patient survival 36 months after liver transplantation. An investigation of long-term graft function in adult liver recipients by Dousset et al showed that one episode of rejection had no influence on graft function 1 year after transplantation. In children registered in the SPLIT database, rejection, listed as either present or absent, within 6 months after transplantation was associated with a significantly lower risk for death or graft loss. However, when analyzed as a time-varying parameter, rejection, either one or more than one episode versus no episodes, lost its effect on patient and graft survival. In a multivariate analysis of many factors affecting posttransplant survival, the predicted effect of one versus no episodes of rejection approached significance for patient survival ( P =.06). The intriguing finding that some rejection may in fact be protective of graft function and survival raises the question that a controlled amount of immune activation may actually be necessary to delete clones of recipient-derived lymphocytes injurious to the graft.

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