Pediatric Cardiac Intensive Care Society 2014 Consensus Statement

Pharmacotherapies in Cardiac Critical Care Immune Therapy

Rakesh K. Singh, MD, MS; Timothy Humlicek, PharmD; Aamir Jeewa, MD3; Keith Fester, PharmD, BCPS

Disclosures

Pediatr Crit Care Med. 2016;17(S1):S69-S76. 

In This Article

Pediatric Heart Transplantation

Introduction

Heart transplantation is the definitive therapy for end-stage heart failure in children. Contemporary outcomes of pediatric transplant recipients have improved over the past few decades, partly related to improvements in immunomodulatory therapy to prevent rejection of the donor heart.[20] Immunosuppression therapy is commonly divided into induction (given at time of transplant), maintenance (chronic medications), and acute rejection therapy.

Induction Therapy

Contemporary induction therapy in organ transplant refers to a group of medications that provide a relatively intense level of immunosuppression and are selectively administered in the pre- or perioperative phase.[21] Although induction is not considered a universal standard of care, the use of induction therapies for pediatric heart transplant has trended upward and an estimated 70% of recipients receive treatment with lymphocyte-depleting or nondepleting agents. The need for induction therapy is based on the empiric observation that early rejection is a common cause of graft and patient mortality. Acute rejection is estimated to cause 12% of deaths within 1 year of transplant.[20]

The role of induction has also evolved to allow delay of the initiation of nephrotoxic calcineurin inhibitors (CNI) during acute kidney injury. Acute renal injury is a common morbidity observed in children undergoing cardiac transplant in the pre- and post-transplant phases as cardiopulmonary bypass, hemolysis, and postoperative fluid overload can worsen kidney function.[22,23] Pretransplant creatinine confers a higher 1-year mortality risk in patients less than 6 years and higher 10-year mortality in all patients. Therefore, it is not surprising that the need for dialysis at the time of transplant confers a higher 1- and 5-year mortality risk.[20] Delaying the initiation of nephrotoxic agents such as CNIs through induction may be beneficial in this regard to facilitate recovery of renal function.[24–26]

Finally, induction in pediatric heart transplantation has also been used to facilitate corticosteroid avoidance[27–29] or early withdrawal in patients at risk for rejection and steroid-induced side effects.[30] Several centers have reported on their experience with acceptable rejection rates, graft, and patient survival and is currently a recommended strategy when complete corticosteroid avoidance is desired.[31,32] From a recent review, survival in pediatric heart transplant recipients avoiding corticosteroids appears to not be different when compared with a cohort using maintenance steroids; however, conclusions on the prevalence, frequency, and severity of rejection could not be elucidated.[33]

Antilymphocyte Antibodies. Antilymphocyte antibodies refer to a group of medications known for their ability to promote opsonization and complement mediated destruction of T and B lymphocytes. The medications can consist of IgM and/or IgG antibodies against multiple cell surface antigens (polyclonal) or an antibody against a single antigen (monoclonal).[34–37]

Preparations of antithymocyte globulin are polyclonal formulations of harvested antibodies from equine (Atgam)[34] or rabbit (Thymoglobulin)[35] sources and differ in their dominance of IgG or IgM subtypes, duration of effect, and side effect profile. On the basis of observations of improved efficacy over horse-based preparations in kidney transplant recipients and in observations of decreased lymphocyte counts without impaired safety,[38–40] we found that rabbit antithymocyte globulin is generally used for induction in pediatric heart transplant centers. Courses and dosages of antithymocyte globulin are varied, but result in substantial lymphocyte depletion, which can persist for months to years following administration. Infusion-related reactions can occur, but can be reduced through premedications with corticosteroids, acetaminophen, and diphenhydramine. Other reactions that can occur include fever, chills, rash, headache, urticaria, severe hypotension, and formation of antithymocyte globulin antibodies, which can cause serum sickness.[41] Because of common side effects of leukopenia and thrombocytopenia, several pediatric transplant protocols have used monitoring of platelets or absolute lymphocyte count.[42–44] Recently, experience with the use of CD3+ T-cell count to monitor induction with rabbit antithymocyte globulin has been published, with no increase in rejection or change in survival at 1 year when patients were dosed to a target CD3 count.[45]

Muromonab-CD3 and alemtuzumab are monoclonal antibodies directed against single T-cell surface antigens CD3 and CD52, respectively. The CD3 glycoprotein is involved in several T-cell–activating functions, and binding by muromonab-CD3 results in impaired response to antigenic challenges and subsequent opsonization and removal.[46] The destruction of CD3+ T cells also results in the liberation of cytokines, which can lead to the potentially life-threatening "cytokine release syndrome." Other phenomenon includes the stimulation of neutralizing antibodies after prolonged use and side effects such as fever, anaphylaxis, and aseptic meningitis. The use of muromonab-CD3 has diminished following concerns over increased adverse effects and limited proven advantage in preventing rejection over other therapies.[47] Binding of CD52 by alemtuzumab also results in profound destruction of both T cell and B cells, but there is limited reported experience on its use in pediatric heart transplant.[30,48]

Several studies using antilymphocyte antibody therapy in pediatric heart transplant have lacked a control group, so overall determinants of efficacy are limited, but it is estimated the freedom from rejection within 1 year is around 45–55%.[42,44] Boucek et al[49] initially demonstrated a survival benefit for centers using induction with either antithymocyte globulin or muromonab-CD3 when compared with centers not using induction with similar use of cyclosporine, azathioprine, and corticosteroids. However, cumulative rejection episodes and rejection as a cause of death were not significantly different. More recently, treated rejection after discharge and within 1 year of transplant may not be different between users of induction and nonusers, despite a survival benefit still being observed.[20] Those that also might benefit from reduced rejection may be patients at elevated risk for rejection and death related to rejection, such as children with elevated panelreactive antibodies and those with a positive crossmatch at the time of transplant.[50–53]

Anticytokine Receptor Antibodies. Investigative trials of anticytokine receptor antibody therapy in transplantation have centered around two CD25 (IL -2) receptor antagonists (RAs): basiliximab, a chimeric murine/human monoclonal antibody, and daclizumab, a humanized monoclonal antibody. These agents occupy the α subunit of the IL-2 receptor on activated T cells, which is expressed following antigenic stimulation.[54] This binding prevents the IL-2–dependent proliferation of T cells without concomitant depletion. These agents may also impair IL-15 signaling, another T-cell growth factor, through nonspecific interaction with the β chain of the IL-2 complex on T cells.[55] Full receptor saturation can be achieved after the first dose, and binding can persist after multiple doses for several weeks in children.[56] IL-2 RAs in pediatric heart transplant are limited, but these agents appear to be effective in the prevention of acute rejection with potentially reduced risks of infectious morbidities.[57]

As a method to decrease the nephrotoxicity of CNIs, Ford et al[58] reported on 29 children undergoing heart transplant who were at risk for perioperative acute renal injury, including children on extracorporeal membrane oxygenation, preoperative inotropic medications, and those who developed renal dysfunction postoperatively. Although lacking a control group, the investigators demonstrated a low prevalence of rejection within 6 months despite CNI trough levels being below institutional standards in most patients within the first 7 days post transplant. Although possibly not specific to the type of induction, a study by Grundy et al[59] suggests that basiliximab administered prior to donor heart reperfusion conferred improved freedom from severe acute cellular rejection in pediatric patients when compared with postoperative administration or placebo. The authors speculated that this may be due to avoidance of early immunologic insult. Despite being reportedly well tolerated, these studies did not directly assess adverse effects, but reported infectious complications and hypersensitivity reactions, the latter of which can occur after initial or repeat administration.

There are no studies in directly comparing outcomes and adverse effects of IL-2 RAs and antilymphocyte antibodies in a pediatric-specific heart transplant cohort.[47] Therefore, the choices surrounding induction will continue to be discussed. A recent literature review found that acute rejection might be reduced by IL-2 RAs when compared with no induction, and by polyclonal antibody induction when compared with IL-2 RA,[60] but there are several confounders with this assertion, such as the immunological risks of the patients being transplanted and institutional-specific approaches to maintenance therapy. Although opportunistic infections remain a risk for patients who receive either IL-2 RA or cytolytic antibodies, at least one study in adults noted an increased risk of infectiousrelated deaths with antithymocyte globulin when compared with basiliximab with similar composite efficacy.[57] The risk of lymphoproliferative diseases in at risk pediatric heart transplant recipients who receive IL-2 RAs has not been shown to be different from patients who receive antithymocyte globulin and may actually be less when compared with patients without induction.[61]

Overall, although the use of induction in pediatric cardiac transplant is increasing, previous concerns over the risk of opportunistic infections and mixed reports on malignancy have limited its overall acceptance. Thus, induction should be considered as individualized and risk-stratified practice given unique immune histories, graft vulnerabilities, and anticipated complications such as infection and postoperative renal injury.

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