Hypoplastic left heart syndrome

Heart transplantation with ABO blood type-incompatible donors has historically been contraindicated because of the high risk of an immediate hyperacute humoral graft rejection. The immature neonatal immune system presents an immunologic window that allows for breaching the ABO barrier before the natural development of anti-ABO antibodies. Information from a small series of neonates has demonstrated similar survival rates and posttransplant outcomes compared to ABO-compatible transplantations. In the posttransplant period, particular attention is placed on the surveillance of graft-specific antibody production and monitoring for immunologic signs and symptoms of early graft vasculopathy. This article presents a case study of a neonate with congenital heart disease who underwent one of the first successful ABO-incompatible heart transplantations in the United States. (Progress in Transplantation. 2005;15:161-165)

Pediatric heart transplantation is increasingly employed in the palliation of children with end-stage heart disease. Among children listed for heart transplantation, death while waiting is highest in infants, with mortality rates ranging between 25% and 50%.1 In infants waiting for a heart transplant, risk factors for death before transplantation include blood type O, hypoplastic left heart syndrome, the need for prostaglandin infusion, and the presence of mechanical ventilatory or inotropic support.2 Blood type O donor hearts are allocated among the 4 blood groups; therefore, patients with blood type O on average wait longer for a donor organ. If feasible, using ABO-incompatible donor hearts may potentially expand the available donor pool, prevent potential organ wastage, and reduce mortality while waiting.3,4 The purpose of this article is to review the background, pathophysiology of ABO-incompatible heart transplantation, physiology of neonatal immunology, and provide an analysis of a pediatric case report.

Background

Blood type is predetermined by biochemical and genetic factors. The ABO and H genes produce glycosyltransferases that determine the blood groups; they are located on chromosomes 9 and 19. Terminal trisaccharides attach to H chains on the membranes of red cells, which constitute the A, B, or AB antigen. In the absence of the A or B antigen, antibodies form and maximal antibody production occurs by 5 to 10 years of age.5 Individuals with blood type O express the H antigen and lack the A and B antigen. They subsequently develop both anti-A and anti-B antibodies. The Table summarizes the possible combinations of ABO antigens and antibodies.6

ABO incompatibility has been a contraindication to heart transplantation because of the association with poor outcome.7 In an immunologically naive recipient who receives an organ from an ABO-incompatible donor, the recipient's preformed immunoglobulin M (IgM) antidonor antibodies may react with the correspending donor antigen and cause hyperacute rejection. Cooper8,9 surveyed 66 centers and reported 8 incidents in which an unintentional ABO-incompatible adult heart transplantation was performed of 4895 heart transplantations. Five of 8 patients (63%) experienced an immediate hyperacute rejection within 24 hours. Two died and 3 required retransplantation. In a recipient with blood type A who received a group B donor heart, pathologic examination revealed an antibody-mediated rejection with microvasculature damage, acute inflammation, and deposition of IgG and complement. Although antibodies may initiate the hyperacute rejection process, graft injury may result from secondary processes including an inflammatory reaction, deposition of complement, clotting factors, fibrinogen, and coagulation within the graft vasculature.10,11

Immunologic Privilege of Infancy

Newborns are born with an immature cellular and humoral immune system that undergoes steady maturation throughout the first year of life.12 Production of ABO antibodies does not begin until approximately 3 to 6 months of age. The immaturity of the neonatal immune system includes (1) enhanced T-lymphocyte suppressor activity, which reduces the function of other lymphocytes and phagocytes; (2) deficient T-helper cell function, which further impedes cellular immune activity; and (3) low cytokine production through 6 months of age.13 In addition, infant B cells lack the capacity to produce antibodies against polysaccharide antigens such as the Streptococcus pneumoniae, Haemophilus influenzas type B, and the complex carbohydrate ABO blood group antigens.14-17 Studies have shown that infants younger than 4 months of age failed to produce antibodies against red blood cell antigens, even after multiple blood transfusions.18,19 ABO antibody tilers progressively reach mature adult levels between 2 to 10 years of age.20,21

ABO-Incompatible Heart Transplants in Infants

West et al22 published seminal work reporting the results of ABO-incompatible heart transplants in 10 infants. Four years after the institution of ABO-incompatible heart transplantation, mortality rates among infants awaiting a transplant fell from 58% to 7%. The posttransplant 1-year survival rate was 80% in the ABO-incompatible group, comparable to the survival rate in ABO-compatible children during the same period. There were no incidences of hyperacute rejection. Based on these early data, we performed an ABO-incompatible transplantation in an infant with congenital heart disease.

Case Study

Presentation

On his first day of life, the infant presented with poor feeding, lethargy, hypoxia, and metabolic acidosis. Echocardiography revealed a hypoplastic left ventricle, mitral and aortic valve atresia, and a dilated right ventricle with severely diminished function. In hypoplastic left heart syndrome, the systemic circulation is dependent on the right ventricle via a patent ductus arteriosus, thus the patient received prostaglandin, to maintain ductal patency. Inotropic support and mechanical ventilation were also instituted because of severe congestive heart failure. During the first week of life, there was no improvement in the patient's clinical condition. The patient was not a candidate for palliative Norwood surgery because of the severe right ventricular dysfunction and mild to moderate tricuspid regurgitation, and he was placed on the heart transplant waiting list with the United Network for Organ Sharing.

The patient was blood type O and at the time of listing was 10 days old and weighed 3.7 kg. After discussion with the family, the decision was made to list him for transplant across all blood groups because of his tenuous condition and high risk of mortality while waiting.

Clinical Management

At the time of listing, every member of the pediatrie transplant team (pediatric cardiac surgeon, pediatric cardiologist, transplant nurses) along with the perfusionist and blood bank personnel were alerted of the patient's status as a candidate listed across blood groups for heart transplantation. Baseline ABO antibody liters at 2 weeks of age were detectable at 1:1 (anti-B) and 1:2 (anti-A). This may have reflected transplacental transmission of maternal anti-A or anti-B IgG antibodies, which has been reported in newborns and infants younger than 4 months.21,23 The patient did not receive any preoperative blood transfusions. Eight days after listing, at 18 days of age, the patient underwent transplantation with a blood type B donor heart. Preoperative immunosuppression included cyclosporine emulsion, azathioprine, and intravenous solumedrol.

During cardiopulmonary bypass before transplantation, all efforts were made to remove both anti-A and especially donor specific anti-B antibodies from the patient's circulation. The cardiopulmonary bypass circuit was primed with type AB plasma, which has no anti-A or anti-B antibodies. The patient's plasma was replaced with type AB plasma through a triple volume exchange transfusion, and all previously removed red cell fractions (type O) were returned to the patient. During the operation, a total of 4 plasma exchange transfusions were performed, followed by laboratory confirmation after each exchange that all antibody titers were negative. The cross-clamp was released and the patient was weaned off bypass onto low-dose dopamine and isoproterenol. Right-sided hemodynamic pressures were excellent and the transesophageal echocardiogram showed normal biventricular function. Postoperatively, packed red cells of recipient blood type (O) and platelets and plasma products of donor blood type (B or AB) were used to prevent the introduction of anti-B antibodies into the patient. Any inadvertent transfusion with a product containing anti-B antibodies could have caused rejection of the donor graft.

Postoperative Immunosuppression

Initial posttransplant immunosuppressive regimen included cyclosporine (to achieve target levels of 300-400 ng/mL in whole blood), mycophenolate mofetil 30 to 50 mg/kg per day in 2 divided doses (to achieve target levels of 3-5 ng/mL), and intravenous solumedrol (10 mg/kg every 8 hours) for a total of 3 doses over 24 hours, followed by prednisone 0.5 mg/kg per day divided into 2 daily doses. Induction therapy was not used.

At 4 weeks after transplantation, the patient had a clinical rejection episode, as evidenced by new onset sinus tachycardia and decreased shortening fraction from baseline. Cyclosporine was discontinued, and tacrolimus was begun at 0.1 to 0.3 mg/kg per day in 2 divided doses with target blood levels of 8 to 12 ng/mL. Drug levels of the immunosuppressive medications were monitored closely in an attempt to prevent oversuppression of the immune system that could predispose an infant to infectious pathogens, opportunistic infections, or comorbid drug toxicities.24

This immunosuppressive protocol was a modification of our standard cyclosporine, azathioprine, and prednisone regimen. Tacrolimus and mycophenolate mofetil were chosen because they inhibit antibodyproducing B lymphocytes. Tacrolimus is 50- to 100-fold more potent and selective than cyclosporine at inhibiting T-cell activation, down-regulating cytokines such as interleukin 2 (IL-2), IL-3, and IL-4, and directly blocking cell division and proliferation of activated B cells, thereby preventing cellular and humoral rejection.25,26 Mycophenolate mofetil is a more potent antimetabolite compared to azathioprine and suppresses the differentiation and proliferation of active plasma cells and thus inhibiting the production of immunoglobulin. A recent double-blind study of 86 heart transplant recipients taking mycophenolate mofetil or azathioprine demonstrated favorable suppression by mycophenolate mofetil of an antiendothelial antibody associated with the development of posttransplant coronary artery disease.27 There are no conclusive studies in the literature that favor one maintenance immunosuppressive regimen over another. Published case reports support an immunosuppressive protocol that is patient tailored in ABO-incompatible infant transplantation.28

Rejection History

The patient had a clinical episode of rejection at 4 weeks after transplantation and a biopsy-proven episode of rejection (grade 2) at 4 months after transplantation. Endomyocardial biopsies were evaluated for signs of cellular and humoral rejection. Immunofluorescent staining for evidence of complement, immunoglobulin, or fibrinogen deposition performed on a biopsy specimen obtained 130 days after transplantation was negative. Coronary angiography was performed 6 and 12 months after transplantation and annually. There was no evidence of graft vasculopathy.

Anti-ABO Antibody Titers

Anti-ABO antibody titers were monitored daily for 2 weeks, weekly for 2 months, and then 1 to 2 months during the first year after transplantation. Surveillance of antibody titers after transplantation has demonstrated low production of anti-A antibodies and no production of donor-specific anti-B antibodies (see Figure). This diminished antibody response may reflect a form of immunologic B-cell tolerance to the donor blood type as demonstrated by the Toronto Group.29

Outcomes

The patient was discharged home 4 weeks after transplantation. He is currently 28 months old with normal cardiac function. The patient has required 1 hospitalization for Pneumocystis carinii pneumonia, which was treated successfully, and has had no evidence of hypertension, posttransplant lymphoproliferative disease, diabetes, or renal/hepatic dysfunction.

Transplant information regarding the ABO-incompatible procedure, immunosuppressive regimen, allergies, and blood transfusion protocol were documented in all charts with every readmission, and caregivers were given a laminated card with all pertinent ABO transplant data.

Discussion

As of April 2005, there are approximately 57 cases of ABO-incompatible infant heart transplantations worldwide (L. J. West, unpublished data, 2005). Posttransplant early survival is 81%, with a median age at transplantation of 2 months and a median follow-up of 2.1 years. All deaths have been unrelated to ABO-incompatibility and there is no evidence of antibody-mediated rejection reported.

By expanding the available donor pool, ABO-incompatible heart transplantation offers neonates with a high risk of death the opportunity for a successful transplant outcome. Comprehensive care by the multidisciplinary transplant team is required to coordinate efforts to remove antidonor ABO antibodies intraoperatively and closely monitor the infant's immunologic response in the postoperative period. It is critical to educate families and all healthcare clinicians that in the event of an emergency requiring a blood transfusion it is vital that these patients receive only those specific blood products indicated after an incompatible blood group transplantation. Medic alert bracelets are highly recommended in this patient population to increase awareness of management protocol.

Conclusion

Although the total number of cases is small and long-term follow-up is needed, the absence of an immediate hyperacute humoral response and the current evidence of B-cell graft tolerance indicate that ABO-incompatible transplantation should be considered an option in selected neonates. Children may be considered eligible for ABO-incompatible transplantation if they have no donor-specific antibodies present, and are therefore not screened by age. They are evaluated on the basis of serologic evidence of antibody development before transplantation.

References

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25. MacDonald AS. A Guide to the Clinical Use of Tacrolimus for Transplant Professionals. 2nd ed. Ontario, Canada: Fujisawa, Canada, Inc: 2001.

26. Saito K, Nakagawa Y, Tanikawa T, et al. Efficacy of tacrolimus in ABO-incompatible kidney transplantation: clinicopathological aspects of humoral rejection. Transplant Proc. 1999;31:2851-2852.

27. Rose ML, Smith J, Dureau G, et al. Mycophenolate mofetil decreases antibody production after cardiac transplantation. J Heart Lung Transplant. 2002;21:282-285.

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29. Fan X, Ang A, Pollock-Barziv SM, et al. Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation. Nature Med. 2004;10:1227-1233.

Rose J. Rodriguez, RN, BSN, CPN, CCTC, Linda J. Addonizio, MD, Jacqueline M. Lamour, MD, Seema Mitai, MD, Ralph Mosca, MD, Lori J. West, MD, DPhil, Jenny C. Nova, RN, BSN, Daphne T. Hsu, MD

Children's Hospital of New York-Presbyterian, New York, NY (RJR, LJA, JML, SM, JCN, DTH), Columbia University College of Physicians and Surgeons, New York NY (RM), Hospital for Sick Children, Toronto, Ontario (LJW)

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