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Ann Thorac Surg 1999;68:176-180
© 1999 The Society of Thoracic Surgeons

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Original Articles

Rejection with heart failure after pediatric cardiac transplantation

^a Division of Pediatric Cardiology, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
^b Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA

Address reprint requests to Dr Flippin, Division of Cardiology, St. Louis Children’s Hospital, One Children’s Place, St. Louis, MO 63110
e-mail: flippin-m{at}a1.kids.wustl.edu

	Abstract

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Background. Rejection associated with heart failure or death occurs after pediatric cardiac transplantation but has had limited analysis.

Methods. We analyzed the records of 96 consecutive pediatric cardiac transplant recipients who survived to hospital discharge.

Results. Eighteen patients (19%) experienced 23 episodes of heart failure or death associated with rejection. Univariate analysis demonstrated black race (p = 0.041), transplantation after 12 months of age (p = 0.032), later time after transplantation (p = 0.037), rejection episode in the first year after transplantation (p = 0.001), and history of two or more rejection episodes (p < 0.001) were significantly associated with rejection seen with heart failure. A multivariate regression analysis identified two or more rejection episodes to be the only independent risk factor for the development of rejection with heart failure (odds ratio 20; 95% confidence limits, 4–104; p < 0.0001).

Conclusions. This study identified pediatric heart transplant recipients with a history of previous rejection episodes to be at a higher risk for symptomatic or fatal rejection. Further studies are needed to determine if intensification of maintenance immunosuppression, long-term rejection surveillance, or both in patients with multiple rejection episodes could reduce morbidity and mortality from rejection.

	Introduction

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Cellular rejection (lymphocytic infiltration with or without myocardial cell necrosis) after cardiac transplantation in children or adults occurs primarily in the first few postoperative months. As a result, immunosuppression and rejection surveillance protocols at most centers tend to become less intensive with increasing time after transplantation. Invasive rejection surveillance (endomyocardial biopsy) is even eliminated at some centers [1, 2] because of the low prevalence of rejection with long-term follow-up.

Rejection, however, continues to be one of the primary causes of death 1 year after transplantation in children and adults [3–6]. Previous studies [7–10] have identified younger age at transplantation, female donor or recipient, cytomegalovirus infection, human lymphocyte antigen mismatch, and recurrent rejection as risk factors for cellular rejection in adults. Few studies have focused specifically on rejection associated with heart failure (HF) or death. Data from the Cardiac Transplant Research Database [5, 11] have identified black race, female sex, and diabetes to be risk factors for rejection with HF or hemodynamic compromise in adults. Cardiac allograft dysfunction in adult recipients is frequently not associated with extensive lymphocytic infiltration or myocardial cell necrosis on biopsy but can be reversed with intensive immunosuppression, thereby implying that the allograft dysfunction is an immunologic event [5, 12, 13].

Rejection in pediatric cardiac transplant recipients follows a similar temporal pattern [14–17] as in adults and has been associated with later age at transplantation, induction therapy, and cytomegalovirus disease [16]. Currently, little is known about symptomatic rejection in infants, children, or adolescents. We sought to characterize rejection associated with HF or death in pediatric heart transplant recipients.

	Material and methods

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Patient population
We retrospectively analyzed the hospital records of 96 consecutive pediatric cardiac transplant recipients operated on at St. Louis Children’s Hospital from July 1986 to June 1997 who survived to hospital discharge and were not having a second transplant procedure. The 13 patients who were not hospital survivors underwent postmortem examination, and none showed evidence of rejection or coronary arteriopathy. The causes of death were primary graft failure in 5 patients and infection in 7 patients; the remaining patient was considered an operative death. The recipient population was 10% black and 42% female. Infants (< 12 months of age at the time of transplantation) made up 45% of the transplant recipients. Median follow-up was 24 months (range, 0.5 to 11 years). All patients received triple immunosuppression therapy with cyclosporine, azathioprine, and steroids without induction therapy under a previously described protocol [18]. Withdrawal of steroids was usually attempted at 6 months after transplantation and was successful without affecting rejection frequency in approximately 80% of the patients in this cohort [19].

Definitions
For this study, HF was defined as a clinical event associated with the signs and symptoms of tachycardia, tachypnea, gallop rhythm, edema, hepatomegaly, or a combination of these. Swan-Ganz catheters were not routinely used in infants and young children. Thus, hemodynamic data were not obtained during the episodes of HF in many of the patients. Every patient who was seen with HF or died underwent endomyocardial biopsy or postmortem examination.

Cellular rejection was defined as a biopsy specimen demonstrating findings of International Society for Heart and Lung Transplantation (ISHLT) grade 3A or greater [15, 20]. Coronary vessels in biopsy specimens were routinely scrutinized for lymphocytic infiltration, intimal thickening, and endothelial injury. However, routine immunofluorescence of biopsy specimens was not performed. For this cohort, patients seen with HF whose initial biopsy results were graded less than 3A subsequently underwent coronary angiography, and the patient was presumptively treated for rejection if angiography failed to demonstrate arteriopathy.

High mortality rates in adult patients with HF associated with rejection [5] have prompted aggressive immunosuppression therapy, and prior to 1995, a polyclonal antilymphocyte antibody preparation was used [21]. Subsequently, such rejection has been treated with a monoclonal antilymphocyte preparation (OKT3, 0.1 mg · kg^-1 · d^-1 up to a maximum dose of 5 mg for 7 to 14 days) [22]. Because this type of rejection has more recently been associated with humoral mechanisms [23], for the past 4 years, plasmapheresis for 5 to 7 days has been added to the treatment regimen if the allograft showed evidence of poor systolic function, thus making inotropic support necessary. No differences in graft survival have been noted with the different modes of intensive immunosuppression.

Data analysis
Analysis of rejection associated with HF (HF rejection) was carried out by comparing the patients who had such rejection episodes with the population who did not. A second analysis comparing individual episodes of rejection associated with HF to those episodes not associated with HF or death was performed. Variables corresponding to characteristics of the donor, recipient, and transplant procedure were examined and are listed in the Appendix.

Standard contingency tables using ² and Fisher’s t test were used to evaluate differences between groups. The Bonferroni/Dunn correction was utilized because of the number of variables analyzed. Kaplan-Meier analysis was performed to compare differences in survival between patients with rejection associated with HF versus patients with rejection not associated with HF. Univariate analysis was performed; variables demonstrating significant associations were entered into a stepwise multivariate logistic regression model to identify independent risk factors for the development of HF rejection. For this study, a p value of less than 0.05 was the criterion for significance.

	Results

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Rejection with HF or death
Eighteen of the 96 patients experienced 23 episodes of HF rejection with the loss of one graft (patient underwent successful retransplantation). Five of the patients died during an HF rejection episode; in 3, death was sudden without anteceding symptoms. The other 2 patients had progressive HF unresponsive to medical management; 1 of them died during an unsuccessful attempt at retransplantation. Thus, HF rejection occurred in 19% (18 of 96) of the patients and 24% (23 of 97) of all rejection episodes. In all 23 rejection episodes with HF, biopsy material, autopsy material, or both were ISHLT grade 3A or greater. Pathologic examination of the hearts of the 5 patients who died as a result of the rejection episode revealed severe multivessel coronary arteriopathy in 3. In this cohort over the study period, the only episodes of HF that were not associated with high-grade biopsy results occurred within the first 3 days after transplantation and were thought to be due to primary graft failure.

Heart failure was associated with atrial flutter or supraventricular tachycardia in four (17%) of the 23 episodes. Seven episodes of rejection with HF (30%) were associated with a need of inotropic support, and four episodes (17%) were seen with tamponade from a pericardial effusion. In the 18 episodes of nonfatal HF rejection, echocardiographic evidence of left ventricular dilatation and decreased systolic function (shortening fraction < 0.28) was observed in five (27%), and 14 (74%) were associated with left ventricular hypertrophy and normal systolic function, findings suggesting left ventricular failure was due to diastolic dysfunction. All but one of the 18 nonfatal episodes of HF rejection demonstrated resolution of abnormalities of left ventricular dilatation, hypertrophy, and reduced ventricular function within 3 months after treatment.

Three (23%) of the 13 patients who survived HF rejection died within 11 months after their first episode of HF rejection. One died of pneumonia 2 months after treatment of HF rejection. One died suddenly 2 months after treatment; postmortem examination revealed no cellular rejection but severe multivessel coronary arteriopathy. The final death occurred in an adolescent who died suddenly 6 months after the second episode of HF rejection (11 months after the first episode). He had persistent evidence of poor left ventricular ejection after the second HF rejection episode. Again, postmortem examination revealed no cellular rejection but severe multivessel coronary arteriopathy. The other 10 survivors have been followed for a median of 24 months. All had coronary angiography 12 months after HF rejection, and there was no evidence of coronary arteriopathy.

HF rejection in patients
There were significant differences between patients who did and did not experience rejection associated with HF. Compared with patients without HF rejection, patients with HF rejection generally had a rejection episode in the first year after transplantation (83% versus 40%; p = 0.001) and had two or more episodes of rejection (89% versus 14%; p < 0.0001). Black recipients made up a greater proportion of the patients with HF rejection as opposed to those without HF rejection (28% versus 10%; p = 0.041). Transplantation in infancy was associated with fewer episodes of HF rejection (67% versus 40%; p = 0.032). Figure 1 illustrates the differences in survival between patients who experienced rejection with HF and those who had rejection without HF. Survival of patients after the first rejection episode with HF was significantly poorer (p = 0.01) than that of patients after the first rejection episode unassociated with HF.

View larger version (14K): [in this window] [in a new window]   Fig 1. Actuarial survival after first rejection episode. Survival of patients with rejection associated with heart failure (HF) was significantly poorer (p = 0.01) than survival of patients who experienced rejection without HF.

View larger version (19K): [in this window] [in a new window]   Fig 2. Frequency of rejection episodes with heart failure versus frequency of rejection episodes without heart failure grouped in 6-month intervals.

	Comment

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Rejection after pediatric cardiac transplantation is common; pediatric recipients average one rejection episode in the first 12 months after transplantation [24]. Although the majority of rejection episodes occur in the first few months after transplantation [14–17], rejection remains a major cause of mortality and morbidity at mid-term and long-term follow-up. Data from ISHLT [4] indicate acute rejection is the cause of 25% of the deaths in pediatric recipients 1 year after transplantation. Rejection associated with rehospitalization was reported to occur in nearly 10% of pediatric recipients 12 to 24 months after transplantation.

Rejection associated with hemodynamic compromise in adult heart transplant recipients is linked to mortality rates of 40% to 50% after onset of the symptomatic rejection episode. Our data also reflect this with a 43% survival at 50 months after the first rejection episode. Black race, female sex of the recipient, and diabetes have been associated with adult HF rejection [5]. Left ventricular dysfunction associated with ISHLT biopsy grades lower than 3A in adults has been reported to be reversible with augmentation of immunosuppression [13], a finding suggesting the dysfunction is a manifestation of immunologic mechanisms other than lymphocytic infiltration of the myocardium. Using augmentation of immunosuppression as the definition of a rejection episode, nearly one third of HF rejection episodes from the Cardiac Transplant Research Database were associated with endomyocardial biopsy grades lower than 3A. Survival was better with episodes associated with ISHLT grades of higher than 3A [5].

The results of our study show that rejection with HF in pediatric heart transplant recipients occurs later after transplantation than rejection without HF and is strongly associated with recurrent rejection. Univariate analysis found infant recipients tend to have less HF rejection. Previous reports from individual institutions [16, 17] have demonstrated that rejection occurs to a lesser extent in infant heart transplant recipients compared with children and adolescents. Data from the Pediatric Heart Transplant Study [25] indicated acute rejection accounts for a smaller proportion of deaths after transplantation in infant recipients than in older recipients.

This study differs from previous adult studies on HF rejection [5, 12] by the absence of HF rejection episodes with ISHLT biopsy grades of less than 3A. Rejection without lymphocytic infiltration (humorally mediated rejection) has been observed in pediatric heart transplant recipients [22]. We have not performed routine immunofluorescence on biopsy specimens because of concerns about the reliability and usefulness of these techniques after cardiac transplantation [26]. Our diagnostic and treatment protocol during the study included coronary angiography to exclude coronary arteriopathy if biopsy specimens were negative and presumptive treatment for rejection if both biopsy specimens and coronary angiography were negative. However, during the time of the study, all patients in whom HF developed had positive biopsy results. Subsequent to the end of this study, 2 patients have had development of HF with biopsy grades lower than 3A without angiographic or intravascular ultrasound evidence of graft vasculopathy; their condition improved with augmentation of immunosuppression. Thus the paucity of these types of HF rejection episodes may be a function of sample size and length of follow-up as opposed to a diminished prevalence in pediatric cardiac transplant recipients.

Clinical signs and symptoms of HF as opposed to hemodynamic, echocardiographic, or pharmacologic (need of inotropic support) criteria were used as the definition of HF rejection in this study. These criteria are likely broader than those applied in adult studies and perhaps account for the higher percentage of HF rejection among total rejection episodes in this study compared with previous studies in adults [5, 10]. The broad criteria also may account for a lower mortality rate, as many of the HF rejection episodes were not associated with a need of inotropic support. These criteria were necessary because symptomatic infants with HF do not undergo routine hemodynamic monitoring. Further, these broad criteria reflect the heterogeneity in the presentation of symptomatic rejection in infants and children, which ranged from tachyarrhythmias to pericardial tamponade to pump failure to sudden death. Pericardial tamponade has also been observed with rejection in adult patients [27, 28]. Echocardiographic findings were also variable, with the appearance of dilated or hypertrophic cardiomyopathy.

Our study has certain methodologic limitations. First, it was conducted in a retrospective manner. A prospective study would have allowed a more inclusive evaluation of variables. Second, this is a relatively small population to justify the use of a multivariate logistic regression model. Although this type of analysis can result in "overanalysis" of the data, our results are similar to those in adults in that black race and history of two or more rejection episodes were identified as risk factors for more severe rejection episodes [29, 30]. Although the 95% confidence intervals were quite high, the odds ratio of 20 along with similar findings in the literature on adults indicates that this is likely a valid conclusion. Continued analysis of our transplant population is thus warranted to further validate our findings or discover other relationships not apparent with this analysis.

In conclusion, we have found a strong association between symptomatic or fatal rejection and recurrent rejection in pediatric cardiac transplant recipients. Recurrent rejection has also been associated with the development of graft coronary arteriopathy in pediatric cardiac transplant recipients [25, 26]. These findings suggest that strategies to minimize multiple rejection episodes could reduce long-term cardiac mortality and morbidity in pediatric cardiac transplant recipients. Such strategies could include higher levels of maintenance immunosuppression and more frequent intervals of rejection surveillance. Further studies are needed to determine if intensification of maintenance immunosuppression or long-term rejection surveillance in patients with multiple rejection episodes could reduce morbidity and mortality in pediatric cardiac transplantation.

	Appendix

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Variables analyzed

Age at rejection Age at transplantation Rejection in first year after transplantation Time of first rejection after transplantation First rejection Previous rejection (two or more rejection episodes) Time from previous rejection Sex Infant Race Cytomegalovirus status No. of human lymphocyte antigen mismatches Panel reactive antibody Cyclosporine levels less than 100 (ng/ml) Donor factors: sex, age, race Donor to recipient sex or race mismatch

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Eric N. Mendeloff Charles B. Huddleston Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Flippin, M. J. Articles by Canter, C. E. Search for Related Content PubMed PubMed Citation Articles by Flippin, M. J. Articles by Canter, C. E.