Leukocyte suppression is associated with improved clinical outcomes in children's status after orthotopic heart transplantation
ABSTRACT Leukocyte suppression is a sequela of immunosuppressive therapy after orthotopic heart transplantation and may result in discontinuation of anti-proliferative agents. Clinical outcomes in this patient population have not been well delineated.
This study was a retrospective review of children who underwent orthotopic heart transplantation at our institution from 1986 to 2003. Leukocyte suppression was defined as a white blood cell count <5,000, prompting the withdrawal of anti-proliferative agents. The population was divided into 2 groups, leukosuppressed (LS) and non-leukosuppressed (NLS), and their clinical outcomes were compared.
The study included 109 patients, of which 44 (40%) became leukosuppressed. The 2 groups were similar regarding demographic data and initial management. The LS Group had a significantly decreased incidence of rejection, being 7 times less likely to have recurrent rejection (p = 0.001). The median time to rejection was 0.8 +/- 0.6 years for the NLS Group, whereas the median time to rejection was not yet reached at 17 years for the LS Group. The LS Group also tended toward a decreased incidence of retransplantation or death (p = 0.06). The organ "half-life" in the NLS Group was 7.5 years vs 12.5 years in the LS Group. There was no difference between the 2 groups in regards to other adverse effects of immunosuppression.
Children who have undergone orthotopic heart transplantation and subsequently become leukosuppressed have a lower incidence of rejection and a tendency toward less organ loss than children who do not become leukosuppressed, without having an increased incidence of adverse side effects.
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ABSTRACT: Mycophenolate mofetil (MMF) is an effective and commonly used immunosuppressant but has frequent adverse events. Genetic polymorphisms may contribute to variability in MMF efficacy and related complications. In this study we explore the distribution frequencies of common single nucleotide polymorphisms (SNPs) of IMPDH1, IMPDH2 and ABCC2 and investigate whether these SNPs influence MMF adverse events in 59 pediatric heart recipients. Genotypes were assessed by TaqMan analysis of: ABCC2 rs717620; IMPDH2 rs11706052; and IMPDH1 rs2288553, rs2288549, rs2278293, rs2278294 and rs2228075. Gastrointestinal (GI) intolerance was defined as diarrhea, vomiting, nausea or abdominal pain requiring dose-holding for >48 hours or MMF discontinuation. Bone marrow toxicity was evaluated using Common Terminology Criteria for Adverse Events Version 3 (CTCAE). GI intolerance occurred in 21 patients, and 21 had bone marrow toxicity. The ABCC2 rs717620 A variant was significantly associated with GI intolerance leading to drug discontinuation (p < 0.001); the IMPDH1 rs2278294 A variant and rs2228075 A variant were also associated with greater GI intolerance (p = 0.029 and p = 0.002, respectively). The IMPDH2 rs11706052 G variant was associated with more frequent neutropenia requiring dose-holding (p = 0.046). In this small sample of pediatric heart transplant patients receiving MMF, ABCC2, IMPDH1 and IMPDH2 SNPs were associated with MMF GI intolerance and bone marrow toxicity. Thus, genetic polymorphisms may directly influence MMF adverse events.The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 05/2010; 29(5):509-16. DOI:10.1016/j.healun.2009.11.602 · 5.61 Impact Factor
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ABSTRACT: Despite more than 40 years' experience in pediatric heart transplantation, cellular rejection remains a significant cause of morbidity and mortality. In this review, strategies and agents to prevent acute cellular rejection are discussed. Strategies to prevent rejection are divided into two phases - induction and maintenance therapies. Currently, the most commonly used induction agents are polyclonal antibodies (rabbit or equine antithymocyte globulin) and interleukin-2 receptor antibodies (daclizumab or basiliximab). Induction therapies have reduced early rejection, are renal sparing, and can reduce corticosteroid exposure, but have not yet been shown to have a longer term survival benefit. Multiple maintenance immunosuppressants are available. Nearly all regimens include a calcineurin inhibitor (either ciclosporin [cyclosporine] or tacrolimus). Most combinations in pediatric heart transplantation include an antiproliferative agent (azathioprine, mycophenolate mofetil or, less commonly, sirolimus). Everolimus has seen increasing use in adult heart transplant patients in Europe but, to date, its use is rare in pediatric heart transplantation. The use of corticosteroids as a third agent is still common, but strategies to avoid or minimize their use are increasing. The 'best' combination of therapies varies between studies. By gaining a better understanding of individuals' genetic and environmental risk factors, we may in the future be able to better predict the course of cardiac allografts and enhance our ability to tailor immunosuppression to individual patient variables with the ultimate goal of inducing a state of immune tolerance.Paediatric Drugs 12/2010; 12(6):391-403. DOI:10.2165/11535990-000000000-00000 · 1.72 Impact Factor
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ABSTRACT: Background: Viral genome in cardiac allograft has been associated with early graft loss in children who have undergone cardiac transplant from unknown mechanisms. Methods: This study is a retrospective review of children who have undergone cardiac transplant at a single institution from 1/2004 to 5/2008. Patients underwent cardiac catheterisations with endomyocardial biopsies to evaluate for rejection - graded on Texas Heart Institute scale - and the presence of virus by polymerase chain reaction. Patients with virus identified during the first year post transplant were compared at 1 year post transplant with virus-free patients. Results: The cohort comprised 59 patients, and the median age at transplant was 5.1 years. Viral genomes were isolated from 18 (31%) patients. The PCR + group had increased inflammation on endomyocardial biopsies, with a median score of 4 (ISHLT IR) versus 1 (ISHLT 1R) in the PCR - group (p = 0.014). The PCR + group had a similar cardiac index (median 3.7 ml/min/m2), pulmonary capillary wedge pressure (median 10 mmHg), and pulmonary vascular resistance index (median 1.7 U m2) comparatively. PCR + patients were more likely to have experienced an episode of rejection (p = 0.004). Conclusions: Children who developed viral endomyocardial infections after a cardiac transplant have increased allograft inflammation compared with virus-free patients. However, the haemodynamic profile is similar between the groups. The ongoing subclinical inflammation may contribute to the early graft loss associated with these patients.Cardiology in the Young 05/2013; 24(2):1-6. DOI:10.1017/S1047951113000425 · 0.86 Impact Factor