Hypogammaglobulinemia after heart transplantation: use of intravenous immunoglobulin replacement therapy in relapsing CMV disease
Introduction
Infectious complication continue to represent a significant source of morbidity and mortality in heart transplant recipients [1]. Among risk factors for 5-year mortality conditional on survival to 1 year, treatment for infection during the first year has been associated with a 28% increase in the risk of mortality [2]. Despite improvement in prophylaxis and treatment, cytomegalovirus (CMV) infection remains the most important infection affecting heart-transplant patients [3]. Hypogammaglobulinemia has been recently identified as a potential contributor to the net state of immunosuppression in heart transplantation and severe CMV infections have been reported in those patients [4], [5]. However, there is no previous information on the use of intravenous immunoglobulin replacement therapy (IVIG) in heart-transplanted patients with documented hypogammaglobulinemia and CMV disease. In a noncomparative, interventional case series study, we report on the effects of IVIG along with antiviral therapy for the treatment of heart-transplanted patients with hypogammaglobulinemia and relapsing CMV disease.
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Patients and methods
We present data on five consecutive heart-transplanted patients between 6/96 and 9/99 whose clinical course after transplantation was complicated by rejection and relapsing CMV disease. Clinical data of the patients are presented in Table 1. The immunosuppressive regimen included prednisone, cyclosporine A, azathioprine, mycophenolate mofetil and tacrolimus. The induction therapy included antithymocyte globulin (ATG) in three patients. Rejection was defined as ISHLT grade 3A or greater. Four
Immunological study
An immunological study was performed because of evaluation for relapsing CMV disease. Serum immunoglobulin levels were measured by nephelometry (Beckman, California, USA). Lymphocyte subsets were quantitated by three-color flow cytometry (FACScan, Becton and Dickinson, San Jose, CA, USA). Immunoglobulin levels were measured in 15 heart-transplanted individuals without CMV disease (control group). Severe hypogammaglobulinemia was defined as IgG levels <400 mg/dl.
Intervention
Intravenous infusions of pooled human immunoglobulin [FLEBOGAMMA®, Instituto Grifols, Barcelona, Spain] were commenced at a dose of 200–400 mg/kg body weight/cycle and repeated every 3 weeks with the goal to maintain normal levels of IgG (>700 mg/dl), along with antiviral treatment with Gancyclovir. Selected batches with the highest anti-CMV titers were set apart for the treatment of the patients (mean units of the Paul-Ehrlich-Institute: 38 U/ml). IVIG infusions were repeated until achievement
Outcome measures
Reduction in CMV antigenemia and improvement in CMV-associated symptoms.
Results
Immunological data of the patients are presented in Table 2. Significantly reduced levels of immunoglobulin G (IgG) were observed in the patients as compared with controls [mean IgG levels: 323±18 and 639±63 mg/dl, respectively (Mann–Whitney test, p=0.003)]. The average of time to the IgG determination after the first diagnosis of CMV infection was 90±63 days, range 30–180 days. CMV-associated symptoms and CMV antigenemia disappeared after IVIG plus antiviral therapy was initiated. Therapeutic
Discussion
Secondary hypogammaglobulinemia after cardiac transplantation may develop as a consequence of intensification of immunosupressive therapy for rejection and hence, confers an increased risk of opportunistic infections, particularly CMV disease [4], [5]. In addition, the immune dysfunction induced by CMV infection may occasionally leads to a true immunodeficiency state [3]. In the cases presented here, an immunologic evaluation showed severe hypogammaglobulinemia at the time of relapsing CMV
Acknowledgements
The authors would like to thank Dr. Juana Gil for performing lymphocyte phenotype analysis.
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