Hypogammaglobulinemia after heart transplantation: use of intravenous immunoglobulin replacement therapy in relapsing CMV disease

doi:10.1016/j.intimp.2004.09.006

International Immunopharmacology

Volume 5, Issue 1, January 2005, Pages 97-101

https://doi.org/10.1016/j.intimp.2004.09.006 Get rights and content

Abstract

Secondary hypogammaglobulinemia after heart transplantation may follow immunosuppressive therapy with the resultant increased risk of infections, including cytomegalovirus (CMV) disease. There is limited information on the use of intravenous immunoglobulin replacement therapy (IVIG) in heart-transplanted patients with hypogammaglobulinemia and CMV disease. We present data on five consecutive heart-transplanted patients with relapsing CMV disease, four of whom developed gastrointestinal disease. The immunosuppressive regimen included prednisone, cyclosporine A, azathioprine, mycophenolate mofetil, tacrolimus and antithymocyte globulin (ATG). Evaluation revealed CMV antigenemia. All the patients had been treated with intravenous ganciclovir. In addition, hyperimmune CMV immunoglobulin was administered in three patients. Significantly reduced levels of immunoglobulin G (IgG) were observed in the patients as compared with 15 heart-transplanted individuals without CMV disease [mean IgG levels: 323±18 and 639±63 mg/dl, respectively (p=0.003)]. IVIG [FLEBOGAMMA], 200–400 mg/kg every 21 days with the goal of maintaining normal serum IgG levels, was added for the treatment of CMV disease. Selected batches with the highest anti-CMV titers were set apart for the treatment of the patients. IVIG treatment, in combination with antiviral therapy, proved able to control CMV disease. There was a favorable clinical response and the patients became free of gastrointestinal symptoms. Detection of CMV antigens was negative after treatment. During IVIG therapy no immediate or delayed adverse effects were observed. Even if our survey was limited to five cases, the results suggest that addition of IVIG to antiviral chemotherapy might improve outcome in heart-transplanted patients with hypogammaglobulinemia and 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.

Section snippets

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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Hypogammaglobulinemia following cardiac transplantation: a link between rejection and infection
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Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center
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The panel concludes that D −/R − recipients with other risk factors for CMV disease, such as the use of lymphocyte-depleting treatments and/or high-risk transplant groups (lung, pancreas, intestinal), could benefit from serological monitoring of CMV primary infection in the first year after transplantation (weak, low). It is now well accepted that hypogammaglobulinemia is a risk factor for CMV disease after SOT transplantation [139–142]. However, there is very little information on the clinical efficacy of administering substitutive therapy.
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Monitoring of immunoglobulin levels identifies kidney transplant recipients at high risk of infection
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Citomegalovirus (CMV) es el patógeno oportunista más importante en el paciente sometido a un trasplante de órgano, incrementando la mortalidad del paciente debido a efectos directos e indirectos. El factor de riesgo más importante para el desarrollo de enfermedad por CMV es la discordancia serológica para CMV entre donante y receptor (donante positivo y receptor negativo), que supone un riesgo de más del 50% de desarrollo de enfermedad por CMV si no se administra profilaxis. El uso de fármacos antivirales muy potentes para la profilaxis de esta complicación en pacientes de alto riesgo ha modificado las características de la enfermedad por CMV en esta población. Otros factores de riesgo clásicos para el desarrollo de enfermedad por CMV incluyen el desarrollo de rechazo agudo del injerto, tipo de órgano trasplantado, coinfección con otros herpesvirus y el tipo de inmunosupresores empleado. Recientemente se han descrito nuevos factores de riesgo para el desarrollo de esta complicación que incluyen las variaciones de genotipo de CMV entre donante y receptor, y alteraciones genéticas de la inmunidad innata en el receptor. En esta revisión se abordan los factores de riesgo clásicos y los últimos hallazgos descritos para el desarrollo de enfermedad por CMV en el receptor de un trasplante de órgano.
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Hypogammaglobulinemia after heart transplantation: use of intravenous immunoglobulin replacement therapy in relapsing CMV disease

Abstract

Introduction

Section snippets

Patients and methods

Immunological study

Intervention

Outcome measures

Results

Discussion

Acknowledgements

J. Heart Lung Transplant.

J. Heart Lung Transplant.

J. Heart Lung Transplant.

Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center

CID