Rapid development of ganciclovir-resistant cytomegalovirus infection in children after allogeneic stem cell transplantation in the early phase of immune cell recovery

Eckle, Tobias; Lang, Peter; Prix, Lothar; Jahn, Gerhard; Klingebiel, Thomas; Handgretinger, Rupert; Selle, Barbara; Niethammer, D.; Hamprecht, Klaus

doi:10.1038/sj.bmt.1703666

Cited by 39 publications

(19 citation statements)

References 15 publications

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“…It has been pointed out that viral clearance is inefficient without an adequate immune response and that lymphopenia, especially in children, is associated with an increased risk of developing GCV resistance early in the transplant period (5,6). The constantly low lymphocyte counts of our patient were primarily induced by the conditioning regimen prior to HSCT and maintained by the necessary immunosuppression.…”

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confidence: 80%

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Fatal Reactivation of Postnatal Cytomegalovirus Infection with Rapid Emergence of Ganciclovir Resistance in an Infant after Allogeneic Stem Cell Transplantation

et al. 2005

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Human cytomegalovirus (HCMV) can cause serious problems after hematopoietic stem cell transplantation. The death of a pediatric transplant recipient after reactivation of a postnatal HCMV infection with bilateral retinitis and pneumonitis is described. Sequencing of the HCMV UL97 region revealed a compartment-specific mutation (H520Q) in urine conferring ganciclovir resistance. CASE REPORTA 3-month-old infant had been diagnosed with juvenile myelomonocytic leukemia (JMML), a rare myeloproliferative disorder of childhood, and was admitted 2 months later for hematopoietic stem cell transplantation (HSCT). An HLAcompatible (HLA-A, -B, -C, -DRB1, and -DQB1-matched, one mismatch in HLA-DPB1), unrelated, human cytomegalovirus (HCMV)-seronegative donor was identified, and the infant was scheduled for an allogeneic HSCT at the age of 6 months. According to the European Working Group on Myelodysplastic Syndrome protocol, the conditioning regimen included busulfan, cyclophosphamide, and melphalan. Antithymocyte globulin was administered as prophylaxis for graftversus-host disease (GVHD) prior to transplantation. Posttransplantation, cyclosporine was used for GVHD prophylaxis, and only mild acute GVHD confined to the skin (maximum, 25%) had occurred. Hematopoietic reconstitution was initially protracted. Analysis of blood DNA short terminal repeats revealed 100% donor chimerism. At the time of pretransplantation evaluation, the HCMV-specific immunoglobulin G (IgG) assay was weakly positive whereas HCMV-specific IgM and HCMV DNA assays were negative. The infant had been breast-fed, but breast milk had not been tested for HCMV DNA by PCR. A retrospective PCR analysis from blood of the Guthrie card obtained during the first days of life of the newborn demonstrated HCMV DNA negativity. Therefore, HCMV-specific IgG antibodies were considered to be of maternal origin, for the mother was HCMV seropositive.Due to severe thrombocytopenia, the infant received a leukocyte-depleted platelet transfusion from an HCMV-seropositive donor at the age of 5 months. One week later, HCMV IgM was detected with increasing sample-to-cutoff ratios from 2.8 to 6.4 over the next 3 weeks. However, during this time, HCMV DNA PCR from leukocytes and urine was negative, and HSCT was performed. Acyclovir prophylaxis was routinely started 1 day after transplantation.On day 10 posttransplantation systemic active HCMV infection was first detected by PCR from blood. Seven days later anti-HCMV therapy was started with intravenous ganciclovir (GCV) at a dose of 2 ϫ 5 mg/kg of body weight per day (Fig. 1). Due to fluctuating HCMV loads and pp65-positive cells in the antigenemia assay as well as increasing myelosuppression, therapy was briefly switched to foscarnet (PFA), followed by alternate medication of GCV and PFA. However, response to therapy with GCV remained poor, which was reflected in continuing fluctuating levels of HCMV antigenemia and the development of HCMV retinitis. On day ϩ62, the infant developed fever with increasing viral loads of HCMV and Ep...

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“…GCV-resistant HCMV strains are isolated relatively frequently in the blood or urine of immunodeficient virus-infected patients after antiviral therapy (5,8). Notably, HCMV resistance has been linked with mutations in the HCMV UL97 protein in up to 90% of isolates examined (3).…”

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Fatal Reactivation of Postnatal Cytomegalovirus Infection with Rapid Emergence of Ganciclovir Resistance in an Infant after Allogeneic Stem Cell Transplantation

et al. 2005

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“…Pediatric patients may be at particularly higher risk for this complication. 47 One patient with grade IV GVHD developed HHV6 disease concomitant with the onset of GVHD. HHV6 may initiate or exacerbate GVHD in T depleted grafts.…”

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confidence: 99%

Unrelated donor or partially matched related donor peripheral stem cell transplant with CD34+ selection and CD3+ addback for pediatric patients with leukemias

Bunin

Aplenc

Grupp

et al. 2005

Bone Marrow Transplant

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“…It is unusual for resistance to develop during the first 6 weeks of therapy, although this has been reported to occur in immunodeficient pediatric populations (69,211). Drug resistance results from the evolution of single or multiple mutations that confer various levels of resistance, with the overall level rising over time as mutations accumulate (180).…”

Section: Clinical Consequences Of Drug Resistancementioning

confidence: 99%

Antiviral Drug Resistance of Human Cytomegalovirus

2010

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SUMMARY The study of human cytomegalovirus (HCMV) antiviral drug resistance has enhanced knowledge of the virological targets and the mechanisms of antiviral activity. The currently approved drugs, ganciclovir (GCV), foscarnet (FOS), and cidofovir (CDV), target the viral DNA polymerase. GCV anabolism also requires phosphorylation by the virus-encoded UL97 kinase. GCV resistance mutations have been identified in both genes, while FOS and CDV mutations occur only in the DNA polymerase gene. Confirmation of resistance mutations requires phenotypic analysis; however, phenotypic assays are too time-consuming for diagnostic purposes. Genotypic assays based on sequencing provide more rapid results but are dependent on prior validation by phenotypic methods. Reports from many laboratories have produced an evolving list of confirmed resistance mutations, although differences in interpretation have led to some confusion. Recombinant phenotyping methods performed in a few research laboratories have resolved some of the conflicting results. Treatment options for drug-resistant HCMV infections are complex and have not been subjected to controlled clinical trials, although consensus guidelines have been proposed. This review summarizes the virological and clinical data pertaining to HCMV antiviral drug resistance.

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Rapid development of ganciclovir-resistant cytomegalovirus infection in children after allogeneic stem cell transplantation in the early phase of immune cell recovery

Cited by 39 publications

References 15 publications

Fatal Reactivation of Postnatal Cytomegalovirus Infection with Rapid Emergence of Ganciclovir Resistance in an Infant after Allogeneic Stem Cell Transplantation

Fatal Reactivation of Postnatal Cytomegalovirus Infection with Rapid Emergence of Ganciclovir Resistance in an Infant after Allogeneic Stem Cell Transplantation

Unrelated donor or partially matched related donor peripheral stem cell transplant with CD34+ selection and CD3+ addback for pediatric patients with leukemias

Antiviral Drug Resistance of Human Cytomegalovirus

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