Multidrug-resistant cytomegalovirus infection in a pediatric stem cell transplantation patient

Bauters, Tieneke; Bordon, Victoria; Florin, Lisa; Padalko, Elizaveta; Andrei, Gracíela; Gillemot, Sarah; Fiten, Pierre; Opdenakker, Ghislain; Snoeck, Robert; Laureys, Geneviève

doi:10.1016/j.antiviral.2016.05.020

Cited by 5 publications

(2 citation statements)

References 33 publications

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“…Although the A594V UL97 was found in blood (RV-1103) and kidney (CS_3_7), the Δ 981-982 and P522S DNA polymerase mutants were present in blood and the T503A mutation in the kidney, indicating that the T503A, detected as a minor population in blood at day 152 by NGS had the ability to infect and replicate in the kidney. Our findings clearly indicate a compartmentalized evolution of the viral subpopulations as highlighted in our previous studies (Bache et al, 2014;Bauters et al, 2016), which warrants genotyping of tissue-specific specimens together with blood in patients unresponsive to antiviral therapy. Because different viral mutants can be selected at relatively low amounts in blood where high levels of viral replication take place and some minor viral variants have the ability to invade the graft causing disease, their rapid detection by NGS should be beneficial.…”

Section: Discussionsupporting

confidence: 76%

Persistent primary cytomegalovirus infection in a kidney transplant recipient: Multi-drug resistant and compartmentalized infection leading to graft loss

Andrei

Loon²,

Lerut³

et al. 2019

Antiviral Research

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Cytomegalovirus (CMV) is one of the most common opportunistic infections after transplantation. To prevent CMV infections, universal prophylaxis and pre-emptive therapy with ganciclovir or its prodrug valganciclovir is applied. However, prolonged antiviral therapy may result in drug-resistance emergence. We describe a case of a 43-year-old CMV-seronegative patient who underwent kidney transplantation from a CMV-seropositive donor and developed CMV disease despite valganciclovir prophylaxis. CMV viral load increased even though valgangiclovir dose was augmented and immunosuppressive therapy reduced. CMV genotyping revealed mutations in the viral UL97 protein kinase, explaining ganciclovir-resistant CMV infection. The viral load failed to respond to foscavir, cidofovir and CMV-neutralizing immunoglobulins. Kidney allograft dysfunction developed 3 months post-transplantation with a histopathologic diagnosis of CMV nephropathy and potentially concomitant T-cell mediated rejection. A transplantectomy was performed on day 164 post-transplantation since the patient had uncontrollable CMV disease associated with a circulating multidrug-resistant DNA polymerase-mutant virus. Detailed monitoring in this patient demonstrated hallmarks of complicated CMV disease: (i) relatively rapid evolution of drug-resistant CMV mutants in the setting of persistent high blood viral loads, (ii) emergence of viral drug-resistance linked to acute graft rejection, (iii) transient and, thereafter, lack of response to various anti-CMV treatments, (iv) compartmentalization and heterogeneity of CMV viral populations, (v) possible differential ability of viral mutants to cause disease in the graft, and (vi) detection of minor viral variants by next generation

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Section: Discussionsupporting

confidence: 76%

Persistent primary cytomegalovirus infection in a kidney transplant recipient: Multi-drug resistant and compartmentalized infection leading to graft loss

Andrei

Loon²,

Lerut³

et al. 2019

Antiviral Research

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“…The primary mode of cCMV resistance is a mutation in the UL97 gene, preventing phosphorylation of GCV. In a minority of cases resistance is caused by mutations in the viral DNA polymerase encoded by UL54, which prohibits the binding of GCV and other antiviral agents not usually applied in neonatal cCMV patients (Biron, 2006;Bauters et al, 2016;Sun et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Onset of valganciclovir resistance in two infants with congenital cytomegalovirus infection

Garofoli

Lombardi

Angelini

et al. 2020

International Journal of Infectious Diseases

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Ganciclovir and its prodrug valganciclovir are elective treatments for cCMV. Neonates with important symptoms undergo 6 months of therapy to ameliorate/prevent symptoms and late sequelae, but evidence of resistance is emerging. Over the last 5 years, we took care of 59 cCMV infants and experienced two cases of resistance among nine cCMV infants receiving long-term valganciclovir therapy. In the first case, valganciclovir therapy was prolonged beyond 6 months due to severity of symptoms, control of viral load, and absence of adverse events. Resistance was detected in the 8th month of therapy. In the second case, after a significant reduction following valganciclovir administration and no adverse events, CMV viral load suddenly increased in the 6th month of therapy due to resistance. Both events were associated with UL97 gene mutation. The cCMV infants, affected by severe symptoms, remained in a steady state during treatment, and their later neurological development was coherent with initial seriousness of diagnosis. Prolonged therapeutic exposure may therefore be a risk for resistance, suggesting that constant dosage/ weight adjustments, monthly surveillance of viral load, and therapeutic drug monitoring could be proposed to monitor resistance onset and optimize the therapy regime. The risk-benefit ratio for longterm therapy, including the possibility of resistance onset, alongside SNHL and neurodevelopmental improvement, should also be evaluated.

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Cidofovir/foscarnet/ganciclovir

2016

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Multidrug-resistant cytomegalovirus infection in a pediatric stem cell transplantation patient

Cited by 5 publications

References 33 publications

Persistent primary cytomegalovirus infection in a kidney transplant recipient: Multi-drug resistant and compartmentalized infection leading to graft loss

Persistent primary cytomegalovirus infection in a kidney transplant recipient: Multi-drug resistant and compartmentalized infection leading to graft loss

Onset of valganciclovir resistance in two infants with congenital cytomegalovirus infection

Cidofovir/foscarnet/ganciclovir

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