Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7)

Ljungman, Per; Cámara, Rafael de la; Robin, Christine; Crocchiolo, Roberto; Einsele, Hermann; Hill, Joshua A.; Hubáček, Petr; Navarro, David; Cordonnier, Catherine; Ward, Katherine N.

doi:10.1016/s1473-3099(19)30107-0

Cited by 335 publications

(376 citation statements)

References 147 publications

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“…The risk of cytomegalovirus (CMV) reactivation and consequent CMV disease remains a severe infectious complication in the treatment of hematopoietic malignancies by hematopoietic cell transplantation (HCT), which is the last therapeutic resort for aggressive leukemias that resist standard therapies. Accordingly, monitoring and management of CMV reactivation in latently infected HCT recipients is a medical task and challenge at transplantation centers worldwide (Seo and Boeckh, 2013;Ljungman et al, , 2019Stern et al, 2019). The aim of HCT is to repopulate the emptied bone marrow (BM) in HCT recipients who have undergone therapy-inherent hematoablative treatment for elimination of the malignant cells.…”

Section: Introductionmentioning

confidence: 99%

Cytomegalovirus-Associated Inhibition of Hematopoiesis Is Preventable by Cytoimmunotherapy With Antiviral CD8 T Cells

Renzaho

Podlech

Kühnapfel

et al. 2020

Front. Cell. Infect. Microbiol.

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Reactivation of latent cytomegalovirus (CMV) in recipients of hematopoietic cell transplantation (HCT) not only results in severe organ manifestations, but can also cause "graft failure" resulting in bone marrow (BM) aplasia. This inhibition of hematopoietic stem and progenitor cell engraftment is a manifestation of CMV infection that is long known in clinical hematology as "myelosuppression." Previous studies in a murine model of sex-chromosome mismatched but otherwise syngeneic HCT and infection with murine CMV have shown that transplanted hematopoietic cells (HC) initially home to the BM stroma of recipients but then fail to further divide and differentiate. Data from this model were in line with the hypothesis that infection of stromal cells, which constitute "hematopoietic niches" where hematopoiesis takes place, causes a local deficiency in essential hematopoietins. Based on this understanding, one must postulate that preventing infection of stromal cells should restore the stroma's capacity to support hematopoiesis. Adoptively-transferred antiviral CD8 + T cells prevent lethal CMV disease by controlling viral spread and histopathology in vital organs, such as liver and lungs. It remained to be tested, however, if they can also prevent infection of the BM stroma and thus allow for successful HC engraftment. Here we demonstrate that antiviral CD8 + T cells control stromal infection. By tracking male donor-derived sry + HC in the BM of infected female sry − recipients, we show the CD8 + T cells allow for successful donor HC engraftment and thereby prevent CMV-associated BM aplasia. These data provide a further argument for cytoimmunotherapy of CMV infection after HCT.

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Section: Introductionmentioning

confidence: 99%

Cytomegalovirus-Associated Inhibition of Hematopoiesis Is Preventable by Cytoimmunotherapy With Antiviral CD8 T Cells

Renzaho

Podlech

Kühnapfel

et al. 2020

Front. Cell. Infect. Microbiol.

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“…Third, CMV− QF+ individuals might represent some false negative IgG test results due to the low sensitivity of some commercial IgG tests. However, in spite of this limitation, determination of serological status is the gold standard in clinical routine to classify solid organ and stem cell transplant patients according to the risk of CMV infection 3,4 . www.nature.com/scientificreports www.nature.com/scientificreports/ In summary, healthy CMV+ QF− volunteers show a lower CMV-specific immunity in comparison to CMV+ QF+ individuals, either in humoral or cellular specific immunity.…”

Section: Discussionmentioning

confidence: 99%

“…Immune discordance shows the high heterogeneity of immunity to CMV in healthy subjects.In the last years, a variety of assays have been developed to measure cell-mediated immunity against cytomegalovirus (CMV-CMI), where the basic principle is the CMV-specific stimulation of T cells for 6-24 hours in cell culture 1,2 . These techniques have been shown to be particularly useful in individuals such as transplant patients who are susceptible to CMV infection, since they identify who is better protected against CMV infection after transplantation, as has been reported in international guidelines on the management of CMV in solid organ or stem cell transplantation 3,4 . Specifically, the detection of CMV-CMI at pretransplant or posttransplant using QuantiFERON-CMV (QF), ELISpot or intracellular cytokine staining has been associated with a lower risk of CMV infection, not only in observational studies 5-9 .Although most individuals show an agreement between CMV-serostatus and CMV-CMI, some of them have a discordance.…”

mentioning

confidence: 99%

Lack of cytomegalovirus (CMV)-specific cell-mediated immune response using QuantiFERON-CMV assay in CMV-seropositive healthy volunteers: fact not artifact

Valle-Arroyo

Aguado

Páez-Vega

et al. 2020

Sci Rep

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The QuantiFERON-CMV (QF) assay measures cell-mediated immunity against cytomegalovirus (CMV-CMI), which is particularly useful in individuals susceptible to CMV infection such as transplant patients. A positive QF result identifies patients that are better protected against CMV infection. However, the significance of a negative QF result in CMV-seropositive individuals needs to be clarified. CMV-CMI was analyzed in healthy subjects using the QF assay, and, in parallel, the Flow-cytometric Assay of Specific Cell-mediated Immune response in Activated whole blood (FASCIA). FASCIA assay measures T-cell proliferation using CMV lysate as stimulus whereas QF assay use a mix of peptides. A total of 93 healthy volunteers were enrolled, and 13/71 CMV-seropositive individuals (18.3%) showed humoral/ cellular discordance using QF assay (CMV+ QF−). Interestingly, with FASCIA assay CD4+ and CD8+ T-cell proliferations were lower in CMV+ QF− than in CMV+ QF+ individuals. Furthermore, CMV+ QF− volunteers had a lower level of anti-CMV IgG than CMV+ QF+ subjects. Discordant CMV+ QF− volunteers can be defined as low responder individuals since they show lower CMV-specific humoral and cellular immune responses in comparison to CMV+ QF+ individuals. Immune discordance shows the high heterogeneity of immunity to CMV in healthy subjects.In the last years, a variety of assays have been developed to measure cell-mediated immunity against cytomegalovirus (CMV-CMI), where the basic principle is the CMV-specific stimulation of T cells for 6-24 hours in cell culture 1,2 . These techniques have been shown to be particularly useful in individuals such as transplant patients who are susceptible to CMV infection, since they identify who is better protected against CMV infection after transplantation, as has been reported in international guidelines on the management of CMV in solid organ or stem cell transplantation 3,4 . Specifically, the detection of CMV-CMI at pretransplant or posttransplant using QuantiFERON-CMV (QF), ELISpot or intracellular cytokine staining has been associated with a lower risk of CMV infection, not only in observational studies 5-9 .Although most individuals show an agreement between CMV-serostatus and CMV-CMI, some of them have a discordance. Therefore, there are CMV-seropositive individuals without CMV-CMI, as well as CMV-seronegative individuals with protective CMV-CMI. Discordant individuals have been reported in both transplant patients and healthy virus carriers 8-12 .The QuantiFERON-CMV is an in vitro assay that measures CMV-CMI by quantifying IFNG released by CD8+ T cells after stimulation with a pool of HLA-restricted CMV peptides 13 . In some observational studies carried out in our group in solid organ transplant patients we found that 20-25% of CMV-seropositive transplant open Scientific RepoRtS | (2020) 10:7194 | https://doi.org/10.1038/s41598-020-64133-x www.nature.com/scientificreports www.nature.com/scientificreports/ candidates lacked CMV-CMI response using the QF assay, and they showed a higher risk of p...

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“…Since HCMV reactivation and HCMV-associated disease are leading reasons for the failure of haematopoietic stem cell transplantations [10-12], antiviral effects exerted by eltrombopag may also contribute to improved therapy outcome. Notably, eltrombopag was effective against resistant clinical HCMV isolates, and resistance formation to the approved drugs is a major challenge after stem cell transplantation [11,12].…”

Section: Discussionmentioning

confidence: 99%

The thrombopoietin receptor agonist eltrombopag inhibits human cytomegalovirus replication via iron chelation

Vogel

Schmidt

et al. 2019

Preprint

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m.michaelis@kent.ac.uk (MM) 18 19 Acknowledgements 20 The work was supported by the Hilfe für krebskranke Kinder Frankfurt e.V. and the 21 Frankfurter Stiftung für krebskranke Kinder. 22 23 2 Abstract 24 The thrombopoietin receptor agonist eltrombopag was successfully used 25 against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to 26 immunomodulatory and antiviral drugs. These effects were ascribed to effects of 27 eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also 28 exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV 29 replication in human fibroblasts and adult mesenchymal stem cells infected with six 30 different virus strains and drug-resistant clinical isolates. Eltrombopag also 31 synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. 32 Time-of-addition experiments suggested that eltrombopag interferes with HCMV 33 replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-34 negative cells, and addition of Fe 3+ prevented the anti-HCMV effects, indicating that it 35 inhibits HCMV replication via iron chelation. This may be of particular interest for the 36 treatment of cytopenias after haematopoietic stem cell transplantation, as HCMV 37 reactivation is a major reason for transplantation failure. Since therapeutic 38 eltrombopag concentrations are effective against drug-resistant viruses and 39 synergistically increase the effects of ganciclovir, eltrombopag is also a drug 40 repurposing candidate for the treatment of therapy-refractory HCMV disease. 41 42 Key words: human cytomegalovirus, antiviral therapy, eltrombopag, thrombopietin 43 receptor agonist, drug resistance, iron chelation 44 45 46

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Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7)

Cited by 335 publications

References 147 publications

Cytomegalovirus-Associated Inhibition of Hematopoiesis Is Preventable by Cytoimmunotherapy With Antiviral CD8 T Cells

Cytomegalovirus-Associated Inhibition of Hematopoiesis Is Preventable by Cytoimmunotherapy With Antiviral CD8 T Cells

Lack of cytomegalovirus (CMV)-specific cell-mediated immune response using QuantiFERON-CMV assay in CMV-seropositive healthy volunteers: fact not artifact

The thrombopoietin receptor agonist eltrombopag inhibits human cytomegalovirus replication via iron chelation

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