Adenovirus infection in children after allogeneic stem cell transplantation: diagnosis, treatment and immunity

Tol, Maarten J.D. van; Claas, Eric C. J.; Heemskerk, Bianca; Veltrop-Duits, Louise A.; Brouwer, Caroline S. de; Vreeswijk, Tamara van; Sombroek, Claudia C.; Kroes, Aloys C.M.; Beersma, Matthias F. C.; Klerk, E. P. A. De; Egeler, R. Maarten; Lankester, Arjan C.; Schilham, Marco W.

doi:10.1038/sj.bmt.1704852

Cited by 50 publications

(40 citation statements)

References 25 publications

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“…29 In patients with viremia, reduction of immunosuppression and initiation of preemptive treatment with cidofovir has become the standard of care in many centers. 29,[31][32][33] However, the observations made at our and other institutions indicate that initiation of antiviral treatment at the time of first detection of viremia may not prevent progression to severe AdV disease in many instances, and that earlier initiation of preemptive treatment could therefore be beneficial. 1,7,11,21,30,[33][34][35][36] Adenoviruses are known to persist in epithelial cells and lymphoid tissue, and AdV infections occurring during the posttransplant period appear to result from virus reactivation in most instances.…”

Section: Discussionmentioning

confidence: 56%

Monitoring of adenovirus load in stool by real-time PCR permits early detection of impending invasive infection in patients after allogeneic stem cell transplantation

et al. 2010

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Invasive adenovirus (AdV) infections are associated with high morbidity and mortality in allogeneic stem cell transplant recipients. We observed that molecular detection of the virus in stool specimens commonly precedes AdV viremia, suggesting that intestinal infections may represent a common source of virus dissemination. To address this notion, we have investigated 153 consecutive allogeneic transplantations in 138 pediatric patients by quantitative monitoring of AdV in stool specimens and peripheral blood by a pan-adenovirus real-time (RQ)-PCR approach. AdV was detectable in serial stool specimens in all cases of AdV viremia during the post-transplant course (Po0.0001). The incidence of AdV viremia in individuals with peak virus levels in stool specimens above 1 Â 10E6 copies per gram (n ¼ 22) was 73% vs 0% in patients with AdV levels in stool specimens below this threshold (n ¼ 29; Po0.0001). Serial measurement of AdV levels in stool specimens by RQ-PCR permitted early diagnosis of impending invasive infection with a sensitivity and specificity of 100% (95% confidence interval (CI) 96-100%) and 83% (95% CI 67-92%), respectively. The median time span between detection of AdV loads in stool specimens above 1 Â 10E6 copies per gram and first observation of viremia was 11 days (range 0-192). Quantitative monitoring of the AdV load in stool specimens therefore provides a rationale for early initiation of antiviral treatment with the aim of preventing progression to life-threatening invasive infection.

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Section: Discussionmentioning

confidence: 56%

Monitoring of adenovirus load in stool by real-time PCR permits early detection of impending invasive infection in patients after allogeneic stem cell transplantation

et al. 2010

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“…12 Rather commonly, immunosuppressive treatment has been reduced, as reconstitution of the lymphocytic immune system is associated with viral clearance. [13][14][15] AdV-specific T cells have been detected in children after HSCT and seem to protect against AdV disease. 16 For this reason, immunotherapy with donor T cells has been suggested, and a novel approach using purified AdV-specific donor T cells is promising, although in need of further evaluation.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a surveillance strategy for early detection of adenovirus by PCR of peripheral blood in hematopoietic SCT recipients: incidence and outcome

Öhrmalm

Lindblom

Omar

et al. 2010

Bone Marrow Transplant

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Adenoviruses (AdV) have emerged as important causes of morbidity and mortality in patients after hematopoietic SCT (HSCT). Early diagnosis of the infection by detection of viral DNA may improve the prognosis. A surveillance strategy was evaluated for detection of AdV DNA by PCR in a prospective study of unselected allogeneic HSCT recipients. In parallel with a routine CMV surveillance program, plasma from 20 children and 77 adults was analyzed by quantitative PCR for detection of AdV DNA. In addition, in 12 unselected patients, the presence of AdV-specific T cells were analyzed by enzyme-linked immunosorbent spot (ELISPOT) at 1 to 3 months after transplantation. A total of 5 of 97 (5%) patients had detectable AdV DNA in peripheral blood. Only one patient had high titers and none developed AdV disease. BM as a source of stem cells and myelodysplastic syndrome as the indication for transplantation were independently associated with higher risk of acquiring AdV infection. AdV-specific T cells were detected in 7 (58%) of 12 patients. Although AdV DNA was found in peripheral blood by quantitative PCR in 5% of patients undergoing allogeneic HSCT, the present surveillance program did not have a significant effect on the clinical outcome.

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“…It has been demonstrated that reconstitution of HAdV-specific T cells is essential to control HAdV infection after allogeneic SCT. [5][6][7][8][9] Manipulation of immune reconstitution by adoptive transfer of donor-derived HAdV-specific T cells may, therefore, be an effective strategy to provide shortand long-term antiviral protection.…”

Section: Introductionmentioning

confidence: 99%

Combined CD8+ and CD4+ adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection

Zandvliet¹,

Falkenburg²,

Liempt³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundHuman adenovirus can cause morbidity and mortality in immunocompromised patients after allogeneic stem cell transplantation. Reconstitution of adenovirus-specific CD4 + T cells has been reported to be associated with sustained protection from adenovirus disease, but epitope specificity of these responses has not been characterized. Since mainly CD4 + T cells and no CD8 + T cells specific for adenovirus have been detected after allogeneic stem cell transplantation, the relative contribution of adenovirus-specific CD4 + and CD8 + T cells in protection from adenovirus disease remains to be elucidated. Design and MethodsThe presence of human adenovirus hexon-specific T cells was investigated in peripheral blood of pediatric and adult allogeneic stem cell transplant recipients, who showed spontaneous resolution of disseminated adenovirus infection. Subsequently, a clinical grade method was developed for rapid generation of adenovirus-specific T-cell lines for adoptive immunotherapy. ResultsClearance of human adenovirus viremia coincided with emergence of a coordinated CD8 + and CD4 + T-cell response against adenovirus hexon epitopes in patients after allogeneic stem cell transplantation. Activation of adenovirus hexon-specific CD8 + and CD4 + T cells with a hexon protein-spanning peptide pool followed by interferon-γ-based isolation allowed rapid expansion of highly specific T-cell lines from healthy adults, including donors with very low frequencies of adenovirus hexon-specific T cells. Adenovirus-specific T-cell lines recognized multiple MHC class I and II restricted epitopes, including known and novel epitopes, and efficiently lysed human adenovirus-infected target cells. ConclusionsThis study provides a rationale and strategy for the adoptive transfer of donor-derived human adenovirus hexon-specific CD8 + and CD4 + T cells for the treatment of disseminated adenovirus infection after allogeneic stem cell transplantation.Key words: allogeneic stem cell transplantation, adoptive immunotherapy, adenovirus infection, adenovirus-specific T cells.Citation: Zandvliet ML, Falkenburg JH, van Liempt E, Lankester AC, Kalpoe JS, Kester MG, van der Steen DM, van Tol MJ, Willemze R, Guchelaar HJ, Schilham MW, and Meij P. Combined CD8 + and CD4 + adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection. Haematologica 2010;95(11):1943-1951. doi:10.3324/haematol.2010

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Adenovirus infection in children after allogeneic stem cell transplantation: diagnosis, treatment and immunity

Cited by 50 publications

References 25 publications

Monitoring of adenovirus load in stool by real-time PCR permits early detection of impending invasive infection in patients after allogeneic stem cell transplantation

Monitoring of adenovirus load in stool by real-time PCR permits early detection of impending invasive infection in patients after allogeneic stem cell transplantation

Evaluation of a surveillance strategy for early detection of adenovirus by PCR of peripheral blood in hematopoietic SCT recipients: incidence and outcome

Combined CD8+ and CD4+ adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection

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