Immune Reconstitution and Clearance of Human Adenovirus Viremia in Pediatric Stem‐Cell Recipients

Heemskerk, Bianca; Lankester, Arjan C.; Vreeswijk, Tamara van; Beersma, Matthias F. C.; Claas, Eric C. J.; Veltrop-Duits, Louise A.; Kroes, Aloys C.M.; Vossen, Jaak M.; Schilham, Marco W.; Tol, Maarten J.D. van

doi:10.1086/427513

Cited by 130 publications

(149 citation statements)

References 52 publications

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“…21 Data obtained in ORD/MUD SCT recipients from our retrospective study indicated that patients with a low T-cell count (either CD4 þ or CD8 þ T cells) after SCT are at risk of developing an HAdV infection. In our prospective study, 5 children with viraemia only survived the infection if lymphocyte numbers increased to above 0.3 Â 10 9 /l in the period of 4 weeks following the first detection of a positive RQ-PCR. An increase of lymphocyte numbers was clearly associated with a decrease of the plasma DNA load.…”

Section: Immunity and Hadv Infectionmentioning

confidence: 87%

“…When infection progressed to viraemia, defined as the presence of an HAdV DNA load of X1000 copies/ml in two consecutive samples, the time point of first detection of DNA in plasma is usually very close to that of the first positive culture. 5 Importantly, in most patients, a time window of several weeks was observed between the first detection of a significant HAdV DNA load in plasma and the terminal stage of HAdV disease, offering opportunity for intervention. Recently, Lion et al 8 reported that detection of HAdV DNA in whole blood samples is associated with disseminated HAdV disease, which eventually may have a fatal course.…”

Section: Monitoring the Occurrence And Course Of Hadv Infectionmentioning

confidence: 99%

“…Immunosuppression consisting of ATG or Campath as part of the conditioning regimen was recognized as risk factor for HAdV infection in a prospective study of 48 children transplanted between 2001 and 2003 at our institute. 5 In paediatric SCT recipients transplanted with a graft from an adult haploidentical family (ORD) or matchedunrelated donor (MUD), reactivation of endogenous HAdV is likely to occur. In this setting, modulation of the graft by depletion of T (and B) cells or enrichment of CD34 þ progenitor cells and immunosuppression using polyclonal (ATG), monoclonal (Campath) antibodies or ciclosporin A are regularly applied.…”

mentioning

confidence: 99%

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

Tol

Claas

Heemskerk

et al. 2005

Bone Marrow Transplant

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Summary:Human adenoviruses (HAdV) are a frequent cause of potentially fatal infections in patients after allogeneic stem cell transplantation, especially in children. Monitoring of serum/plasma by real-time quantitative PCR is a sensitive tool for the recognition of patients at risk of a potentially fatal infection and for the evaluation of the efficacy of treatment. Data from a retrospective study and from a prospective study demonstrate that recovery of immunity after transplantation is essential for the elimination of HAdV infection. The feasibility of several approaches for the manipulation of immunity in the immunocompromised host to prevent a fatal course of the infection is discussed. Bone Marrow Transplantation (2005) 35, S73-S76.

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Section: Immunity and Hadv Infectionmentioning

confidence: 87%

Section: Monitoring the Occurrence And Course Of Hadv Infectionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Tol

Claas

Heemskerk

et al. 2005

Bone Marrow Transplant

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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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“…adenovirus infection has been correlated with the lack of endogenous T-cell immunity, capable of controlling such infectious agents (Chakrabarti et al, 2002;Feuchtinger et al, 2005;Heemskerk et al, 2005). Current antiviral agents are often limited by weak activity against adenovirus and by side effects, including suppression of bone-marrow function and renal toxicity (Bordigoni et al, 2001;Gavin & Katz, 2002;Ljungman et al, 2003;Lankester et al, 2004;Leruez-Ville et al, 2004).…”

mentioning

confidence: 99%

Safe adoptive transfer of virus‐specific T‐cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation

et al. 2006

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SummaryDuring periods of immunosuppression, such as postallogeneic stem cell transplantation (SCT), patients are at significant risk for severe viral infections. Human adenovirus (HAdV) infection is a serious complication post‐SCT, especially in children. Virus‐specific T cells are essential for the clearance of HAdV, as antiviral chemotherapy has revealed limited success. We present feasibility data for a new treatment option using virus‐specific donor T cells for adoptive transfer of immunity to patients with HAdV‐infection/reactivation. Virus‐specific donor T cells were isolated and infused into nine children with systemic HAdV infection after SCT. Isolation was based on γ‐interferon (IFN‐γ) secretion after short in vitro stimulation with viral antigen, resulting in a combination of CD4+ and CD8+ T cells. 1·2–50 × 103/kg T cells were infused for adoptive transfer. Isolated cells showed high specificity and markedly reduced alloreactivity in vitro. Adoptive transfer of HAdV‐specific immunity was successful in five of six evaluable patients, documented by a dose‐independent and sustained in vivo expansion of HAdV‐specific T cells, associated with a durable clearance/decrease of viral copies. T‐cell infusion was well tolerated in all nine patients, except one case with graft‐versus‐host disease II of the skin. In conclusion, induction of a specific T‐cell response through adoptive transfer was feasible and effective. When performed early in the course of infection, adoptive T‐cell transfer may protect from HAdV‐related complications.

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Immune Reconstitution and Clearance of Human Adenovirus Viremia in Pediatric Stem‐Cell Recipients

Abstract: Lymphocyte reconstitution appears to play a crucial role in clearance of HAdV viremia and survival of the host, warranting further development of therapeutic interventions aimed at improving immune recovery.

Cited by 130 publications

References 52 publications

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

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

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

Safe adoptive transfer of virus‐specific T‐cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation

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