Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation

The aim of this study was to analyse the incidence and risk factors for cytomegalovirus infection (CMV-I) and disease (CMV-D) after a reduced intensity conditioning allogeneic hematopoietic stem cell transplantation (alloHSCT-RIC). We included 186 consecutive alloHSCT-RIC adult patients at risk for CMV reactivation (patient and/or donor CMV seropositivity). Conditioning regimen was based on fludarabine plus an alkylating agent. For guiding pre-emptive anti-CMV therapy, Pp65 Antigenemia (pp65Ag) (n ¼ 116) or quantitative polymerase chain reaction (quantPCR) (n ¼ 70) were used. The 2-year incidence of CMV-I and/or CMV-D was 36% (11% for CMV-D). Of note, 12/14 (86%) episodes of CMV-D in the pp65Ag group had lung involvement compared with only 3/ 15 (20%) in the quantPCR group (P ¼ 0.01). Importantly, the number of patients who developed CMV pneumonia with prior negative screening tests was unusually high (67% overall). Multivariate analysis of risk factors for CMV-D identified two risk factors: (i) steroid therapy for moderateto-severe graft-vs-host disease (GVHD) (hazard ratio 4.7, P ¼ 0.02); and (ii) alternative donors (non-HLA-identical siblings) [hazard ratio 2.7, P ¼ 0.002]. Our findings suggest that CMV is still a major concern in alloHSCT-RIC. Variables associated with poor anti-CMV T-cell recovery (that is, GVHD and donor type) are helpful in identifying patients at higher risk for CMV-D in the alloHSCT-RIC setting.

Section: Discussionmentioning

confidence: 99%

Cytomegalovirus infection and disease after reduced intensity conditioning allogeneic stem cell transplantation: single-centre experience

Piñana

Martino

Barba

et al. 2009

“…The magnitude of the CMV-specific immune response is such that it has been shown to have a positive influence on the total lymphocyte count within peripheral blood, and this may be at least partly reflected in our study. 30 Lymphopenia is known to be a predictive factor for CMV reactivation after allogeneic transplantation 11,31 and may potentially be used as a surrogate marker for poor virus-specific immunity in situations where technology for ascertaining the CMV-specific immune response is not available.…”

Section: Discussionmentioning

confidence: 99%

“…9 In HSCT patients a low lymphocyte count and CD4 þ T-cell count of less than 40 per ml at 3 months post transplant have been demonstrated as risk factors for development of late CMV disease. 10 Hakki et al 11 also showed that low CD4 (o100 per ml) and CD8 (o50 per ml) T-cell counts at this time point are associated with poor CMV-specific immunity. The functional potential of the cellular immune response is also critical and dysfunctional Ag-specific CD8 þ T cells have been found as risk factors for CMV reactivation.…”

Section: Introductionmentioning

confidence: 99%

Early reconstitution of effector memory CD4+ CMV-specific T cells protects against CMV reactivation following allogeneic SCT

Pourgheysari

Piper

McLarnon

et al. 2008

Reactivation of CMV is a common complication following allogeneic haematopoietic SCT and is associated with significant morbidity and mortality. The relative importance of the CD4 þ and CD8 þ components of the CMVspecific immune response in protection from reactivation is unclear. The CMV-specific CD4 þ and CD8 þ immune response was measured at serial time points in 32 patients following allogeneic HSCT. Intracellular cytokine staining following CMV lysate stimulation and HLA-peptide tetramers were used to determine CMV-specific CD4 þ and CD8 þ responses, respectively. A deficient CMVspecific CD4 þ T-cell immune response within the first 30-50 days post transplant was associated with high risk of viral reactivation. Patients with combined impairment of the CD4 þ and CD8 þ immune response within the first 100 days were susceptible to late viral reactivation. The frequency of CMV-specific CD4 þ T cells correlated with CMV-specific CD8 þ T cells, comprising 10% of the whole T-cell repertoire. Early CMV-specific CD4 þ T-cell reconstitution was dominated by effector memory cells with normal levels of IL-2 resuming 6 months following transplantation. In summary, both CD4 and CD8 CMV-specific immune reconstitution is required for protection from recurrent activation. Measurement of the magnitude of the CMV-specific CD4 þ immune response is useful in managing viral reactivation following HSCT.

“…5,6 Despite these advances, the proper reconstitution of CMVspecific immunity is the most important factor in controlling the reactivation of the virus and in establishing longterm protection. 7 Restoration of adaptive immunity after HSCT is a slow process. Naı¨ve T-cells first appear at about 4 months after HSCT, and the full restoration of the naı¨ve T-cell pool may require 1 to 2 years.…”

Section: Introductionmentioning

confidence: 99%

Signature profiles of CMV-specific T-cells in patients with CMV reactivation after hematopoietic SCT

Krol

Stuchlý

Hubáček

et al. 2010

Depletion of cellular immunity as a consequence of conditioning before allogeneic hematopoietic SCT (HSCT) frequently results in CMV reactivation, which may in turn lead to life-threatening infections and require timely antiviral treatment. We have investigated the functional signatures of CMV-specific CD4 þ and CD8 þ T-cells in 191 samples from 118 individuals. We compared healthy donors with both patients with high and undetectable viral loads, and those who controlled and did not control their CMV reactivations. Polychromatic flowcytometric measurements of CD154 (CD40L), intracellular cytokines (IFNc, IL2) and a degranulation marker (CD107a) allowed us to assess the functional status of various T-cells simultaneously. We found that dual IFNc/ IL2-producing CD8 þ T-cells were present in patients controlling their CMV reactivations but absent from noncontrollers. CD8 þ T-cells that produce only IFNc were the most abundant subtype, but they most likely represent non-protective memory cells. Distinct functional signatures were examined by hierarchical clustering, and this revealed that, unlike polyfunctional CD8 þ T-cells, CD8 þ T-cells that produce IFNc alone were not functioning in concert with other subsets. In conclusion, our study revealed functional signatures that may be useful for immune monitoring, and it could change the interpretation of previous studies that assessed only IFNc.