Cumulative incidence of IFN-γ⁺ and IFN-γ⁺/IL-2⁺ CD4⁺ and CD8⁺ T-cell recovery in HSCT recipients.

<p>(A) HCMV-seropositive and (D) HCMV-seronegative young HSCT recipients. The cumulative curve indicating levels of protection during follow-up is also reported. Five (20%) of the 25 patients who developed HCMV-specific CD8+ T-cell response only a median time of 57 (16–340) days prior to appearance of CD4+ T-cells, had high DNAemia levels requiring antiviral treatment. The correlation (Spearman correlation test) between time to protection by HCMV-specific (B) CD4⁺ or (C) CD8⁺ T-cells and time to HCMV clearance from blood is shown. Within 12 months after transplantation, 95/131 patients developed specific T-cell immunity: 2 CD8+ only, and 93 both CD4 and CD8 T-cells. Of these 93, 85 developed specific immunity above the cutoff levels established for immune compromised patients (but 5 required antiviral treatment because of steroid therapy for GvHD), and 8 only levels above the cutoffs established for immune competent subjects (and were found to be also protected from reactivation).</p

Flow-chart of HCMV-specific T-cell response.

<p>Immune control of HCMV infection in the 131 young patients enrolled in the study. During follow-up, 12/42 HCMV-seronegative and 89/89 HCMV-seropositive patients developed HCMV infection/immunity, for a total of 101 patients. Forty-three patients required pre-emptive therapy to control HCMV infection prior to development of specific immunity. Six patients died for underlying disease relapse. Of the 93 remaining patients, 88 (95%) were protected, while 5 (5%) were treated with additional courses of pre-emptive therapy because the steroid therapy employed for treating GvHD promoted reactivation of viral infection, with a viral load in blood reaching the established cutoff.</p

HCMV-specific T-cell response to HCMV infection in 4 young patients receiving HSCT transplantation.

<p>(A) Early specific CD4⁺and CD8⁺ T-cell response with no HCMV infection. (B) Delayed CD4⁺ and CD8⁺ T-cell response with high viral load in a patient pre-emptively treated. (C) Early CD8⁺ T-cell response which did not prevent HCMV infection until HCMV-specific CD4⁺ response appeared. (D) In the presence of acute and chronic GvHD requiring steroid treatment, specific immune reconstitution did not protect against HCMV infection, which required ganciclovir (GCV) treatment, and was eventually prevented by a protective CD4⁺ and CD8⁺ T-cell response.</p

Cumulative incidence of HCMV infection in 131 young patients receiving HSC transplantation.

<p>(A) HCMV-seropositive patients. (B) HCMV-seronegative patients. (C) HCMV viral load in 88 patients with self-resolving or no HCMV infection, and in 43 patients requiring antiviral treatment. Among patients receiving T-cell depleted transplantation (TCD), 14/28 were included in the pre-emptive treatment group. Similarly, 10/11 patients receiving cord blood transplantation (CBT) were included in the pre-emptive treatment group.</p

Probability of survival, transplant-related mortality and GvHD in the HSCT studied population.

<p>(A) event-free survival (EFS), (B) overall survival (OS): no significant difference was found by the log-rank test. (C) Transplantation–related mortality (TRM), and (D) acute and chronic GvHD were expressed as cumulative incidence, taking into account the appropriate competing risks: no difference was found by the Gray test. HCMV-seropositive and HCMV-seronegative young HSCT recipients are reported separately.</p

Characteristics of the 131 patients analyzed.

<p>TBI: total body irradiation; GvHD: graft <i>vs</i> host disease; CS-A: cyclosporine-A; MTX:methotrexate; ALG: anti-lymphocyte globulin methotrexate; ALG: anti-lymphocyte globulin.</p>*<p>Among patients with malignant disease.</p