Human Cytomegalovirus (HCMV) - specific T-cell response after letermovir prophylaxis is predictive for subsequent HCMV reactivation in haematopoietic stem cell transplant recipients.

BACKGROUND: Human Cytomegalovirus (HCMV) is still one of the major concerning infection in hematopoietic stem cell transplant (HSCT) recipients. Letermovir (LTV) has been recently introduced for HCMV prophylaxis in adult patients who received allogeneic HSCT. However, many aspects related to immune reconstitution need to be further explored. The aim of this study was to define the prognostic role of HCMV-specific T-cell frequency measured at the end of LTV prophylaxis in predicting the risk for clinically significant HCMV infection (i.e. infection requiring antiviral treatment) after the stop of the prophylaxis. METHODS: Sixty-six adult patients who underwent allogeneic HSCT were enrolled and HCMV DNAemia was prospectively monitored. Additionally, HCMV-specific T-cell response was evaluated using ELISpot assay against two different antigens (HCMV infected cell lysate and pp65 peptide pool). RESULTS: Ten patients (15.2%) developed at least one positive HCMV DNAemia episode during LTV prophylaxis, whereas 50/66 (75.8%) patients developed at least one positive HCMV DNA event after LTV prophylaxis. Of note, 25 of them (50%) experienced a clinically significant HCMV infection. The median HCMV-specific T-cell response measured against HCMV lysate but not against pp65 peptide pool was lower in patients who developed HCMV clinically significant infection after prophylaxis. A ROC analysis revealed that the level of 0.04 HCMV-specific T cells/µl should be used as cut-off for development of clinically significant HCMV reactivation after prophylaxis. CONCLUSION: Assessment of HCMV-specific immunity upon discontinuation of universal prophylaxis with LTV should be considered as a method for identification of patients at risk for clinically significant HCMV infection.

Human Cytomegalovirus-Specific T-Cell Reconstitution and Late-Onset Cytomegalovirus Infection in Hematopoietic Stem Cell Transplantation Recipients following Letermovir Prophylaxis.

Letermovir (LTV), recently approved for the prophylaxis of human cytomegalovirus (HCMV) reactivation after hematopoietic stem cell transplantation (HSCT), has been shown to decrease the rate of infection in the first months post-transplantation. The aim of this study was to evaluate the impact of LTV prophylaxis on immune reconstitution and late-onset infection. We studied HCMV infection and HCMV-specific T cell reconstitution in 2 matched groups of HSCT recipients, those treated with LTV prophylaxis (n = 30; LTV group) and those receiving preemptive therapy (n = 31; PET group). We analyzed the rates of graft-versus-host disease (GVHD), neutropenia, baseline disease recurrence, and overall survival in the 2 groups. Clinically significant infections necessitating preemptive therapy showed a similar rate in the 2 groups (PET: 21 of 31 [68%]; LTV: 17 of 30 [57%]; P = .434) but occurred significantly later (after prophylaxis discontinuation) in the LTV group. There was no between-group difference in peak HCMV DNAemia level (P = .232). HCMV-specific T cell recovery was delayed by approximately 100 days in the LTV group. HCMV-specific CD4 and CD8 T cell counts were significantly lower in the LTV group at days 120 to 360 and days 90 to 120, respectively. A lower rate of chronic GVHD (P = .024) was seen in the LTV group. Time to engraftment, rate of disease relapse, and 1-year survival were not different between the 2 groups, whereas trends toward a lower rate of neutropenia (P = .124) and a higher rate of acute GVHD grade III-IV (P = .103) were observed in the LTV group. Because LTV prophylaxis delays HCMV infection and HCMV-specific immune reconstitution, immunologic and virologic monitoring should be implemented after discontinuation of prophylaxis. The potential effect of LTV prophylaxis in reducing chronic GVHD should be evaluated in prospective studies.

Early T cell reconstitution and cytokine profile may help to guide a personalized management of human cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation.

Human cytomegalovirus (HCMV) infection is one of the major causes of mortality and morbidity after allo-hematopoietic stem cell transplantation (HSCT). Antiviral therapies are associated with toxicity and high economic burden. The aim of this retrospective study was to identify allo-HSCT HCMV-seropositive recipients at low risk of clinically significant HCMV infection who could avoid antiviral therapies. Sixty adult patients who underwent allo-HSCT were clustered in two groups: i) 22 (37%) spontaneously controlling HCMV reactivation (Controllers); ii) 38 (63%) developing clinically significant HCMV infection and receiving pre-emptive therapy (Non-Controllers). We analyzed several patient baseline characteristics, total/HCMV-specific CD4+ and CD8+ T-cell counts and their cytokine production (IFNγ, TNFα, IL2). Controllers presented a higher number of total/HCMV-specific CD4+ and CD8+ T-cells (P=0.001 and P=0.017 for total CD4+ and CD8+ T-cells respectively; P<0.001 for HCMV-specific T-cells) and a lower percentage of mono-functional IFNγ-producing HCMV-specific CD8+ T-cells (P=0.002). In bi-variable models, the prognostic impact of the percentage of mono-functional HCMV-specific CD8+ T-cells on treatment-free survival, adjusted for total/HCMVspecific CD4+ and CD8+ T-cells, was confirmed. An HCMV-seronegative donor was the only baseline characteristic associated with a clinically significant infection. These data, when confirmed by a larger prospective study, may provide information for guiding the personalized management of HCMV infection in allo-HSCT recipients.

Human cytomegalovirus-specific CD4+ and CD8+ T-cell reconstitution in adult allogeneic hematopoietic stem cell transplant recipients and immune control of viral infection.

BACKGROUND: Human cytomegalovirus infection is the most frequent viral complication in patients undergoing hematopoietic stem cell transplantation. We investigated the development of human cytomegalovirus-specific T cells in adult recipients of hematopoietic stem cell transplants. DESIGN AND METHODS: From May 2003 through October 2006 a total of 45 patients were monitored for human cytomegalovirus-specific T-cell reconstitution. Human cytomegalovirus-infected autologous dendritic cells were used as a stimulus to detect interferon-gamma-producing human cytomegalovirus-specific CD8(+) and CD4(+) T cells during the first year after transplantation. Interleukin-2 production by specific T cells was also determined. RESULTS: Human cytomegalovirus infection was detected in the blood of 39/45 patients at a median of 29 days after transplantation. Human cytomegalovirus-specific T-cell reconstitution followed reactivation of latent human cytomegalovirus infection at a median time of about 2 months after transplantation. Only donor human cytomegalovirus-seronegativity and bone marrow as a stem cell source were found to delay specific T-cell reconstitution significantly. Levels of three CD8(+) and one CD4(+) human cytomegalovirus-specific T-cells/microL blood had a positive predictive value of around 80% for identifying patients able to control human cytomegalovirus infection spontaneously. Five patients who received high doses of steroids for treatment of graft-versus-host disease developed human cytomegalovirus infection requiring pre-emptive treatment despite high levels of interferon-gamma-producing T cells in response to human cytomegalovirus. Specific interleukin-2 production was not detected in patients with human cytomegalovirus infection requiring treatment, while 90% of patients who spontaneously controlled human cytomegalovirus infection had T cells that produced interleukin-2 and interferon-gamma. CONCLUSIONS: Pre-transplant human cytomegalovirus infection of the recipient is a major factor driving human cytomegalovirus-specific immune reconstitution. Control of human cytomegalovirus infection likely requires the presence of both interferon-gamma and interleukin-2 producing T cells. Corticosteroid treatment may favor active viral replication even in patients with specific T cells.

Long-term study on symptomless human metapneumovirus infection in hematopoietic stem cell transplant recipients.

From October 2004 through October 2006 a study was performed to evaluate the prevalence of human Metapneumovirus (hMPV) infection in adult hematopoietic stem cell transplant (HSCT) recipients. Sequential nasopharyngeal aspirates (NPA) were collected independently from respiratory symptoms and evaluated for hMPV-RNA by polymerase chain reaction (PCR) and sequence analysis. Results indicate epidemiological and molecular differences between the 2004-2005 and 2005-2006 periods and that hMPV seems not to symptomatically affect HSCT patients or cause late respiratory sequelae. In addition, data collected suggest a hospital origin of hMPV infection in most HSCT patients during the 2004-2005 period.

Nephrotic syndrome after allogeneic hematopoietic stem cell transplantation as a late complication of chronic graft-versus-host disease.

BACKGROUND: This study aims to determine the incidence and outcome of nephrotic syndrome in patients who underwent allogeneic stem cell transplantation in a single center. METHODS: Records of 279 adult patients with hematological diseases who underwent allogeneic hematopoietic stem cell transplantation were analyzed to evaluate the incidence and outcome of nephrotic syndrome. The diagnosis of chronic graft-versus-host disease was based on clinical evidence with histological confirmation whenever possible. RESULTS: Of the 279 patients, 105 with a minimum follow-up of 100 days developed chronic graft-versus-host disease: six of these had nephrotic syndrome. The cumulative incidence of nephrotic syndrome was 8% at day +1,681. Patients grafted with peripheral blood stem cells had a higher probability of developing nephrotic syndrome than did those grafted with bone marrow: 24% and 3%, respectively. The pathological diagnosis was membranous glomerulonephritis in four patients, and minimal change disease in one; the diagnosis could not be histologically confirmed in the sixth patient. All patients had extensive chronic graft-versus-host disease and were receiving treatment with cyclosporine A and steroids (four patients). Response to immunosuppressive therapy with cyclosporine A and steroids was achieved in all patients at a median time of 12 weeks after transplantation. CONCLUSION: Patients with chronic graft-versus-host disease may be considered to be at risk of nephrotic syndrome: careful monitoring of renal function is advisable, particularly in patients receiving allogeneic peripheral stem cell grafts.