Infectious complications following nonmyeloablative allogeneic hematopoietic stem cell transplantation

Abstract: Nonmyeloablative hematopoietic stem cell transplantation (NST) has been explored in hematological malignancies and solid tumors in an attempt to minimize treatment‐related toxicity. Whether this approach is associated with reduced risk of infectious complications is unclear. The aim of the current study was to evaluate the infectious complications in a series of 32 consecutive adult patients who received NST at our institution. Peripheral blood stem cell grafts (n=30) or marrow grafts (n=2) were infused from human leukocyte antibody (HLA)‐matched sibling (n=30), partially matched related (n=1), or unrelated (n=1) donors. Neutropenia developed in two‐thirds of patients and lasted 16 days. Acute graft‐versus‐host disease (GVHD) grade II to IV was observed in 25% of patients, whereas 35% of patients had signs of extensive chronic GVHD. Twenty‐two patients (69%) had at least one significant infectious episode. Bacteremia occurred in 19% of patients (n=5 gram‐positive, n=1 gram‐negative microorganisms). Cytomegalovirus (CMV) infection was observed in 10 out of 28 (36%) evaluable patients; 4 of these had recurrent or persistent CMV antigenemia requiring a second‐line treatment, but eventually the viremia cleared. No patients experienced CMV disease. Fungal infections were documented in five (16%) patients, comprising invasive fungal infections in two cases and mucosal fungal infections in three. Four patients died of transplant‐related causes, and three of these died before day +100. Infection was considered the primary cause of death in one patient (pulmonary aspergillosis) and contributed to death in another two. The actuarial probability of nonrelapse mortality at 100 days was 10% (95% confidence interval, 3–26%). Our preliminary results suggest that NST is associated to a low incidence of bacteremia or fungal and viral infections. Whether these findings would translate into an improved overall survival needs to be confirmed in larger prospective studies.     

Immune reconstitution following hematopoietic stem-cell transplantation

Hematopoietic stem-cell transplantation is associated with a profound immune deficiency manifested as an increased propensity to develop infections and probably also malignancies. Innate immunity, including epithelial barriers and phagocytes, typically recovers within weeks after grafting, and B-cell counts and CD8 T-cell counts recover within months. CD4 T-cell counts are low for years, and their recovery is particularly slow in older patients with poor thymic function. Therapies to improve immune function include vaccinations, immunoglobulins for recurrent infections, cytokines, and antigen-specific donor lymphocyte infusions.     

Immune reconstitution and tolerance after allogeneic hematopoietic stem cell transplantation

We have evaluated recovery of CD56 positive and other cell types following allogeneic stem cell transplantation and have found that the recovery of CD56 positive cells was faster than other lymphoid cells after allogeneic stem cell transplantation, while the recovery of CD4 positive cells was markedly delayed. Chimerism analysis showed that mixed chimerism was often observed in younger (<30 years old) patients. Mixed chimerism in older (> or =30 years old) patients was associated with rejection and relapse, while this was not found in younger patients. Among the chimerism of various cell populations, donor-derived CD56-positive cells are important in early engraftment when determined in allogeneic nonmyeloablative stem cell transplantation (allo-NST), regardless of the proportion of donor-derived CD3-positive cells. Complementarity-determining region three (CDR3) size spectratyping in T-cell receptor (TCR) chain subfamilies (Vbeta) showed that high level of diversity in TCR Vbeta repertoire is important for a late rejection and skewed TCR Vbeta repertoire is correlated with the occurrence of graft-versus-host disease (GVHD) especially chronic GVHD. Expression of inhibitory natural killer (NK) cell receptors such as CD158b and CD94/NKG2A on peripheral CD3-negative and -positive cells were increased in parallel with GVHD. Interestingly, these cells appeared to control GVHD, while preserving graft-versus-leukemia (GVL) effect. Analysis of cytokine gene expression in peripheral blood mononuclear cells showed that type 1 helper T cells (Th1)-derived cytokines increased in severe GVHD, while Th2-derived cytokines such as IL-4, IL-10 and IL-13 increased in mild GVHD. These results indicate that Th2 cells suppress GVHD, although Th1 cells augment GVHD. Taken together, evaluation of immune reconstitution and tolerance in patients receiving allogeneic stem cell transplantation from the various viewpoints is essential and useful to obtain better clinical outcome.     

Major complications following hematopoietic stem cell transplantation

Tens of thousands of patients undergo hematopoietic stem cell transplantation (HSCT) annually, 15 to 40% of whom are admitted to the intensive care unit. Pulmonary complications are the most life threatening conditions that develop in HSCT recipients. Both infectious and noninfectious complications occur more frequently in allogeneic HSCT. The management of HSCT recipients requires knowledge of their immune status, appropriate diagnostic evaluation, and early treatment. During the pre-engraftment phase (0 to 30 days after transplant), the most prevalent pathogens causing infection are bacteria and Candida species and, if the neutropenia persists, Aspergillus species. The early post-engraftment phase (30 to 100 days) is characterized by cytomegalovirus (CMV), Pneumocystis jiroveci, and Aspergillus infections. During the late posttransplant phase (> 100 days), allogeneic HSCT recipients are at risk for CMV, community-acquired respiratory virus, and encapsulated bacterial infections. Antigen and polymerase chain reaction assays are important for the diagnosis of CMV and Aspergillus infections. Diffuse alveolar hemorrhage (DAH) and peri-engraftment respiratory distress syndrome occur in both allogeneic and autologous HSCT recipients, usually during the first 30 days. Bronchiolitis obliterans occurs exclusively in allogeneic HSCT recipients with graft versus host disease. Idiopathic pneumonia syndrome occurs at any time following transplant. Bronchoscopy is usually helpful for the diagnosis of the infectious pulmonary complications and DAH.     

Immune reconstitution after autologous hematopoietic stem cell transplantation in relation to underlying disease, type of high-dose therapy and infectious complications

BACKGROUND AND OBJECTIVES: Autologous peripheral stem cell transplantation (APSCT) is increasingly used for various hematologic malignancies and solid tumors. The objective of this study was to analyze the immune reconstitution after APSCT and see if there was any correlation with diagnosis, age, type of high-dose therapy, CD34(+) selection of the autograft and double vs single APSCT. DESIGN AND METHODS: Lymphocyte subset recovery was studied in 46 consecutive patients with hematologic malignancies and breast cancer, who underwent APSCT. Eleven patients with multiple myeloma received tandem autografts. Thirty-one patients were given total body irradiation (TBI) as part of the high-dose treatment. Eighteen patients received a CD34(+) selected graft. The percentage and absolute numbers of lymphocyte populations, T-cells (CD2(+), CD3(+)), B-cells (CD19(+)), NK cells (CD56(+ )CD3(-) and CD16(+)CD3(-)) and T-cell subpopulations (CD4(+), CD8(+), CD4(+)CD45RA(+), CD4(+ )CD45RO(+), CD4(+)DR(+), CD8(+ )CD45RO(+), CD8(+)DR(+)), were monitored with flow cytometry during the first year after APSCT. RESULTS: The total B-cell (CD19(+)) and T-cell (CD3(+)) counts were reconstituted to normal levels 2-4 months after APSCT. All patients had a low CD4/CD8 ratio during the observation period, related to both a low number of CD4(+) cells and elevated numbers of CD8(+) cells. The low number of CD4(+) cells was due to a persistently low level of naive CD4(+)CD45RA(+) cells. A high proportion of the CD8+ cells displayed a phenotype compatible with activated T-cells (CD8(+)DR(+)) up to 10 months after autografting. The number of NK cells (CD56(+)3(-) or CD16(+)3(-)) reached normal values within one month post-transplant. No single variable, such as diagnoses, age, TBI as part of the high-dose treatment, tandem autografting or CD34(+) selection of the graft, influenced the immune or hematopoietic reconstitution and no correlation with documented infectious complications was found. INTERPRETATION AND CONCLUSIONS: Despite heterogeneity of diseases, age, initial treatment and high-dose regimens, lymphocyte subset analysis did not reveal any differences in hematopoietic or immune reconstitution. All patients had a low CD4(+)/CD8(+) ratio during at least the first year post-transplant, caused by a persistent increase of CD8(+) lymphocytes and a constant reduction of CD4(+) lymphocytes, making the patients susceptible to infections for a prolonged period of time post-transplant.     

Low incidence of pulmonary complications following nonmyeloablative stem cell transplantation.

Bone marrow transplantation is associated with pulmonary opportunistic infections and immune-mediated pulmonary processes such as idiopathic pneumonia syndrome and bronchiolitis obliterans. The aim of the present study was to test the hypothesis that nonmyeloablative stem cell transplantation (NST) has less adverse effects on the lungs. A review was undertaken of the pulmonary complications occurring in 53 patients with various haematological malignancies, some of whom were considered high-risk patients with chemoresistant disease, who underwent fludarabine-based irradiation-free conditioning for NST performed between March 1996 and October 1998. All data related to transplant procedure, disease outcome, graft-versus-host disease (GVHD), chest imaging, microbial cultures and lung biopsies, were retrieved from information collected prospectively at the time of transplantation. The median follow-up period after transplantation was 45 months, with 35 patients surviving > 100 days. Approximately half of the patients displayed some form of GVHD, with 11% developing severe chronic GVHD. In 17 (32%) patients, the lungs were somehow adversely affected. Only two (3.8%) patients developed a clinical picture consistent with idiopathic pneumonia syndrome and none developed diffuse alveolar haemorrhage or bronchiolitis obliterans. Dose-reduced conditioning is associated with a low rate of pulmonary toxicity and side-effects. These findings may extend understanding of significant immune-mediated complications occurring after bone marrow transplantation.     

Immune reconstitution and implications for immunotherapy following haematopoietic stem cell transplantation

Recovery of a fully functional immune system is a slow and often incomplete process following allogeneic stem cell transplantation. While innate immunity reconstitutes quickly, adaptive B- and especially T-cell lymphopoeisis may be compromised for years following transplantation. In large part, these immune system deficits are due to the decrease, or even absence, of thymopoiesis following transplantation. Thereby, T-cell reconstitution initially relies upon expansion of mature donor T cells; a proliferation driven by high cytokine levels and the presence of allo-reactive antigens. This peripheral mechanism of T-cell generation may have important clinical consequences. By expanding tumouricidal T cells, it may provide a venue to enhance T-cellular immunotherapy following transplantation. Alternatively, decreased thymic function may impair long-term anti-tumour immunity and increase the likelihood of graft-versus-host disease.     

Immune reconstitution following hematopoietic progenitor cell transplantation: challenges for the future

Successful hematopoietic progenitor cell transplantation requires rapid and complete transfer of the donor hematopoietic and immune systems to the host. Whereas the uncontrolled transfer of a nontolerant donor immune system results in GVHD in many cases, strategies which diminish GVHD also diminish immune reconstitution. Thus, the reliable, rapid and safe transfer of immunity from donor to host remains a major challenge for the field. Advances in the understanding of the biology of immune reconstitution have elucidated that thymic-dependent immune reconstitution can restore global immunity, but is especially vulnerable to toxicities associated with transplant. Alternatively, homeostatic peripheral expansion can be exploited for targeted immunity toward pathogens and tumors, but is difficult to manipulate without exacerbating GVHD risk. New translatable strategies are needed to safely augment one or both of these pathways in the setting of allogeneic hematopoietic progenitor cell transplantation.     

Low incidence of infectious complications after nonmyeloablative compared with myeloablative allogeneic stem cell transplantation

Allogeneic stem cell transplantation (SCT) using a myeloablative (MA) conditioning regimen is limited to relatively young patients because of increased transplant-related mortality in elderly patients. Nonmyeloablative (NMA) conditioning regimens have been developed aiming to reduce transplant mortality. In this study, we set out to evaluate the post-transplant occurrence of infectious complications in recipients of grafts from human leukocyte antigen (HLA)-identical sibling donors treated with either NMA or MA conditioning regimens. Data of 78 consecutively treated patients were analyzed. An NMA conditioning regimen was used in 40 patients and an MA regimen in 38 patients. A significantly lower rate of episodes of febrile neutropenia (0% vs. 34%, P<0.01) and post-transplant Epstein-Barr virus reactivations (0% vs. 18%, P<0.05) was found in SCT recipients treated with an NMA conditioning regimen compared with an MA conditioning regimen. Furthermore, fewer invasive fungal infections (2% vs. 12%, not significant) were diagnosed in the NMA group. The incidence of cytomegalovirus (CMV) reactivations and bacterial infections was low in both groups (CMV reactivations: 13% in both groups; bacterial infections: 10% in the NMA group vs. 8% in the MA group), while CMV disease developed in only 1 patient. Overall, compared to our MA regimen, we found a very low rate of infectious complications after NMA SCT.     

Pulmonary complications following hematopoietic stem cell transplantation: diagnostic approaches

Pulmonary complications are a significant cause of morbidity and mortality in hematopoietic stem cell transplant recipients. Pulmonary infiltrates in such patients pose a major challenge for clinicians because of the wide differential diagnosis of infectious and noninfectious conditions. It is rare for the diagnosis to be made by chest radiograph, and commonly these patients will need further invasive and noninvasive studies to confirm the etiology of the pulmonary infiltrates. This review describes the role of the different diagnostic tools available to reach a diagnosis in a timely manner in this patient population.     

Immune restoration following hematopoietic stem cell transplantation: an evolving target

Hematopoietic stem cell transplantation (HSCT) is the definitive cure for many malignant and nonmalignant diseases. However, delays in immune reconstitution (IR) following HSCT significantly limit the success of transplantation and increase the risk for infection and disease relapse in the transplant recipient. Therefore, ways to measure and to manipulate immune recovery following HSCT are emerging and their success depends directly upon an enhanced understanding for the underlying mechanisms responsible for reconstituted immunity and hematopoiesis. Recent discoveries in the activation, function, and regulation of dendritic cell (DC), natural killer (NK) cell, and T-lymphocyte subtypes have been critical in developing immunotherapies used to prevent graft-versus-host disease and to enhance graft-versus-leukemia. For example, regulatory T cells that induce tolerance and NK receptor-tumor ligand disparities that result in tumor lysis are being used to minimize GVHD and tumor burden, respectively. Furthermore, expansion and modulation of immune effector cells are being used to augment hematopoietic and immune recovery and to decrease transplant-related toxicity in the transplant recipient. Specifically, DC expansion and incorporation into antitumor and anti-microbial vaccines is fast approaching application into clinical trials. This paper will review our current understanding for IR following HSCT and the novel ways in which to restore immune function and decrease transplant-related toxicity in the transplant recipient.     

Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation

It is unknown whether the severity, timing, and quality of graft-versus-host disease (GVHD) may be different after nonmyeloablative as compared with myeloablative hematopoietic stem cell transplantation (HSCT). Therefore, GVHD incidence, morbidity of skin, liver, and gut, requirements for immunosuppressive therapy, and survival were retrospectively analyzed in 44 patients who underwent nonablative HSCT and 52 who underwent ablative HSCT (median ages, 56 and 54 years, respectively). The nonablative transplantation regimen consisted of low-dose total body irradiation (TBI), preceded in some patients by fludarabine administration and followed in all patients by immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). Those who underwent myeloablative HSCT were prepared with different TBI- and non-TBI-containing regimens and received CSP plus methotrexate or MMF for GVHD prophylaxis. The cumulative incidence of grades II-IV acute GVHD was lower after nonablative transplantation (64% vs 85%; P =.001), but there were no differences in the cumulative incidence of chronic GVHD requiring treatment (73% vs 71%; P =.96). Nonablative transplantation was associated with the delayed initiation of steroid treatment for GVHD (0.95 months vs 3.0 months; P <.001) and with the use of fewer systemic immunosuppressants in the first 3 months after transplantation (P 相似文献   

Current status of hematopoietic stem cell transplantation after nonmyeloablative conditioning

PURPOSE OF REVIEW: Allogeneic hematopoietic stem cell transplantation was originally developed as a form of rescue from high-dose chemoradiotherapy, which is given both to eradicate malignancy and provide sufficient immunosuppression for allogeneic engraftment. However, it was observed that allogeneic immunocompetent cells transplanted with the stem cells, or arising from them, mediated therapeutic antitumor effects independent of the action of the high-dose therapy. This was termed a graft-versus-tumor effect. This has prompted the recent development of nonmyeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation that have opened the way to include elderly patients and those with comorbid conditions. RECENT FINDINGS: Recent retrospective studies comparing hematopoietic stem cell transplantation after myeloablative or nonmyeloablative regimens suggested that the use of nonmyeloablative conditioning might be associated with lower transplant-related toxicity, lower nonrelapse mortality, and at least similar intermediate-term progression-free survival. SUMMARY: Hematopoietic stem cell transplantation after nonmyeloablative conditioning might become the procedure of choice also for younger patients. Phase 3 studies are needed to determine outcomes for different diseases and age groups.     

Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation

The recent hypothesis that postnatal microglia are maintained independently of circulating monocytes by local precursors that colonize the brain before birth has relevant implications for the treatment of various neurological diseases, including lysosomal storage disorders (LSDs), for which hematopoietic cell transplantation (HCT) is applied to repopulate the recipient myeloid compartment, including microglia, with cells expressing the defective functional hydrolase. By studying wild-type and LSD mice at diverse time-points after HCT, we showed the occurrence of a short-term wave of brain infiltration by a fraction of the transplanted hematopoietic progenitors, independently from the administration of a preparatory regimen and from the presence of a disease state in the brain. However, only the use of a conditioning regimen capable of ablating functionally defined brain-resident myeloid precursors allowed turnover of microglia with the donor, mediated by local proliferation of early immigrants rather than entrance of mature cells from the circulation.