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.     

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.     

The spectrum of noninfectious pulmonary complications following hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is an established treatment for a variety of malignant and nonmalignant conditions. Pulmonary complications, infectious and noninfectious, are a major cause of morbidity and mortality in these patients. The recent advances in prophylaxis and treatment of infectious complications increased the significance of noninfectious pulmonary conditions. Acute lung injury due to diffuse alveolar hemorrhage or idiopathic pneumonia syndrome are the main acute complications, while bronchiolitis obliterans remains the most challenging pulmonary complications facing clinicians who are taking care of HSCT recipients. There are other noninfectious pulmonary complications following HSCT that are less frequent. This report provides a clinical update of the incidence, risk factors, pathogenesis, clinical characteristics and management of the main noninfectious pulmonary complications following HSCT.     

Late complications after hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) offers the opportunity for cure to patients with leukemia, lymphoma and severe non-malignant diseases. More than 40,000 HSCTs are performed annually worldwide. Therefore, the number of long-term survivors, free of the disease for which they were transplanted is continuously increasing. Despite the improved prognosis of HSCT, long-term outcome may be impaired by transplant-associated morbidity and mortality. Long-term survivors can present a variety of malignant and non-malignant complications, impairing physical and psychological performance, normal integration in family and social life, and quality of life. Conditioning regimens, particularly when including total-body irradiation as well as graft-versus-host disease, play a key role in the development of late effects. However, with increasing time since transplantation new types of late effects may emerge. Awareness on long-term effects after HSCT is crucial to provide adapted pretransplant counseling, and recommendations for post-transplant screening, prevention and early treatment.     

造血干细胞移植的肺部并发症

造血干细胞移植(HSCT)目前已广泛应用于临床,为血液系统肿瘤及实体肿瘤,免疫性及遗传性疾病患者带来了生存的希望.但HSCT术后肺部并发症时常发生.本文就HSCT术后可能发生的肺部并发症的发病因素、诊断及治疗方面作一综述.     

Immune reconstitution and early infectious complications following nonmyeloablative hematopoietic stem cell transplantation

Non-myeloablative stem cell transplantation (NMT) has been increasingly used in compromised patients who would otherwise have been unable to undergo allotransplant. There is little understanding of the kinetics of immune reconstitution and its influence on infective complications following NMT. The aim of present study was to evaluate lymphocyte subset reconstitution over the first 12 months post-transplant in 15 adult patients receiving NMT with comparison to that of 30 patients grafted with a conventional hemopoietic stem cell transplantation (HSCT). NMT recipients were conditioned with fludarabine-based conditioning regimens. Peripheral blood stem cell (PBSC) was the source of stem cells in 13 NMT recipients and in 24 conventional HSCT recipients. Absolute numbers of helper (CD4+) T cells, naive (CD4+ CD45RA+) and memory (CD4+ CD45RO+) T cells as well as suppressor (CD8+) T cells, CD19+ B cells and NK cells were comparable in the two groups at all time points after transplantation. A median value of 200 CD4+ T cells/microl was achieved at 2 months post-transplant by the NMT and HSCT recipients. The CD4:CD8 ratio remained severely depressed throughout the study period. Almost all CD4+ lymphocytes expressed CD45RO antigen in the both groups of patients B lymphocytes showed low counts throughout the entire study period in both groups. Bacteremia and CMV antigenemia occurred respectively in 13 and 36% of the patients in the NMT group and in 15 and 39% of the patients in the HSCT group. Our preliminary data indicate that patients receiving a NMT have a lymphocyte reconstitution similar to that observed in patients who received a conventional HSCT. The incidence of bacteremia and CMV infection were not significantly different between the groups. Nevertheless, due to the small sample size, these results should be considered suggestive rather than definitive.     

Endocrine complications of hematopoietic stem cell transplantation.

Advances in hematopoietic stem cell transplantation (HSCT) have resulted in broader indications for this therapeutic modality in both malignant diseases and nonmalignant conditions. This article focuses on the late endocrine abnormalities that are most commonly observed following successful HSCT, with a special emphasis on pediatric HSCT recipients, for whom long-term follow-up data are increasingly available.     

Pulmonary complications after allogeneic hematopoietic stem cell transplantation

We investigated the occurrence of pulmonary complications in patients who underwent allogeneic hematopoietic stem cell transplantation at our institution. Pulmonary complications were observed in 12 out of 60 patients. Interstitial pneumonia developed in 12 cases: 7 idiopathic, 2 cytomegalovirus-associated, 1 P. carinii, 1 HSV, and 1 HHV-6-associated. HSV- and HHV-6-associated pneumonias were exhibited 100 days after transplantation. PCR analysis was diagnostically useful for detection of viral DNA in bronchial alveolar lavage fluid. Respiratory disease with airway obstruction was observed in 4 patients with chronic graft-versus-host disease, and all 4 had a history of interstitial pneumonia. Three patients died of respiratory failure. Mycobacicrium avium complex was detected in 2. Exacerbation of respiratory failure may be associated with mycobacterial infection.     

Infections following hematopoietic stem cell transplantation.

Numerous advances have been made in the management of infection in HSCT recipients. With increasing knowledge the authors are able to prevent several serious infections from occurring, and reduce the severity of infections once they occur. Despite these advances, several previously unrecognized pathogens have emerged and pose risks to this population. Ongoing surveillance and reporting of atypical infections are warranted. Transplant and infectious disease clinicians alike must be vigilant to the shifts in infectious syndromes as a consequence of various prophylaxis and preemptive strategies, and be ready to modify empiric strategies to meet the changing microbiologic milieu. As we increase our understanding of the HSCT process, and use the immune system rather than relying on high-dose chemotherapy, the authors are likely to reduce toxicities and improve patient outcomes.     

ABO主血型不合的非清髓性异基因造血干细胞移植2例

目的：观察ABO主血型不合的非清髓性异基因造血于细胞移植(NST)治疗2例慢性髓细胞自血病(CML)患者的耐受性、疗效及其ABO血型转变。方法：采用氟达拉宾、白消安、抗人淋巴细胞球蛋白和骁悉的非清髓性预处理，异基因造血干细胞移植，移植后2周开始供者淋巴细胞输注(DLI)，每例5～6次；应用STR—PCR及染色体核型分析检测供者嵌合体；每半月～1个月监测血型。结果：2例患者移植后造血恢复较快，骨髓细胞混合嵌合体形成分别为 15～ 23d，完全嵌合体形成为 23～ 43d；例1血型为O型，于 388d血型转变为供者血型A型，移植后6个月细胞遗传学水平复发．DLI后Ph染色体转阴，但发生皮肤慢性移植物抗宿主病。例2于 45d血型由A型转变为供者血型AB型，移植后5个月与1年2次出现纯红细胞再生障碍性贫血表现，均用DLI后红系造血恢复，Ph染色体转阴。结论：ABO主血型不合的NST易出现红系造血延迟及纯红细胞再生障碍性贫血，DLI具有促进供者嵌合体形成，防治复发效应。     

Antigen-specific immunity following hematopoietic stem cell transplantation

Most studies evaluating immune reconstitution following hematopoietic stem cell transplantation (HSCT) have focused on immunophenotypic analysis and the capacity of the immune system to respond to mitogenic stimulation. However, protection against infectious pathogens and potentially anti-tumor responses correlate with the presence of antigen-specific immunity, not the immunophenotypic presence of T lymphocytes. Antigen-specific T lymphocytes present after HSCT can be derived from donor antigen-specific T lymphocytes present in the transplantation inoculum if it is not T cell depleted. Furthermore, the naive T lymphocytes contained in the HSCT inoculum have the potential to develop into antigen-specific T lymphocytes. If the transplantation inoculum is T cell depleted, then all antigen-specific T lymphocytes will have to be derived from the newly engrafted hematopoietic stem cells following their differentiation through the recipient thymus. Thus, defects in thymopoiesis will result in delays or the absence of naive T lymphocytes and ultimately defects in antigen-specific immunity.     

Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation

Recognition and management of gastrointestinal and hepatic complications of hematopoietic stem cell transplantation has gained increasing importance as indications and techniques of transplantation have expanded in the last few years. The transplant recipient is at risk for several complications including conditioning chemotherapy related toxicities, infections, bleeding, sinusoidal obstruction syndrome, acute and chronic graft-versus-host disease (GVHD) as well as other long-term problems. The severity and the incidence of many complications have improved in the past several years as the intensity of conditioning regimens has diminished and better supportive care and GVHD prevention strategies have been implemented. Transplant clinicians, however, continue to be challenged with problems arising from human leukocyte antigen-mismatched and unrelated donor transplants, expanding transplant indications and age-limit. This review describes the most commonly seen transplant related complications, focusing on their pathogenesis, differential diagnosis and management.     

Allogeneic hematopoietic stem cell transplantation: complications and results

Acute complications such as veno-occlusive disease of the liver, acute and chronic graft-vs-host disease (GVHD), and infectious conditions remain major obstacles for the success of allogeneic hematopoietic stem cell transplantation (HSCT). Progress in allogeneic HSCT depends on several factors, including the adequate prevention and management of associated complications, advances in the conventional management of diseases currently treated with allogeneic HSCT, expansion of the donor pool, selective control of GVHD, development of more effective preparative regimens to eradicate the neoplastic cell population, characterization of a new generation of hematopoietic growth factors and cytokines, and development of newer techniques for ex vivo manipulation of stem cells. Hematopoietic growth factor-mobilized donor progenitor cells collected from peripheral blood have been shown to be associated with rapid hematopoietic engraftment without an increase in the incidence of acute GVHD compared with allogeneic bone marrow transplantation. Implementation of this approach will enhance donor acceptance, eliminate the risk of general anesthesia, decrease cost, and reduce the risk of infectious complications by reducing the duration of neutropenia. Nonmyeloablative allogeneic stem cell transplantation represents a novel treatment approach that may lead to reduced toxic effects and extended use of this treatment in older patients and in those with malignant and nonmalignant disorders. However, GVHD and disease recurrence remain a challenge. Promising results have been reported in patients with refractory hematologic malignancies and in metastatic renal cell cancer. Because late complications are commonly encountered in patients receiving allogeneic HSCT, lifelong observation is needed.     

Hepatic veno-occlusive disease following hematopoietic stem cell transplantation

The clinical syndrome of hepatic veno-occlusive disease (VOD) is one of the most common and serious complications following hematopoietic stem cell transplantation (SCT). High-dose chemotherapy or chemoradiation therapy in the context of autologous and allogeneic SCT can profoundly injure sinusoidal endothelium and hepatocytes within zone 3 of the liver acinus, producing the clinical syndrome of hepatomegaly and/or right upper quadrant pain with jaundice and fluid retention, typically manifest as weight gain. The incidence is variable and ranges from 10 to 60%. Mild to moderate disease is characterized by eventual complete resolution. In contrast, severe disease frequently results in multiorgan failure and death. The purpose of this review is to discuss the pathophysiology and clinical features of VOD, and the current status and future directions of research for both prevention and treatment.