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.     

T-cell therapy after hematopoietic stem cell transplantation

PURPOSE OF REVIEW: The separation of graft versus host disease from graft versus leukaemia reactivity and the reconstitution of immunity to infectious agents are the main goals of T-cell therapy after allogeneic hematopoietic stem cell transplantation. We describe how an improved understanding of T-cell mediated graft versus leukemia and of antiviral responses is providing effective approaches to T-cell immunotherapy. RECENT FINDINGS: Over the past several years, researchers have developed strategies to eliminate alloreactive T cells from the graft, to expand naturally occurring regulatory T cells, and to select and expand antigen-specific T cells specific for tumor-associated or viral antigens. Incorporation of suicide genes allows the selective destruction of allodepleted or antigen-selected cells after infusion, further increasing the safety and potential applicability of these approaches. SUMMARY: In this review we describe current strategies for adoptive T-cell immunotherapy after hematopoietic stem cell transplantation.     

Secondary malignancies after hematopoietic stem cell transplantation

Advances in the field of hematopoietic stem cell transplantation have led to an increasing number of cures of malignant and non-malignant diseases with this therapeutic approach. Long-term survivorship may, however, be associated with secondary malignancies, the result of a complex interaction of treatment-, recipient- and immunosuppression-related factors. Furthermore, the increasing use of donors other than human leukocyte antigen-identical siblings is associated with more intense immunosuppression, delayed immune recovery and higher incidence of B-cell post-transplantation lymphoproliferative disorders. Here, we review the incidence and the risk factors associated with these complications of hematopoietic stem cell transplants.     

Secondary malignancies after hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) offers patients with malignant and nonmalignant diseases the oportunity to pursue life-prolonging therapy. The number of survivors after successful HSCT is continually increasing. However, HSCT can induce tissue and organ damage that occurs not only "on treatment" , but long after completing therapy. Secondary malignancies belong to serious late complications after HSCT. A significant association of certain risk factors with increased likelihood of secondary malignancies after HSCT has been published over the last ten years. Better knowledge of pathogenesis of these complications, their early identification and treatment may contribute to better health outcomes of allogeneic and autologous hematopoietic stem cell transplantation recipients. We review here the incidence and risk factors of secondary malignancies after hematopoietic stem cell transplantation.     

Cytomegalovirus appendicitis after hematopoietic stem cell transplantation

We present the case of a young man with acute lymphoblastic leukemia who developed cytomegalovirus (CMV) appendicitis after receiving alemtuzumab for acute refractory graft‐versus‐host disease after allogeneic hematopoietic stem cell transplantation (HSCT). CMV appendicitis is a rare complication; and we are reporting the first case to our knowledge of CMV appendicitis following HSCT. Our case highlights the importance of recognition of CMV viral reactivation following the use of alemtuzumab. Using a preemptive strategy of checking CMV PCR, with initiation of early effective treatment on detection of CMV replication, may be appropriate following use of alemtuzumab in hematologic malignancies in patients after 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.     

Toxoplasmosis after hematopoietic stem cell transplantation.

Forty-one cases of toxoplasmosis were diagnosed in 15 European transplantation centers in patients who had undergone allogeneic hematopoietic stem cell transplantation (HSCT) from 1994 through 1998. Most patients (39 [94%]) were seropositive for Toxoplasma gondii before they underwent transplantation, and 30 (73%) had developed moderate to severe acute graft-versus-host disease before they developed toxoplasmosis. Thirty-five (85%) patients had Toxoplasma disease with evidence of organ involvement, whereas 6 (15%) patients had Toxoplasma infection, as defined by fever and a positive polymerase chain reaction (PCR) finding for T. gondii in blood. Nine patients were diagnosed at autopsy. Thirty patients (73%) had not received antimicrobial prophylaxis with anti-Toxoplasma activity after undergoing transplantation. The median day of onset of disease after HSCT was 64. Twenty-two (63%) patients died from toxoplasmosis, and 23 (66%) received adequate anti-Toxoplasma therapy for > or =3 days. Among these 23 patients, 11 (48%) showed a complete response and 3 (13%) showed improvement. In univariate and multivariate analyses, having received adequate therapy and experiencing late infection (>63 days after HSCT) were associated with a lower risk of dying from toxoplasmosis. Toxoplasmosis after HSCT is a severe infection with a high mortality rate even when diagnosed soon after HSCT, and PCR may help establish the diagnosis earlier.     

CMV infections after hematopoietic stem cell transplantation

CMV can cause disease in several different organs after SCT. Seropositivity remains a major risk factor for TRM in unrelated SCT patients. In a study using the EBMT registry, CMV-seropositive patients receiving seropositive unrelated donor grafts had improved survival and reduced TRM compared with those receiving seronegative grafts, and a similar result was found in a single center study. Preventive measures can be divided into prevention of a primary infection or recurrence of CMV (prophylaxis) or prevention of development of disease when a reactivation has occurred (preemptive therapy). The standard therapy for CMV pneumonia has been i.v. ganciclovir combined with high-dose Ig, but this standard has never been evaluated in a controlled study and more recent studies have questioned whether the addition of Ig improves outcome.     

Fungal infections after hematopoietic stem cell transplantation

Invasive fungal infections (IFIs) are associated with considerable morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Despite that epidemiology of IFIs has changed notably by evolution in transplantation procedures as well as preventative strategies, the attributable mortality still remains high, mainly because of delayed initiation of treatment due to its diagnostic difficulty. Hence high-resolution computed tomography and non-culture based adjunctive diagnostic tests such as enzyme-linked immunosorbent assay for galactomannan and (1,3)-β-d-glucan have been incorporated into clinical practice, and global antifungal prophylaxis has been applied particularly to high-risk patients. Newer mold-active agents with higher efficacy and lower toxicity are currently being introduced as prophylaxis, and the combination of these agents are being evaluated as salvage therapy. This review summarizes recent advances in the diagnosis and management of IFIs in HSCT recipients. Further improvement of clinical outcome will be achieved by optimizing diagnostic, prophylactic and therapeutic approach based on individual patient’s risk and situation.     

Non-infectious bronchiolitis as an early pulmonary complication of hematopoietic stem cell transplantation

Pulmonary complications occur in up to 60% of patients after hematopoietic stem cell transplantation (HSCT), causing significant morbidity and mortality. Among them, non-infectious bronchiolitis is considered a late complication in the form of bronchiolitis obliterans. We report a patient who developed non-infectious bronchiolitis within four weeks after undergoing HSCT for biphenotypic leukemia. Chest CT revealed centrilobular nodules that were reminiscent of diffuse panbronchiolitis, and lymphocytic bronchiolitis was confirmed by biopsy. Infection and bronchiolitis obliterans were ruled out, and the bronchiolitis resolved when leukemia relapsed. This case suggests that bronchiolitis may be another early, non-infectious pulmonary complication of HSCT.     

Treatment of late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: the role of corticosteroids

We aimed to evaluate the treatments, particularly the role of corticosteroids, in patients with late-onset hemorrhagic cystitis (LOHC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). One hundred and sixty-three consecutive patients who underwent non-T-cell-depleted allo-HSCT and met the criterion of LOHC after allo-HSCT were enrolled in this study. The median time from allo-HSCT to the occurrence of LOHC was 29 (range, 4–155) days. Pathogens identified in blood and/or urine samples from 143 patients were mostly viruses. All of the patients with LOHC received intravenous fluid hydration, alkalization, and forced diuresis, of which 2 patients achieved complete remission (CR) after these treatments. The remaining 161 patients received anti-infection therapies and 71 achieved CR after the therapies. Corticosteroids were additionally applied to 83 out of 90 patients who did not achieve CR after anti-infection therapies, and 88.0% (n?=?73) of them showed a grade 3 to 4 LOHC at the beginning of corticosteroid therapy. Thirty-five patients showed an immediate response (CR or downgraded at least one grade) within 1 week after the beginning of the corticosteroid therapy. Sixty-four patients (77.1%) achieved CR after corticosteroid therapy, and the median period from the beginning of corticosteroid therapy to CR was 17 days. Thus, we observed that viruses were the most common pathogens in LOHC after allo-HSCT and that anti-infection therapies were critical. For patients not showing a satisfactory response to anti-infection therapies, additional corticosteroid therapy may help to achieve CR.     

Chronic lung disease after hematopoietic stem cell transplantation

Tens of thousands of patients undergo hematopoietic stem cell transplantation (HSCT) each year, mainly for hematologic disorders. In addition to the underlying diseases, the chemotherapy and radiation therapy that HSCT recipients receive can result in damage to multiple organ systems. Pulmonary complications develop in 30% to 60% of HSCT recipients. With the widespread use of prophylaxis for certain infections, the spectrum of pulmonary complications after HSCT has shifted from more infectious to noninfectious complications. This article reviews some of the noninfectious, chronic pulmonary complications.     

Varicella-zoster virus infection after hematopoietic stem cell transplantation

Of 264 patients aged 15 years or more who underwent hematopoietic stem cell transplantation between 1989 and September 1998 at the Tokyo Metropolitan Komagome Hospital, 47 were infected by the varicella-zoster virus (VZV). In 2 patients, visceral disease preceded cutaneous dissemination. One of these patients exhibited gastrointestinal symptoms followed by disseminated skin rash 6 days later. In the other patient, epigastralgia developed and was followed by seizures secondary to meningitis; the appearance of a skin rash 5 days after these initial symptoms yielded the diagnosis. Early diagnosis and treatment of VZV infection are important, especially for patients who present with visceral symptoms suspected to be due to VZV.     

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.     

Heart failure after allogeneic hematopoietic stem cell transplantation

Background

Heart failure (HF) occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is rare but severe. We examine the role of pre-HSCT therapeutic exposures, conditioning regimens, pre-HSCT comorbidities, severe transplant-related complications, and post-HSCT cardiovascular risk factors in the development of heart failure after allo-HSCT.

Methods

A nested case-control study was designed. Cases with HF and controls matched for age, year of allo-HSCT, and length of follow-up were identified from a cohort of 2455 patients who underwent allo-HSCT between 2000 and 2011 for hematologic malignancies.

Results

Forty-two patients suffered from HF; mean age at presentation was 35 years (± 14 years) and mean time to presentation was 5 months (± 9 months) post-HSCT. The number of pre-HSCT cycles of chemotherapy was significantly greater (7 vs. 5 courses, P = 0.023). Cases were significantly more likely to have severe acute GVHD (≥ grade III), hemorrhagic cystitis (≥ grade 2), and multiple severe transplant-related complications compared with controls (42.9% vs. 20.4%, P = 0.008). Multivariate analysis revealed that pre-HSCT cycles of chemotherapy of ≥ 5 courses (OR = 3.5, P = 0.003) and two or more severe transplant-related complications (OR = 3.6, P = 0.003) were independently associated with HF.

Conclusions

These results identify the individuals who are at higher risk of developing HF after allo-HSCT. We should pay more attention to these patients and more active management would be reasonable.     

Pulmonary function after allogeneic hematopoietic stem cell transplantation

This study was undertaken to identify the factors influencing pulmonary function in patients who underwent hematopoietic stem cell transplantation (HCT). Pulmonary function tests were evaluated before and after HCT in 51 adult patients who underwent HCT between 1993 and 1998. The patients with hematologic malignancies were given total body irradiation. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A and short-term methotrexate. Six patients suffered from acute GVHD above grade II and 27 patients suffered from chronic GVHD. The post-transplant % diffusing capacity (%DLco) 100 days after HCT was significantly lower than pretransplant values (82 +/- 21% versus 71 +/- 15%, p < 0.01). The %DLco at 100 days was significantly lower in patients with chronic GVHD than in patients without chronic GVHD (66 +/- 16% versus 77 +/- 9%, p < 0.05). These findings suggested chronic GVHD is related to the decreased %DLco values observed 100 days after HCT.     

High-grade cytomegalovirus antigenemia after hematopoietic stem cell transplantation

Clinical impact of high-grade (HG) cytomegalovirus (CMV) antigenemia after hematopoietic stem cell transplantation has not been clarified. Therefore, in order to investigate the risk factors and outcome for HG-CMV antigenemia, we retrospectively analyzed the records of 154 Japanese adult patients who underwent allogeneic hematopoietic stem cell transplantation for the first time from 1995 to 2002 at the University of Tokyo Hospital. Among 107 patients who developed positive CMV antigenemia at any level, 74 received risk-adapted preemptive therapy with ganciclovir (GCV), and 17 of these developed HG-antigenemia defined as > or = 50 positive cells per two slides. The use of systemic corticosteroids at > or = 0.5 mg/kg/day at the initiation of GCV was identified as an independent significant risk factor for HG-antigenemia. Seven of the 17 HG-antigenemia patients developed CMV disease, with a cumulative incidence of 49.5%, which was significantly higher than that in the low-grade antigenemia patients (4%, P<0.001). However, overall survival was almost equivalent in the two groups. In conclusion, the development of HG-antigenemia appeared to depend on the profound immune suppression of the recipient. Although CMV disease frequently developed in HG-antigenemia patients, antiviral therapy could prevent a fatal outcome.     

Autoimmune thyroid dysfunction after hematopoietic stem cell transplantation

Autoimmune thyroid disease (AITD) may occur in patients after hematopoietic stem cell transplantation (HSCT). In all, 10 cases of AITD (seven allogeneic and three autologous HSCT) were diagnosed among 721 HSCT recipients, including two patients with sequential hyper- and hypothyroidism. The 5-year actuarial rates for AITD after allogeneic and autologous HSCT were 2.9 and 4%, respectively. Significant risk factors included HSCT for chronic myeloid leukemia, the HLA B46 and DR9 loci and the A2B46DR9 haplotype, while female donors showed trend to significance. On multivariate analysis, only female donors and HLA DR9 remained significant. For autologous HSCT, the associations with HLA B46 and DR9 were also significant. Only three donors had a family history of AITD. A review of other reported cases confirmed the predominance of female donors, although the other associations including graft-versus-host disease, familial AITD and other autoimmune phenomena might be related to reporting bias. Since the actuarial incidence of AITD from female donors with predisposing HLA alleles may be over 30%, susceptible recipients should be carefully monitored. Owing to the small number of reported cases and different HLA associations with AITD in different populations, our observations await confirmatory data from other registries.