Donor immunization with pneumococcal conjugate vaccine and early protective antibody responses following allogeneic hematopoietic cell transplantation

Patients undergoing hematopoietic cell transplantation (HCT) are at increased risk for infections with Streptococcus pneumoniae and have long-lasting, impaired antibody responses to pneumococcal polysaccharide vaccines. We examined whether donor immunization with a heptavalent pneumococcal conjugate vaccine (PCV7) would elicit protective antibody responses to additional doses of vaccine administered early after transplantation. Ninety-six patients scheduled to receive an allogeneic hematopoietic cell transplant were randomized with their donors to receive either a dose of PCV7 vaccine or no vaccine before transplantation. All patients received PCV7 at 3 months, 6 months, and 12 months following transplantation, and serotype-specific antibody concentrations were determined after each dose. Following HCT, geometric mean antibody concentrations of patients in the immunized donor group were significantly higher for 5 of the 7 vaccine serotypes after one dose (P <.05) and for 4 of the 7 serotypes after 2 doses of vaccine (P <.03). Sixty-seven percent of patients in the immunized donor group had presumed protective IgG concentrations more than or equal to 0.50 microg/mL to all 7 serotypes following the first dose of vaccine compared to 36% in the unimmunized donor group (P =.05). After the third dose of vaccine, both groups had more than 60% of patients with concentrations at least 0.50 microg/mL to all vaccine serotypes. Donor immunization enhances early antibody responses of patients undergoing HCT to pneumococcal conjugate vaccine. A 3-dose schedule of PCV7 vaccine at 3, 6, and 12 months is immunogenic in these patients regardless of donor immunization.     

异基因造血干细胞移植后早期嵌合状态研究

目的:建立多重PCR扩增短串联重复序列(STR)结合毛细管电泳,定量检测异基因造血干细胞移植(Allo-HSCT)后受者体内供、受体来源血细胞嵌合率的方法及灵敏度。并探讨该方法的早期定量检测对Allo-HSCT后白血病早期复发进行干预的指导意义。方法:将2名健康成人静脉血分离单个核细胞,并按供、受体单个核细胞不同百分比制成模拟嵌合体标本并提取基因组DNA,用多重PCR扩增后,进行毛细管电泳,确定基因位点及相应峰面积。15例Allo-HSCT患者移植前采集供、受者外周血,移植后采集受者外周血,分别提取DNA,进行PCR扩增和毛细管电泳,确定STR基因位点及峰面积,计算混合样本中2单个样本DNA含量百分比及Al-lo-HSCT患者嵌合率。结果:①当混合样本中某一细胞比例为4%以上时,即可从电泳图中明确区分混合样本中该单个样本的基因型,且扩增前细胞百分率与扩增后两者峰面积比值呈直线相关;②所有患者在移植后2周内均出现供者来源的细胞,13例患者在术后30d内均达稳定嵌合。2例患者移植后出现不稳定混合嵌合状态或复发,经干预治疗后转为完全嵌合状态。结论:STR毛细管电泳PCR方法非常敏感,能应用于Allo-HSCT后早期嵌合体的定量检测。嵌合状态的早期定量检测对了解Allo-HSCT后的移植物的植入状态和指导早期干预治疗均有重要参考价值。     

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.     

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.     

地中海贫血儿童非亲缘造血干细胞移植后BK病毒相关出血性膀胱炎临床特征分析

［摘要］　目的　分析输血依赖型地中海贫血儿童非亲缘造血干细胞移植后BK病毒（BKV）相关出血性膀胱炎的发生率、临床特征和影响因素。方法　回顾性分析2018年2月至2021年2月厦门大学附属中山医院62例输血依赖型地中海贫血儿童接受非亲缘造血干细胞移植后的临床资料,包括患儿年龄、人类白细胞抗原（HLA）相合程度、急性移植物抗宿主病（aGVHD）和慢性移植物抗宿主病（cGVHD）的发生以及与BKV感染的关联性。结果　14例（22.58%,14/62）发生出血性膀胱炎,尿液中均检出BKV感染,BKV copies最高达10⁷/ml,出血性膀胱炎与BKV感染符合率为100.00%。在预处理方案相同情况下,非亲缘全相合、移植物抗宿主病（GVHD）是发生BKV相关出血性膀胱炎的影响因素。结论　BKV感染是输血依赖型地中海贫血儿童非亲缘造血干细胞移植后发生出血性膀胱炎的主要原因,非亲缘全相合、GVHD是发生BKV相关出血性膀胱炎的影响因素。     

NK-cell education is shaped by donor HLA genotype after unrelated allogeneic hematopoietic stem cell transplantation

The rules governing natural killer (NK)-cell education in the allogeneic environment created by unrelated hematopoietic stem-cell transplantation (HSCT) are still largely elusive, especially in an unrelated donor setting. NK-cell inhibitory receptors for self-human leukocyte antigen (HLA) play a central role in the acquisition or maintenance of NK-cell functional competence. Therefore, the responsiveness of different NK-cell subsets was assessed as a function of their expression or absence of expression of self-HLA-specific inhibitory receptors, in a large cohort (n = 60) of unrelated HSCT recipients. A fully effective NK-cell education process was achieved within the first year after allogeneic HSCT and lasted for at least 3 years thereafter. In addition, HLA-mismatched HSCT led to a stable education pattern that was determined by the donor's HLA ligands. These data suggest that the NK cell's education partner could be of hematopoietic rather than extrahematopoietic origin. This donor-ligand-driven NK-cell education model would suggest a sustained graft-versus-leukemia effect after HLA-mismatched HSCT.     

Comparison of long-term outcomes after allogeneic hematopoietic stem cell transplantation from matched sibling and unrelated donors

Long-term survivors of hematopoietic stem cell transplants remain at risk of potentially fatal complications that detract from life quality. Long-term morbidity and mortality were compared between matched recipient cohorts surviving 2 or more years and defined by donor type, HLA matched sibling donor (MSD) or volunteer unrelated donor (URD). Patients were previously entered into the prospective multicenter International Unrelated Search and Transplant Study. Thirty-nine centers provided data on 108 URD and 355 MSD recipients surviving more than 2 years. Long-term survival, performance status, chronic GvHD (c-GvHD), secondary malignancy, endocrine dysfunction, cataracts, bone necrosis and dental pathology were compared between cohorts. Twelve year survival was 77+/-5% for the MSD and 67+/-11% for the URD cohort (P=0.1). Late death occurred in 105 of 463 recipients alive at 2 years, 73 after 355 (21%) MSD and 32 after 108 (30%) URD transplants, P=0.10. Of 105 deaths, the cause was relapse in 60 and unrelated to relapse in 45 cases. Cumulative incidence of extensive c-GvHD (P=0.002), cataracts (P=0.02) and bone necrosis (P=0.02) was higher after URD transplants. No long-term difference in endocrine dysfunction, secondary malignancy and major dental pathology was detected. This landmark study will assist physicians counseling patients pre-transplant and with their long-term care post transplant.     

Comparable outcomes between unrelated and related donors after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation in patients with high-risk multiple myeloma

The purpose of this study was to assess the results of allogeneic stem cell transplantation (allo-SCT) after reduced-intensity conditioning (RIC) from matched related donors (MRD) and unrelated donors (URD) in 40 patients with high-risk multiple myeloma (MM) in a single centre. Seventeen (43%) (Group 1) and 23 patients (57%) (Group 2) had URD and MRD, respectively. Thirty-nine patients (98%) received one or more autologous transplantation. The median follow-up was 22 months (1-49). None of our patient experienced a graft rejection. The cumulative incidence of grade II-IV acute GVHD was higher (47%) for the URD vs. (17%) for the MRD (P = 0.092). The cumulative incidence of chronic GVHD was no different between the two groups (24% vs. 30%, respectively). At 2 yr, the TRM probabilities were lower in the unrelated group 12% vs. 22% in the related group (P = 0.4). Also at 2 yrs, for patients receiving unrelated transplantation overall and progression-free survivals, 59% and 42%, respectively compared to patients with related donor transplantation, 66% and 44% (P = 0.241). In conclusion, these results suggest that URD in MM is feasible. The small number of patients with URD emphasizes the need to delineate indications and perform prospective protocols.     

Factors affecting antibody levels after allogeneic hematopoietic cell transplantation

To obtain insight into the mechanism(s) of posttransplantation humoral immunodeficiency, we evaluated factors affecting serum antibody levels against polio, tetanus, Haemophilus influenzae, and Streptococcus pneumoniae in 87 patients. Patients with hematologic malignancies were randomized to receive marrow versus blood stem cells, which contain approximately 10 times more lymphocytes than marrow. Blood stem cell recipients did not have higher antibody levels than marrow recipients. Recipient pretransplantation antibody levels were correlated with the posttransplantation levels, especially in the first 6 months after transplantation when the correlation coefficients typically exceeded 0.6. Donor pretransplantation antibody levels had less of a correlation with posttransplantation levels in the recipient. Patient or donor age, total body irradiation, and graft-versus-host disease or its treatment appeared to have no effect. In conclusion, antibody levels in the first year after transplantation are affected primarily by pretransplantation antibody levels in the recipient and, to a lesser degree, in the donor. These findings suggest that immunization of the recipient and the donor before transplantation may be more effective in improving antibody immunity after transplantation than manipulating graft-versus-host disease, changing conditioning, or increasing the number of lymphocytes in the graft.     

Non-atopic IgE and eosinophil cationic protein after allogeneic hematopoietic stem cell transplantation in children

Allogeneic hematopoietic stem cell transplantation (HSCT) in childhood is associated with severe pulmonary complications, but the pathophysiologic mechanisms remain unclear. Our aim was to evaluate the association of total and specific IgE, eosinophil cationic protein (ECP) and eosinophilia in HSCT recipients with pulmonary complications. We prospectively measured total and specific serum IgE, eosinophils, and ECP before and 28, 100, and 180 days after HSCT. We included 30 children (age 2–17 years) undergoing HSCT. Nine patients had a history of previous atopy without being associated with pulmonary complications after HSCT until day +360. Specific IgE levels showed a decline after HSCT, associated with the absence of allergy symptoms, suggesting a reduction of atopy. Elevated total serum IgE levels occurred in seven patients on day +28 after HSCT. This elevation did not coincide with allergy symptoms. ECP showed no correlation with total allergy symptoms, eosinophilia, IgE levels, or pulmonary complications. There was a significant correlation (p = 0.0367) between ECP levels on day +28 and concurrent acute graft-versus-host disease (GvHD). Non-atopic serum ECP and IgE levels are elevated on day +28 after HSCT in children, with ECP showing a potential relation to acute GvHD.     

Acute eosinophilic pneumonia after allogeneic hematopoietic stem cell transplantation

A 55-year old woman with multiple myeloma was treated with hematopoietic stem cell transplantation (HSCT). She developed cutaneous and hepatic graft-vs-host disease (GVHD). Sixty-five days after HSCT, acute respiratory failure occurred. A thoracic computed tomography scan showed bilateral patchy infiltrates. Bronchoalveolar lavage revealed 40% eosinophils on differential cell count with no infectious pathogens. These findings were in favor of acute eosinophilic pneumonia. High-dose steroid treatment was started, which had a rapid and lasting favorable course. After HSCT, clinicians should be aware that acute eosinophilic pneumonia mimics infectious pneumonitis and can be associated with GVHD.     

Human metapneumovirus infection after allogeneic hematopoietic stem cell transplantation

Background

The clinical characteristics of human metapneumovirus (hMPV)-associated lower respiratory tract infection (LRTI) after allogeneic hematopoietic stem cell transplantation (HSCT) is not well described. We describe the clinical course in eight HSCT recipients suffering from hMPV infection.

Methods

We prospectively included all patients with hMPV-associated LRTI after allogeneic HSCT during a period of 1?year. hMPV was diagnosed by multiplex polymerase chain reaction (PCR) from bronchoalveolar lavage (BAL).

Results

Eight patients with hMPV-associated LRTI were identified from 93 BAL samples. Three of the eight patients had co-infections with other pathogens. The median age of the patients was 45?years [interquartile range (IQR) 36.8?C53.5], the median time posttransplant was 473?days (IQR 251?C1,165), 5/8 patients had chronic graft-versus-host disease (cGvHD), and 6/8 patients received immunosuppression. Chest computed tomography (CT) scanning showed a ground-glass pattern in 7/8 patients. Seven of eight patients required hospitalization due to severe symptoms and hypoxemia. All were treated with intravenous immunoglobulin (IVIG), which was combined with oral ribavirin in six patients. The mortality rate was 12.5?% (1/8).

Conclusions

hMPV-associated LRTI in allogeneic HSCT recipients are not uncommon and present with unspecific respiratory symptoms, ground-glass pattern in CT scanning, and co-infection.     

CD25单抗在无血缘关系造血干细胞移植中的作用研究

目的探讨CD25单抗在无血缘关系造血干细胞移植(UHSCT)中对干细胞植入和移植物抗宿主病(GVHD)的作用。方法27例UHCST中,移植后1、4 d给予CD25单抗1 mg/kg。结果27例中,除1例早期死亡外,26例患者造血全部重建。17例发生急性GVHD,其中Ⅱ度以上急性GVHD 6例(23%)。复发3例,严重感染3例。26例可评价患者中,19例无病生存(73%)。结论CD25单抗在UHSCT中对保证干细胞植入和预防GVHD有肯定的作用,白血病复发并不增加。此研究为UHCST和HLA不合的造血干细胞移植提供一个可选择的途径。