Successful bone marrow transplantation and treatment of BCG infection in two patients with severe combined immunodeficiency

We report successful bone marrow transplantation (BMT) in two patients with severe combined immunodeficiency (SCID), who had developed BCG infection following neonatal vaccination. Patient 1 had Omenn Syndrome, associated with hypertrophic nonobstructive cardiomyopathy. Patient 2 had SCID due to adenosine deaminase deficiency. This communication demonstrates that with appropriate anti-mycobacterial cover, immunological reconstitution together with full recovery from BCG infection can be achieved by BMT. As demonstrated by persistant negative Mantoux tests, specific cell-mediated immunity to BCG was not acquired following BMT. We suggest that these children may continue to be at risk from mycobacterial infection.     

HLA部分相合父母供髓骨髓移植二次治疗重型地中海贫血

目的探讨同胞脐血植入失败的重型β地中海贫血患者,应用HLA部分相合父母亲骨髓进行第二次移植的效果。方法两例分别应用同胞HLA2个位点不合和全相合脐血移植的重型β地中海贫血患者,首次移植后均发生植入失败,前者表现为重型再生障碍性贫血,后者自体造血恢复。分别于首次移植13、12个月后,应用HLA部分相合的父亲、母亲骨髓进行第二次移植,观察临床疗效。结果一例重型再生障碍性贫血患者,应用HLA4个位点相合的父亲骨髓进行第二次移植,再次发生植入失败;另一例自体恢复者,应用HLA5个位点相合的母亲骨髓进行第二次移植获成功植入,现已脱离输血20个月。结论在选择合适的移植时机和预处理方案的前提下,父母供髓的二次移植对植入失败的重型β地中海贫血可起到有效的治疗作用。     

Addison disease 10 years after bone marrow transplantation for Wiskott-Aldrich syndrome

We report a 10-year-old boy with familial Wiskott-Aldrich syndrome (WAS) who underwent successful bone marrow transplantation (BMT) at the age of 9 months. With the exception of auto-immune haemolytic anaemia due to warm antibodies lasting 15 months there had not been any complication after BMT. Ten years later the patient presented with diarrhoea, hyperpigmentation of skin and oral mucosa, fatigue and polyuria. Diagnosis of Addison disease was confirmed by typical electrolyte imbalance and absent cortisol response to adrenocorticotrophic hormone. Adrenal antibodies were positive. On therapy with oral gluco- and mineralocorticoids, the symptoms disappeared and electrolytes normalized. To our knowledge auto-immuno endocrinopathy after BMT for WAS has not yet been reported.     

非血缘相关骨髓移植治疗重型地中海贫血的临床研究

目的为进一步拓展供髓源,探讨非血缘相关骨髓移植治疗重型地中海贫血(简称地贫)的可行性。方法9例地贫患儿进行了非血缘骨髓移植,其基因突变类型为地贫纯合子或双重杂合子,均确诊为重型β地贫。HLA高分辨配型全相合2例,1个亚型不合5例,2个亚型不合2例,6例红细胞血型不合。预处理为白消安16mg/kg,分4天口服;环磷酰胺200mg/kg,分4天静滴;抗人胸腺细胞免疫球蛋白30mg/kg,分3天静滴和氟达拉宾125mg/m2,分3天静滴。环孢素A和氨甲蝶呤预防移植物抗宿主病(graftversushostdisease,GVHD)。结果9例患儿均出现明显的过敏反应,1例有一过性低血压,皮肤急性GVHD7例,肝脏GVHD1例,肠道GVHD2例,慢性GVHD1例,高血压脑病1例,间质性肺炎2例。1例急性肺出血死亡。外周血中性粒细胞>0.5×109/L的时间为12～26天,WBC恢复正常的时间为23～110天,PLT于61～142天>50×109/L,Hb则于23～116天升至100g/L,最后一次输血时间为13～62天。PCR扩增短串联重复序列检测证实:8例患儿获得完全供体植入,1例未植入。随访6～24个月,7例原重型β地贫基因已消失,5例血型不合者已转成供者相同血型;7例患儿术后无需输血,Hb维持在110g/L以上。结论本组9例重型地贫的非血缘骨髓移植为国内首次尝试,初步证明非血缘骨髓移植根治重型地贫较安全可靠,为解决本病移植治疗的供髓源提供了新途径。     

Fungal pneumonia: the predominant lung infection causing death in children undergoing bone marrow transplantation

The study included 6 children (aged 4–14 years) receiving a conditioning regimen for bone marrow transplantation (BMT) and 14 children (aged 2-14 years) with bone marrow transplants (13 allo-geneic, 1 autologous). The children underwent flexible fibre-optic bronchoscopy (FFB) with broncho-alveolar lavage during 6 and 17 episodes of pneumonia, respectively. The aim was to compare the results of the two groups with respect to bronchoscopy findings, pneumonia-causing agents and outcome. During the conditioning regimen, the aetiological agents were recovered by bronchoscopy in 1/6 (17%) episodes and revealed by autopsy in another episode. In three episodes where the aetiology was uncertain, bacterial pneumonia was suspected in two, and Candida pneumonia in one. In episodes after transplantation the aetiological agents were recovered from bronchoscopy material in 14/17 (82%) patients. Autopsy confirmed the premortal diagnosis in the four children who died. In three episodes, bacterial pneumonia was clinically suspected. Based on clinical manifestations, FFB and autopsy findings, bacterial and fungal pneumonia were the most common diagnoses both during conditioning and after BMT. Fungal pneumonia was the most common cause of death in both groups.     

Granulocyte-colony-stimulating factor after allogeneic and autologous bone marrow transplantation in children

We evaluated the use of granulocyte CSF (G-CSF) after both allogeneic BMT (allo-BMT) and autologous BMT (ABMT) in children. After allo-BMT, G-CSF was used in 15 children who were compared with 20 historical controls. The ABMT patients were two sequential groups: the G-CSF group of 13 children and 11 historical controls. The patients were conditioned with different high-dose chemotherapy regimens with or without total body irradiation. G-CSF was administered at 5 μg/kg/day s.c. and was continued until an absolute neutrophil count (ANC) of 1,000 × 10⁶/l was reached. Following allo-BMT, G-CSF accelerated myeloid engraftment with a difference of 5 days at the ANC level of 500 × 10⁶/l (P < 0.02) and 9 days at 1,000 × 10⁶/l (P < 0.001). In the ABMT patients, G-CSF also accelerated myeloid engraftment. The difference between the G-CSF group and the control group was 6 days at ANC 200 (P < 0.05), 11 days at ANC 500 (P < 0.02), and 17 days at ANC 1,000 (P < 0.005). In the ABMT patients, benefit by G-CSF was also observed in a smaller number of days with fever and days on antibiotics. We conclude that G-CSG significantly accelerated myeloid engraftment, after both allogeneic and autologous BMT in children, and also decreased the duration of febrile illness in the ABMT patients. © 1996 Wiley-Liss, Inc.     

Pubertal development and growth after total-body irradiation and bone marrow transplantation for haematological malignancies

Pubertal development after total-body irradiation (TBI) was investigated in 40 children (21 boys) treated with allogeneic bone marrow transplantation (BMT) for haematological malignancies at a mean age of 11.3 years. The mean age at the last visit was 19.0 years. Twenty-five patients (15 boys) were prepubertal at BMT. Data on secondary sexual characteristics, the pituitary-gonadal axis and longitudinal growth were retrospectively collected from the medical records. In boys not receiving additional testicular irradiation (n = 19), penile growth and pubic hair development was normal and all had serum testosterone levels within the adult range. The majority of them, however, had incidental elevations of LH, suggesting minor Leydig cell damage. Testicular volume at last measurement was small (mean: 10.5 ml) and serum FSH levels were elevated in all boys, with normalisation in only one, suggesting severe impairment of reproductive gonadal function. Of the ten girls who received BMT before puberty, six had a spontaneous onset of puberty and menarche; the four other girls needed hormonal substitution therapy. Recovery of gonadal function after cessation of substitution was seen in one girl, who became pregnant but had a spontaneous abortion. Decrease in height SDS was seen in the majority of patients and was positively correlated with male gender and lower age at the time of BMT. Conclusion Careful monitoring of both gonadal function and growth after bone marrow transplantation and total body irradiation is warranted in order to detect disturbances early and ensure normal pubertal development in children treated for haematological malignancies. Received: 30 December 1998 / Accepted: 15 May 1999     

Ovarian function after successful bone marrow transplantation in postmenarcheal females

Ovarian function was followed serially in a group of six postmenarcheal females after successful bone marrow transplantation (BMT). The patients were between 13 9/12 and 22 6/12 (median 16 5/12) years of age at the time of BMT and were followed a median of 20 months (range 17-45 months) posttransplantation. Two subjects received short-term high-dose cyclophosphamide combined with single-dose total lymphoid irradiation (Group I), whereas the remaining four were treated with short-term, high-dose chemotherapy plus single-dose total body irradiation (Group II). Group II subjects also received combination chemotherapy prior to BMT. One subject from Group I continues to have regular menses and normal gonadotropin levels, 36 months post-BMT. The remaining five patients have demonstrated persistently elevated plasma concentrations of LH and FSH over a 17- to 45-month period of time. None of the four patients in Group II has menstruated since undergoing BMT. We conclude that single-dose radiation combined with short-term, high-dose chemotherapy results in profound ovarian damage in the majority of young women undergoing BMT.     

Cataracts after autologous bone marrow transplantation in children

We recorded the incidence and degree of posterior subcapsular cataract (PSC) in 29 children who had undergone autologous (n = 28) or syngeneic (n = 1) bone marrow transplantation (BMT) due to haematologic or lymphoid malignancy. Conditioning prior to transplantation consisted either of a combination of chemotherapy and total body irradiation (TBI) (n = 21) or of chemotherapy only (n = 8). TBI was given in one fraction of 7.5 Gy. Nine patients had received previous cranial irradiation. The patients were followed for 4-10y (median 8 y) after transplantation. Of 29 patients, 22 developed PSC, all within 4 y after BMT. With the exception of one patient who developed unilateral PSC, all had received TBI. Conversely, 100% of those who received TBI developed PSC. In this group (+TBI), eight patients (38%) developed significant PSC, defined as best corrected visual acuity <0.8 in either eye. Six patients (10 eyes) have since needed surgical repair consisting of extracapsular cataract extraction and intraocular lens implantation. There was no clear relationship between previous cranial irradiation and cataract development, nor any other obvious baseline differences between those in the +TBI group who developed significant PSC and those who did not. Although effects of previous therapy cannot be ruled out, TBI appears to be the main cause of PSC in this group of patients. Twelve patients in the +TBI group had well-preserved visual acuity throughout the study, reflecting a slow progression of PSC. This compares favourably with previous reports of allogeneic BMT, possibly owing to less need for corticosteroids after autologous BMT. We conclude that the incidence of PSC was high after autologous BMT where the conditioning regimen included total body irradiation.     

Severe combined immunodeficiency: treatment by bone marrow transplantation in 15 infants using HLA-haploidentical donors

In 15 infants with severe combined immunodeficiency (SCID), immunological reconstitution was attempted by bone marrow transplantation (BMT) from HLA-haploidentical parents. To prevent graft versus host disease (GvHD), marrow grafts were depleted of contaminating T-lymphocytes using lectin agglutination and rosette formation with sheep red blood cells. Thirteen patients received transplants without undergoing prior cytoreductive conditioning. Eleven of these developed donor-dependent T-cell functions, two failed to do this. One of these two as well as two further patients received cytoreductive treatment prior to repeat and to first transplants and in two, complete lymphohemopoietic reconstitution was observed. Of the 15 patients who received transplants, 11 are currently alive. Two recently treated patients remain in the hospital, nine are at home with stable T-cell functions. Normal humoral immune functions have developed upto now in three patients. In the others, gammaglobulins are regularly substituted. Complications of acute or chronic GvHD were not observed with the exception of one case who developed transient GvHD of the skin.These results suggest that in a majority of patients with SCID, T-cell functions can develop without GvHD following haploidentical, T-cell-depleted BMT. Exceptional patients require preconditioning to allow donor cell engraftment, an approach that also appears to facilitate reconstitution of humoral immune functionsAbbreviations SCID severe combined immunodeficiency - BMT bone marrow transplantation - GvHD graft versus host disease - HLA histocompatibility antigens - MNC mononuclear cells - SRBC sheep red blood cells - DTH delayed type hypersensitivity - ADA adenosine deaminase     

Chemotherapy versus bone marrow transplantation in childhood acute lymphoblastic leukaemia

Twenty-five years ago over 90% of children with acute lymphoblastic leukaemia (ALL) died of this disease. Dramatic improvement has been achieved since then by employing risk-adapted, aggressive polychemotherapy protocols. More than 90% of children with ALL treated according to, for example BFM-protocols, have nowadays cure rates in the range of 70%–80%. However, 10% of patients do not initially respond adequately to standard induction chemotherapy. They are characterized by distinct chromosomal abnormalities such as translocation (9; 22) or combinations of early treatment failure and other risk factors as cytogenetic abnormalities, lineage-specific surface markers or tumour load at diagnosis. In this group of patients in first complete remission and certainly in the vast majority of relapsed patients, allogeneic bone marrow transplantation (BMT) has evolved as an alternative approach allowing further intensification of myeloablation and the introduction of an additional antileukaemic alloreactivity. Nevertheless, the decision for a marrow transplant in children has to be made very carefully because of a significant increase in treatment related mortality and BMT-specific risks like acute and chronic graft-versus-host disease with a critical iatrogenic chronic morbidity. This is even more evident, if mismatched or unrelated transplants are being considered. The indications for one or the other treatment modality according to the current BFM strategy are discussed.     

Hypertrophic obstructive cardiomyopathy in neonatal beta-cell adenoma of the pancreas

Summary A case of beta-cell adenoma of the pancreas in a neonate with congestive heart failure due to severe hypertrophic cardiomyopathy is reported. In the course of the illness, he developed myocardial infarction, which was probably caused by the limited coronary reserve of the hypertrophied myocardium.     

Normal long-term parathyroid function after autologous bone marrow transplantation in children

Parathyroid function was recently reported to be affected in more than one-third of pediatric BMT patients conditioned without irradiation. Our aim was to describe parathyroid function in children with malignant hematological disease after autologous BMT with and without TBI. PTH, albumin-corrected serum calcium, and serum phosphate were analyzed in 35 children followed for six months to nine yr after BMT. Twelve patients were conditioned with chemotherapy alone, and 23 patients received TBI as well. In the TBI group, 11 patients had previously received additional CRT. We found normal levels of PTH in children post-BMT, with the exception of four patients (11%) who showed transient PTH elevation during the first year of follow-up, There was no difference between those who had received irradiation and those who had not. Serum calcium was unchanged after BMT. An age-corrected quotient of serum phosphate decreased slightly. Renal function which was normal before BMT decreased slightly in both groups after BMT, but was within the normal range. Parathyroid function was found to be normal during the time frame of this study, irrespective of whether irradiation had been given.     

兔骨髓间充质干细胞自体移植对扩张型心肌病左心室功能的影响

目的观察自体骨髓间充质干细胞(MSCs)移植对扩张型心肌病(DCM)兔的心脏形态大小、功能及脑钠肽(BNP)的影响。方法26只健康大耳白兔随机分为细胞移植组和DCM对照组,经兔耳缘静脉注射盐酸阿霉素建立DCM模型后,移植组移植MSCs[1×106],DCM对照组注射DMEM/F12培养基。于用药前、移植前和移植后4周采用超声心动图测量二组动物的心脏形态大小和心功能,酶联免疫吸附试验测定血浆BNP水平。移植后4周左心导管测定血流动力学指标,免疫荧光检测移植区组织内存活的移植细胞。结果超声心动图检查证实MSCs移植后4周移植组左室腔内径较DCM对照组明显减小(P<0.05),射血分数(EF)增加并显著大于DCM对照组(P<0.01)。左心导管测压显示移植组左室收缩压较DCM对照组增高,舒张末期压显著降低(均P<0.01)。移植后4周移植组的血浆BNP水平显著下降(P<0.01),而DCM对照组无显著性改变。移植组组织切片可见5溴-2脱氧尿苷(BrdU)染色阳性细胞,另外还发现部分移植细胞分化为血管内皮细胞,DCM对照组未见BrdU染色阳性细胞。结论DCM兔心肌内注射MSCs能减轻阿霉素致DCM后左室腔扩大,有效改善DCM兔的心功能。     

Growth and growth hormone secretion in children after bone marrow transplantation

Long-term sequelae of bone marrow transplantation (BMT) are a major concern among long-term survivors since the procedure has been considerably developed over the past decade. In this study, linear growth and growth hormone (GH) secretion were evaluated in 25 children (14 males and 11 females) with various neoplastic or non-neoplastic hematological disorders who had survived for more than 3 years after BMT. Impaired linear growth after BMT, as defined by a change in height standard deviation score (SDS) by more than ? 1.0 SD, was observed in 14 patients (56%). Four children showed severe growth suppression with a decrease in SD score by more than 2.0, and 10 exhibited a moderate reduction by between 1.0 and 2.0 SD. A recovery of normal height velocity was observed in those who had received BMT at a younger age. The type of disease, a difference in preconditioning regimen, the presence of chronic graft-versus-host disease or a GH secretory capacity 1 year after BMT were not contributing factors for impaired growth. A serial examination of GH secretion with insulin-induced hypoglycemia demonstrated that poor GH secretion was not necessarily a prerequisite for impaired growth. These results indicate that the secretory status of GH does not predict the future growth pattern of children who received BMT.     

Shwachman-Diamond syndrome: early bone marrow transplantation in a high risk patient and new clues to pathogenesis

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterised by exocrine pancreas insufficiency, metaphyseal dysostosis and bone marrow dysfunction. Recurrent severe bacterial infections and susceptibility to leukaemia are the major causes of morbidity and mortality occurring preferentially in patients with pancytopenia and features of myelodysplasia. Here we report a patient with SDS leading to recurrent bacterial infections and a deteriorating condition since early infancy. Extensive investigations disclosed severe pancytopenia, myelodysplasia and a clonal cytogenetic abnormality, inv(14)(q11q32), as risk factors of leukaemic transformation. He therefore underwent allogeneic geno-identical bone marrow transplantation which resulted in correction of all haematological and immunological abnormalities within an 18-month follow up period. Conclusion Bone marrow transplantation may be considered early as a valuable treatment option especially in high risk Schwachman-Diamond syndrome patients anticipating malignant transformation, life-threatening severe infections or further organ damage. Received: 19 February 1999 / Accepted: 22 June 1999     

Disease of the liver following bone marrow transplantation in children: incidence, clinical course and outcome in a long-term perspective

Sixty-four consecutive cases of allogeneic ( n = 16), autologous ( n = 47) or syngeneic ( n = 1) bone marrow transplantation (BMT) in children with haematological or lymphoid malignancy, aplasia or metabolic disease were reviewed to assess the incidence, clinical presentation and outcome of liver disease. Median follow-up time was 5 y (1.0-10). No liver diagnosis was established at the pre-transplant check-up. During the first 100d post-transplant, 81% of the patients had impaired liver function as documented by various biochemical parameters. Three of 64 patients (5%) met diagnostic criteria for veno-occlusive disease. Four (25%) of the 16 receiving allografts were diagnosed as having acute graft vs host disease (GVHD) with liver involvement (grades II-III). No patient died of liver disease. During the late post-transplant follow-up, one patient developed HCV hepatitis after packed erythrocyte transfusion. Four patients were diagnosed as having chronic GVHD with liver involvement; three of them also had an episode of CMV hepatitis. At their latest follow-up, the patients with chronic GVHD had aminotransferase values 1.5–3 times the normal, whereas all other long-term survivors had normal or near-normal liver function tests. We conclude that the incidence of serious liver disease was low in this paediatric population of bone marrow recipients.     

CRRT机血浆置换预防儿童ABO血型不合骨髓输注的溶血反应

目的观察血浆置换技术在ABO血型主侧不合的非亲缘异基因供髓骨髓移植中的应用价值。方法对3例ABO血型主侧不合非亲缘供髓骨髓移植的患儿进行血浆置换。均先置换6％羟乙基淀粉注射液500ml，再根据体重大小置换不同剂量的AB血型血浆，以去除血浆抗红细胞抗体，防止异型骨髓输注ABO血型不合的溶血反应，检测血浆置换前后受者血浆抗红细胞抗体浓度并观察溶血反应。结果血浆置换后，3例患儿血浆抗红细胞抗体IgM抗体滴度分别由最高1：1024、1：32、1：256降为1：8、1：0、1：0，IgG抗体滴度分别由1：256、1：32、1：128降为1：16、1：0、1：4，分别输注ABO血型主侧不合骨髓680ml、800ml、1000ml，仅1例发生轻微急性溶血反应，未出现迟发性溶血反应，3例患儿均植入成功，其中1例发生Ⅰ度、2例发生Ⅱ度急性移植物抗宿主病（皮肤型）。结论血浆置换是预防ABO血型主侧不合骨髓移植溶血反应的安全有效的方法。     

CRRT机血浆置换预防儿童ABO血型不合骨髓输注的溶血反应

目的观察血浆置换技术在ABO血型主侧不合的非亲缘异基因供髓骨髓移植中的应用价值。方法对3例ABO血型主侧不合非亲缘供髓骨髓移植的患儿进行血浆置换,均先置换6%羟乙基淀粉注射液500 ml,再根据体重大小置换不同剂量的AB血型血浆,以去除血浆抗红细胞抗体,防止异型骨髓输注ABO血型不合的溶血反应,检测血浆置换前后受者血浆抗红细胞抗体浓度并观察溶血反应。结果血浆置换后,3例患儿血浆抗红细胞抗体IgM抗体滴度分别由最高1:1 024、1:32、1:256降为1:8、1:0、1:0,IgG抗体滴度分别由1:256、1:32、1:128降为1:16、1:0、1:4,分别输注ABO血型主侧不合骨髓680 ml8、00 ml1、000 ml,仅1例发生轻微急性溶血反应,未出现迟发性溶血反应,3例患儿均植入成功,其中1例发生Ⅰ度、2例发生II度急性移植物抗宿主病(皮肤型)。结论血浆置换是预防ABO血型主侧不合骨髓移植溶血反应的安全有效的方法。     

CD25抗体预防移植物抗宿主病在儿童白血病半匹配骨髓移植中的应用

目的　探讨CD2 5抗体用于预防儿童白血病半匹配未去除T细胞骨髓移植重度移植物抗宿主病 (GVHD)的疗效。方法　 10例儿童白血病患者接受人类白细胞抗原 (HLA) 2～ 3个位点不合半匹配骨髓移植 ,移植方法除了供者用粒细胞集落刺激因子 (G CSF)及受者应用环孢素A(CSA)、氨甲蝶呤 (MTX)、抗胸腺细胞球蛋白 (ATG ,FreseniusHemocare ,Germany)和霉酚酸酯 (MMF)预防GVHD的综合措施外 ,加用抗CD2 5单克隆抗体 (舒莱 ,novartispharmaswitzerland)预防GVHD ,剂量各为 2 0mg ,在移植前 2h和移植后第 4天应用 ,观察移植后的疗效 ,移植结果与前期未用CD2 5抗体移植组作回顾性比较。结果　 10例移植后均获造血重建 ,粒细胞 >0 5× 10 9/L的中位天数是 19d ,血小板大于 2 0× 10 9/L的中位天数是 2 2d ,骨髓植活直接证据检测证实为完全供者造血。无一例发生急性Ⅱ～Ⅳ度GVHD ,未用CD2 5抗体对照组 8例中发生急性Ⅱ～Ⅳ度GVHD有 4例 ,差异有显著性(P =0 0 14 7)。可评价慢性GVHD的 8例均发生慢性GVHD ,为局限性慢性GVHD。中位随访 12个月 (范围 9～ 2 4个月 ) ,2例为移植相关死亡 ,1例移植后 14个月因复发死亡 ,实际无病生存率是70 %。结论　儿童半匹配未去除T细胞骨髓移植中应用舒莱 ,明显降低急性重症GVHD发生 ,临床