Non-myeloablative allogeneic transplantation – State-of-the-art

Abstract:  Work by several groups of investigators has brought about changes in the way hematopoietic cell allografts are being done to treat patients with hematologic diseases. Less intensive conditioning regimens have been introduced, and in the case of patients with hematologic malignancies, the burden of eradicating malignant cells has shifted from high-dose chemoradiation treatment toward using the hematopoietic cell donor's T lymphocytes for that purpose by invoking allogeneic graft-versus-tumor effects. While the majority of the transplant regimens used in these efforts are still fairly intense and toxic, a radical departure from conventional transplantation focuses on the almost exclusive use of immunosuppressive agents with little toxicity to establish the allografts. The success of the procedure for patients with hematologic malignancies rests on replacing the host's hematopoietic cells by the allograft. For non-malignant diseases, the procedure can be used to establish a stable state of mixed donor/host hematopoietic chimerism, which, in itself, may be sufficient to cure disease manifestations.     

Sickle cell anemia and hematopoietic cell transplantation: When is a pound of cure worth more than an ounce of prevention?

Abstract:  Hematopoietic cell transplantation (HCT) is curative therapy for sickle cell anemia (SCA). However, its widespread use is constrained by donor availability and by concerns about its short-term and long-term toxicities. Current efforts to identify suitable candidates for HCT, to decrease the toxicity of HCT, and to broaden its availability are discussed.     

Cytomegalovirus infection in children who underwent hematopoietic stem cell transplantation at a single center: A retrospective study of the risk factors

Abstract:  CMV infection is one of the major causes of morbidity and mortality after HSCT. The aim of this single center retrospective study was to analyze risk factors for CMV infection in pediatric patients who underwent HSCT. We retrospectively reviewed the medical records of 117 pediatric patients who underwent allogeneic HSCT at Asan Medical Center between December 2000 and January 2007. After HSCT, CMV antigenemia was detected by identifying CMV pp65 early antigen in white blood cells. The incidence of CMV antigenemia was 24% (28/117) at a median of 38 days (range: 19–123 days) after HSCT. In multivariate analysis, CMV antigenemia occurred significantly more often in CMV seropositive recipients, patients who received grafts from alternative donors, T-cell depleted grafts, patients on ATG-containing conditioning regimens, or patients who received steroid for acute GVHD (p < 0.05). CMV antigenemia tend to develop earlier in patients who received ATG-containing conditioning regimens (p = 0.09). A second episode of CMV antigenemia was observed in three out of 28 patients (11%). The incidence of CMV disease was 5.9% (7/117) at a median of 97 days (range: 34–120 days). Manifestation of CMV disease included retinitis in two, pneumonitis in two, hepatitis in one, hepatitis with colitis in one, and gastritis in one. Six of the 12 patients (50%) with HG antigenemia (CMV pp65 antigen positivity ≥40 cells) developed clinical CMV disease, a rate that was significantly higher than seen in patients with LG antigenemia (6.25%; p < 0.01). We recommend that patients with these risk factors should carefully undergo regular evaluations for CMV infection. We also suggest that earlier and more aggressive preemptive treatment and serial follow-up of CMV disease is necessary in patients with HG-antigenemia.     

Frequent methylprednisone pulse therapy is a risk factor for steroid cataracts in children

Background: Pediatricians use corticosteroids for prolonged periods of time for the treatment of many diseases, including rheumatic disease. The side-effects of corticosteroids, especially cataracts, are widely recognized, but the predictive risk factors for steroid-induced cataracts have not yet been fully characterized.
Methods: The relationship between the formation of cataracts and steroid therapy was evaluated in patients with rheumatic disease.
Results: The initiation of steroid therapy in children under 12 years of age ( P  = 0.041) and i.v. methylprednisone pulse therapy (IVMP) ( P  = 0.046) are significant risk factors for inducing cataracts. In contrast, the cumulative corticosteroid dose, sex, and daily corticosteroid dose were not associated with cataract formation.
Conclusions: Younger children, who need frequent IVMP to treat their rheumatic diseases, should be examined by ophthalmologists frequently to avoid developing amblyopia from cataracts.     

High-risk adenovirus-infected pediatric allogeneic hematopoietic progenitor cell transplant recipients and preemptive cidofovir therapy

Abstract:  ADV has emerged as an important pathogen in children undergoing allogeneic HPCT. A prospective study of the epidemiology of ADV infection and preemptive therapy of high risk ADV infections in children undergoing HPCT was undertaken. Cultures of throat, urine, and stool for viral pathogens and plasma for ADV PCR were obtained prior to transplantation, weekly for the first 100 days, and then monthly for one yr. Children developing high-risk ADV infections were treated preemptively with cidofovir 1 mg/kg/day given three times weekly for three wk. A case-controlled study was performed to identify risk factors for high-risk ADV infections. Seven (18%) of the 38 subjects developed high-risk ADV infections usually within 100 days of HPCT and were preemptively treated with i.v. cidofovir at a dose of 1 mg/kg/dose three times weekly for nine doses. High-risk ADV infections resolved in all seven patients without renal toxicity. CMV viremia occurred in two of seven patients during or shortly after therapy with cidofovir. A case–control study did not identify any risk factors that achieved statistical significance. Treatment with a modified dosing regimen of cidofovir was well-tolerated and high-risk ADV infections resolved in all patients.     

Aspergillus "fungus ball" of the bladder after hematopoietic transplantation in a pediatric patient: successful treatment with intravesical voriconazole and surgery

Abstract:  Aspergillosis is an important cause of mortality in allogeneic HSCT. A "fungus ball" formation of Aspergillus in the bladder has seldom been reported. We report a child that underwent HSCT and developed possible disseminated aspergillosis with an intravesical "fungus ball," diagnosed by genitourinary MRI and PCR of the mass that was removed from the bladder. It is important to consider this complication in a patient with HC after HSCT. The treatment included a combination of systemic antifungal therapy along with intravesical voriconazole and surgical removal.     

Efficacy of the bell and pad alarm therapy for nocturnal enuresis

Aim:   (i) To determine the efficacy of bell and pad alarm therapy as an initial and relapse treatment for nocturnal enuresis; (ii) to explore risk factors for treatment failure; and (iii) to explore risk factors for relapse within 12 months of successful bell and pad alarm therapy.
Methods:   A 22-item questionnaire was sent to 240 children who received bell and pad alarm therapy in a 6-year period via a community centre. The questionnaire recorded demographic characteristics of the child, length of the first bell and pad alarm therapy, outcome of initial treatment and relapse information.
Results:   The initial response and relapse rates of bell and pad alarm therapy were 84 and 30%, respectively. Female gender, absence of diurnal symptoms and willingness to use alarm therapy were associated with better treatment outcomes. Treatment success was associated with shorter treatment length. The success rate of repeating alarm therapy after relapse was 78%, with an average length of treatment of 10 weeks.
Conclusion:   The bell and pad alarm therapy is an effective treatment for nocturnal enuresis both as initial therapy and after relapse. The association between patient characteristics and treatment response found in our study may help inform clinicians of likely treatment outcomes, and identify those who may need a different approach.     

儿童感染性心内膜炎33例临床特点及疗效分析

目的 探讨儿童感染性心内膜炎的临床特点及影响疗效的因素。方法 回顾性研究2013年11月至2015年11月上海儿童医学中心心内科诊断并治疗的33例感染性心内膜炎患儿的临床资料,分析其病原学特点、心脏基础疾病、赘生物分布特点、治疗方案及预后情况。结果 感染性心内膜炎病原菌的检出率为75.76%。具有先天性心脏基础疾病的比例为93.94%。赘生物主要位于反流的瓣膜,占63.64%,其次为植入的人工材料、缺损处分流及血流冲击处等。手术结合足疗程的抗感染治疗效果较好。结论 感染性心内膜炎的血培养阳性率高,且多发生于具有心脏基础疾病的患儿。早期彻底的手术治疗联合全程抗感染治疗是治疗感染性心内膜炎的关键。     

The paediatrician – past, present and future – a conversation with Nils Rosén von Rosenstein

An imagined conversation takes place with the author of the first textbook of Paediatrics, Nils Rosén von Rosenstein. Enormous progress in the prevention and treatment of diseases of children is demonstrated. But a different spectrum of diseases has replaced the old one. And in spite of unprecedented material well-being a substantial minority of our children cannot make full use of their capabilities.
Conclusion:  We must resume the full responsibility for our children and act as their advocates in society.     

Effect of upper limb botulinum toxin-A therapy on health-related quality of life in children with hemiplegic cerebral palsy

Aim:   Currently, the use of upper limb botulinum toxin-A (UL BTX-A) is based on evidence of functional efficacy without supporting evidence of positive change in health-related quality of life (HRQOL). While function may improve, this cannot be directly correlated with an improvement in HRQOL. Most paediatric studies use caregiver/parent proxy reports. The inclusion of child self-reports is increasing as poor correlation with proxy reports is being demonstrated. This paper aims to study the effect of UL BTX-A therapy on HRQOL in children with hemiplegic cerebral palsy (CP).
Method:   Design: Pilot prospective randomised trial. Participants: 22 children with hemiplegic CP aged 7 years 0 month−13 years 11 months (12 treatment, 10 control). Treatment: One series BTX-A injections into UL. HRQOL assessed at baseline, and 1, 3 and 6 months post-injection by completion of Pediatric Quality of Life (PedsQL) 4.0 Generic Core Scales and PedsQL 3.0 CP Module. Outcome: 1. Change in PedsQL scores. 2. Concordance between child self-report and parent proxy-report scores.
Results:   No statistically significant difference between treatment and control groups was observed for any domain of HRQOL. Intraclass concordance was good for the PedsQL CP Module Daily Activities, and Speech and Communication scores ( P  = 0.0005).
Conclusion:   This pilot work adds to the emerging evidence that UL BTX-A therapy has no statistically significant effect on the HRQOL of children with hemiplegic CP. With the increasing use of this therapy in children with CP, further research across the broader CP population is needed to identify whether this therapy is indicated in other target populations. Both child and parent proxy reports should be collected when assessing HRQOL in this population.     

儿童再生障碍性贫血造血干细胞移植后并发播散型带状疱疹3例报告并文献复习

目的 探讨儿童再生障碍性贫血（AA）造血干细胞移植（HSCT）后并发播散型带状疱疹的诊断、高危因素、预防及治疗措施。方法 回顾性分析2014年12月至2015年9月中山大学孙逸仙纪念医院儿科收治的3例AA患儿接受全相合非血缘相关供者HSCT后予免疫抑制剂治疗期间出现播散型带状疱疹的临床资料。结果 3例患儿年龄分别为13、12和10岁,移植后未出现移植物抗宿主病,予抗病毒药物单药预防水痘-带状疱疹病毒（VZV）期间均未出现VZV再激活,在HSCT后4.0、5.5和8.0个月停用抗病毒药物,分别在停用抗病毒药物后13.0、10.5和3.0个月出现皮肤播散型带状疱疹,予静脉更昔洛韦联合口服伐昔洛韦及外用喷昔洛韦抗病毒治疗至皮疹结痂,并予丙种球蛋白治疗,均完全治愈。结论 接受HSCT的AA患者是播散型带状疱疹的高发人群,其发病率高、病情严重且病死率高。移植后予预防性抗病毒处理,出现播散型带状疱疹时减少免疫抑制剂量,联合更昔洛韦、伐昔洛韦及丙种球蛋白治疗,可明显改善疗效。     

Access to hematopoietic stem cell transplant for patients with sickle cell anemia

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for patients with phenotypically severe sickle cell anemia, and survival rates following matched‐sibling HSCT are very high. However, despite cure rates much higher than HSCT for malignant diseases, the field has been slow to adopt this treatment modality for sickle cell anemia. This article explores some of the social forces that may contribute to this dichotomy.     

Perinatal stem-cell and gene therapy for hemoglobinopathies

Most genetic diseases of the lymphohematopoietic system, including hemoglobinopathies, can now be diagnosed early in gestation. However, as yet, prenatal treatment is not available. Postnatal therapy by hematopoietic stem cell (HSC) transplantation from bone marrow, mobilized peripheral blood, or umbilical cord blood is possible for several of these diseases, in particular for the hemoglobinopathies, but is often limited by a lack of histocompatible donors, severe treatment-associated morbidity, and preexisting organ damage that developed before birth. In-utero transplantation of allogeneic HSC has been performed successfully in various animal models and recently in humans. However, the clinical success of this novel treatment is limited to diseases in which the fetus is affected by severe immunodeficiency. The lack of donor cell engraftment in nonimmunocompromised hosts is thought to be due to immunologic barriers, as well as to competitive fetal marrow population by host HSCs. Among the possible strategies to circumvent allogeneic HLA barriers, the use of gene therapy by genetically corrected autologous HSCs in the fetus is one of the most promising approaches. The recent development of strategies to overcome failure of efficient transduction of quiescent hematopoietic cells using new vector constructs and transduction protocols opens new perspectives for gene therapy in general, as well as for prenatal gene transfer in particular. The fetus might be especially susceptible for successful gene therapy approaches because of the developing, expanding hematopoietic system during gestation and the immunologic naiveté early in gestation, precluding immune reaction towards the transgene by inducing tolerance. Ethical issues, in particular regarding treatment safety, must be addressed more closely before clinical trials with fetal gene therapy in human pregnancies can be initiated.     

Increased blood plasma concentrations of TGF-β1 and TGF-β2 after treatment with intravenous immunoglobulins in childhood autoimmune diseases

Transforming growth factor-β (TGF-β), a multifunctional, immunosuppressive cytokine, is shown to be present in substantial amounts in commercially available intravenous immunoglobulin (IVIG) preparations. To assess whether TGF-β isoforms are changed in the plasma of paediatric patients with childhood autoimmune diseases after IVIG infusion, 17 patients who received over a period of 12 months overall 56 IVIG infusions (Endobulin) were enrolled in a study. High levels of TGF-β1 (16.95 ± 8.16 ng/ml) as well as TGF-β2 (62.71 ± 9.50 ng/ml) were detected in the used 56 IVIG probes. TGF-β1 and TGF-β2 plasma concentrations were measured prior and 120 min after IVIG infusions by specific TGF-β ELISA. Interestingly, significant increased TGF-β1 and TGF-β2 plasma levels were found in patients after treatment with IVIG. This data suggest that a TGF-β-mediated mechanism of action may accompany other molecular effects of IVIG therapy. The amount of the potent anti-inflammatory TGF-β isoforms within the IVIG preparations may exert a differentiated view regarding the manifold indications of IVIG therapy.     

Hematopoietic stem cell transplantation for curing children with severe autoimmune diseases: Is this a valid option?

The cure of children with severe AD, especially patients with severe, progressive, and therapy-resistant autoimmunity, represents a challenge for current medical practice. The idea of HSCT as a promising therapeutic opportunity was borne accidentally from finding patients who, after undergoing HSCT for a hematological indication, were cured of a concomitant AD. Thus, over the last two decades, HSCT has been extensively investigated, and it has become an appealing therapy for rheumatological (juvenile rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis) and hematological diseases (immune cytopenias). Recently, interesting results have been also described in type 1 diabetes mellitus and Crohn's disease. Although the use of HSCT has been steadily rising in the last few years, many questions are still open, especially after the discoveries of many new biological agents. Given the low incidence of ADs in children, most of the data about the use of the HSCT for these diseases are taken from a mixed cohort of adults and children. The aim of this review is to summarize the published studies and to try to answer the question as to whether this procedure can be considered a promising approach.     

Exclusive enteral nutrition for children with Crohn's disease: Use in Australia and attitudes of Australian paediatric gastroenterologists

Aim:   Although available data support a role for exclusive enteral nutrition (EEN) in children with Crohn's disease (CD), use of this therapy varies. The aim of this study was to define the patterns of use of EEN across Australia and to better understand the reasons for this variation.
Methods:   Using an existing email network, Australian paediatric gastroenterologists were asked to provide details of their attitudes towards, and use of, EEN in children. A questionnaire was designed to direct responses, with regard to use of EEN, to current EEN protocols and patterns of use.
Results:   Twenty-one replies were received (58% response). Although 12 respondents felt that EEN was an appropriate therapy for CD, only 8 regularly used EEN for their patients. Usage varied between states and within units. Current use was related to practitioners' experiences of EEN during their gastroenterology training. The concerns of those who did not recommend EEN included compliance, cost and resource demands. The doctors who recommend EEN reported that family support, team approach and disease location were important factors for a positive outcome from EEN. Current protocols varied in terms of type of formula, length of therapy and use of concurrent medications.
Conclusions:   Variations in care were illustrated across these paediatric gastroenterologists. Practitioners have many reasons and concerns about the use of EEN: these impede the wider use of EEN for paediatric CD. More consistent protocols for the use of EEN and an improved understanding of the mechanisms of EEN could lead to enhanced use of this therapy.     

Anthroposophic therapy for children with chronic disease: a two-year prospective cohort study in routine outpatient settings

Background  

Many children with chronic disease use complementary therapies. Anthroposophic treatment for paediatric chronic disease is provided by physicians and differs from conventional treatment in the use of special therapies (art therapy, eurythmy movement exercises, rhythmical massage therapy) and special medications. We studied clinical outcomes in children with chronic diseases under anthroposophic treatment in routine outpatient settings.     

Leflunomide therapy for BK virus allograft nephropathy in pediatric and young adult kidney transplant recipients

Araya CE, Garin EH, Neiberger RE, Dharnidharka VR. Leflunomide therapy for BK virus allograft nephropathy in pediatric and young adult kidney transplant recipients.
Pediatr Transplantation 2010: 14: 145–150. © 2009 Wiley Periodicals, Inc.
Abstract:  BKVAN affects about 5% of kidney transplant recipients and may lead to graft failure. Treatment for BKVAN is challenging. Leflunomide, an immunosuppressant with antiviral activity in vitro was used successfully in some adult patients but there are no reports of its use in pediatric patients. We present our experience with three kidney transplant recipients with BKVAN who received leflunomide. Three male patients aged 9, 12, and 20 yr developed BKVAN at 9, 12, and 2 months after a kidney transplant. Immunosuppression was reduced and cidofovir was administered in all patients 2–3 wk apart. Due to inability to travel to receive cidofovir in one, lack of reduction in BK viral load in the second, and rising serum creatinine despite cidofovir in the third patient, we discontinued cidofovir and initiated leflunomide. Teriflunomide target trough levels were 30–60 μg/mL. The patients received leflunomide for 27, 26, and 24 months, respectively. BK viral load decreased below 1000 DNA copies/mL in one and was undetectable in two patients after beginning leflunomide. All patients tolerated leflunomide without side effects. Leflunomide use in a select group of patients is well tolerated and may provide an alternative for treatment of BKVAN in pediatric patients.     

Hematopoietic stem cell transplantation in Langerhans cell histiocytosis: case report and review of the literature

Abstract:  The prognosis in children with LCH who do not respond to the conventional therapies is very poor. SCT may be a new approach. However, there are limited data about the results of the transplantations. Herein we report a patient with refractory multisystem LCH who underwent allogeneic bone marrow transplantation and is disease and treatment free 54 months after transplantation. Further studies are required to establish the role of SCT in refractory LCH.     

Iron overload in survivors of childhood leukemia after allogeneic hematopoietic stem cell transplantation

Abstract:  Iron overload has not been studied extensively and prospectively in pediatric survivors of allogeneic hematopoietic stem cell transplantation (HSCT); therefore, we conducted a prospective long-term study of 133 survivors of childhood leukemia to assess the incidence of and risk factors for iron overload and to investigate its association with organ dysfunction. One yr after HSCT, the mean serum ferritin level was 1158 ng/mL (range, 22–3264 ng/mL), with 124 patients (93.2%) having a serum ferritin level that exceeded the upper limit of the normal range (110 ng/mL). Thereafter, the serum ferritin level declined over time. There was a positive correlation between the level of serum ferritin and that of total bilirubin (r   =   0.21, p < 0.001) and glutamate pyruvate transaminase (r   =   0.17, p < 0.001). A high concentration of serum ferritin was associated with low cardiac fractional shortening (r   = −0.15, p  =  0.047). In addition, patients with hypothyroidism and GH deficiency had a higher level of serum ferritin than those without (p < 0.02). We conclude that iron overload is common after HSCT and is associated with hepatic, cardiac, and endocrine dysfunction.