Infection following haematopoietic stem cell transplantation

Haematopoietic stem cell transplantation is offered to increasing numbers of patients, with the potential of curing underlying disease. Whilst survival rates have significantly improved over recent years, with survival for some procedures over 90%, infection remains a significant cause of morbidity and mortality. Strategies to improve the outcome of patients who develop infection through the transplant period are being introduced. Minimal intensity conditioning regimens reduce the period of bone marrow aplasia when patients are most at risk of developing life-threatening bacterial or fungal infection. Reduction or omission of serotherapy as part of the conditioning regimen preserves donor lymphocytes and results in more rapid viral clearance. Weekly surveillance for herpes- and adenovirus infection enables pre-emptive treatment before disease develops – new antiviral treatments are currently being trialled. Cellular therapies are more effective at countering viral infection. New methods of graft manipulation remove T lymphocytes more likely to cause GvHD, but retain Natural Killer cells and specific T lymphocyte subsets more likely to exhibit antiviral activity. Immunomodulatory methods of treating graft-versus host disease enable a reduction in conventional immunosuppression, which allows control of viral infection. New methods of generating virus-specific cytotoxic T lymphocytes will facilitate donor banking of such cells to treat patients with third party lymphocyte infusions.     

Pulmonary hypertension following haematopoietic stem cell transplantation for primary haemophagocytic lymphohistiocytosis

We report two children who developed severe, fatal pulmonary hypertension (PHT) after mismatched unrelated donor cord blood transplantation using reduced intensity conditioning for HLH. PHT was diagnosed on post mortem lung biopsies with no evidence of HLH, pulmonary veno‐occlusive disease, infection or of idiopathic pulmonary hypertension. PHT may be an association with HLH and physicians treating HLH should be aware of this potential association. Pediatr Blood Cancer 2013; 60: 521–523. © 2012 Wiley Periodicals, Inc.     

KIR/HLA-I mismatching and risk of relapse in paediatric patients undergoing non-haploidentical allogeneic haematopoietic stem cell transplantation

In HSCT setting, KIR-driven alloreactivity might be better predicted if the donor KIR genotype is considered in addition to the recipient HLA genotype. The prediction of NK cell alloreactivity relies on the missing ligand in the recipient, a scenario that can be found in HLA-identical and non-identical allotransplants. The aim of this study was to investigate at genetic level the prognostic impact of recipient HLA-I lacking for donor KIR on allotransplanted patients outcome. We analysed donors KIR genotype and HLA genotype of 60 paediatric patients who received related (n=15) or unrelated (n=45) transplantation. When patients were grouped based on the KIR gene type involved in the KIR/HLA-I mismatch, we did not observe any relapse in the group of patients characterized by mismatches involving only inhibitory KIR. On the contrary, all relapses were observed in patients showing at least one activating gene involved in the mismatch (p<0.05). Although the biological mechanism accounting for this putative genetic rule is still to be clarified, we suggest that a careful survey of KIR/HLA-I mismatching should be taken into account in the selection of donor in related and unrelated HSCT.     

Early predictors of mortality in children with pulmonary complications after haematopoietic stem cell transplantation

PC are a main cause of death following HSCT in children. We aimed to evaluate early predictors of mortality in paediatric recipients with PCs. A retrospective observational study of 35 patients with 49 episodes of PI on chest radiography (of 124 patients) who had undergone HSCT at a tertiary university hospital between January 2011 and December 2012 was performed. During follow‐up (median 26.1 months), 15 episodes led to death (30.6%). An aetiologic diagnosis was made by non‐invasive tests in 24 episodes (49.0%) and by adding bronchoalveolar lavage and/or lung biopsy in 7 episodes with diagnostic yield (77.8%, P = .001). Thus, a specific diagnosis was obtained in 63.3% of the episodes. Aetiology identification and treatment modification after diagnosis did not decrease mortality (P = .057, P = .481). However, the number of organ dysfunctions at the beginning of PI was higher in the mortality group, compared to the survivor group (1.7 ± 1.2 vs 0.32 ± 0.59; P = .001). Hepatic dysfunction (OR, 11.145; 95% CI, 1.23 to 101.29; P = .032) and neutropaenia (OR, 10.558; 95% CI, 1.07 to 104.65; P = .044) were independently associated with risk of mortality. Therefore, hepatic dysfunction and neutropaenia are independent early predictors of mortality in HSCT recipients with PCs.     

Outcome in six children with mucopolysaccharidosis type IH, Hurler syndrome, after haematopoietic stem cell transplantation (HSCT)

AIM: To follow-up six children with severe mucopolysaccharidosis type IH, Hurler syndrome, who were treated before 24 months of age with haematopoietic stem cell transplantation. METHODS: In Sweden, during the last 10-year period, six consecutive children born with severe mucopolysaccharidoses type IH have been successfully transplanted using matched unrelated donors between the ages of 11 and 24 months (mean age 18 months). Three children received intravenous enzyme replacement therapy once a week, from diagnosis until engraftment of their bone marrow. RESULT: Two children developed chimerism and a progressive increase in recipient cells and later received a successful re-transplantation. One to two years after transplantation the children demonstrated some developmental delays in cognitive function. Latterly this was followed by normalization. Orthopaedic operations on the spine and hips and carpal tunnel syndrome were still required following transplantation. Cardiac valve involvement remained progressive in the children. CONCLUSION: The outcome of six children in this study confirms that early haematopoietic stem cell transplantation in mucopolysaccharidosis type I, Hurler syndrome, preserves an affected child's mental ability. Consequently, it is essential that clinical recognition and early diagnosis take place, providing an additional challenge to paediatricians treating this condition.     

From Severe Combined Immunodeficiency to Omenn syndrome after hematopoietic stem cell transplantation in a RAG1 deficient family

Background: Mutations in RAG genes cause a spectrum of severe immunodeficiencies ranging from Severe Combined Immunodeficiency (SCID) T‐B‐NK+ to Omenn syndrome (OS) through intermediate phenotypes, even for the same alteration. Nowadays, hematopoietic stem cell transplantation (HSCT) is the unique curative treatment available. Methods: We describe three related patients from a Moroccan consanguineous family. Patient 1 developed at 1 month of age moderate eczematous dermatitis with eosinophilia, followed by infections and enteritis. He was transplanted and received reduced intensity conditioning regimen previous to HSCT. His brother, patient 2, was born preterm with a severe neonatal erythroderma, hepatosplenomegaly and lymphadenopathy. Patient 3, cousin of the two siblings, was also born preterm and fulfilled all criteria for classical OS. Immunological evaluation was performed and RAG genes were sequenced. Results: Immunological data from all three patients were very diversed, from T lymphopenia to marked lymphocytosis, and different degrees of eosinophilia and IgE levels. Non‐responder T cells and absent B cells were constant. All patients presented the same homozygous mutation in RAG1 gene (c.631delT). Patient 1 fully recovered both clinically and immunologically after HSCT. Two years later, he lost the accomplished lymphoid chimera and the disease relapsed as a classical OS, leading to patient’s death. Conclusions: This is the first report of a RAG1 deficient patient with a changed clinical and immunological phenotype from SCID to OS after HSCT. The use of a myeloablative conditioning regimen that eliminates reminiscent T cells might have improved patient’s outcome and it should be considered in similar cases.     

Bacterial meningitis from Rothia mucilaginosa in patients with malignancy or undergoing hematopoietic stem cell transplantation

Opportunistic infections contribute to morbidity and mortality of patients undergoing hematopoietic stem cell transplantation and treatment for malignancies. Rothia mucilaginosa, a gram-positive bacterium, is responsible for rare, but often fatal meningitis in severely immunocompromised patients. We describe two cases of meningitis from discrete strains of R. mucilaginosa on our pediatric bone marrow transplant unit, summarize the published cases of R. mucilaginosa meningitis in oncology and stem cell transplant patients, and provide updated recommendations regarding the use of antibiotic therapy in this patient population.     

Accelerated phase in partial albinism with immunodeficiency (Griscelli syndrome): genetics and stem cell transplantation in a 2-month-old girl

A 2-month-old girl presented with fever, hepatosplenomegaly, pancytopenia, hypertriglyceridaemia and silvery-greyish hair, suggesting the diagnosis of Griscelli syndrome (partial albinism with immunodeficiency). This diagnosis was confirmed by the characteristic agglomeration of melanin in the hair shaft and accumulation of melanosomes in melanocytes of the skin. The patient was homozygous for polymorphic markers around the myosin-Va gene on chromosome 15q21, which co-localize to the Griscelli disease locus. Natural-killer cells were in the lower range. The stimulation of lymphocytes with antigen and mitogen was normal. The patient's accelerated phase, characterized by haemophagocytosis was treated with prednisolone, rabbit anti-thymocyte globulins, and intrathecal methotrexate. Remission was maintained with cyclosporin A until HLA-compatible peripheral blood stem cell transplantation from her mother. Conclusion The silvery-greyish hair associated with fever, pancytopenia and hypertriglyceridaemia is the clue to early diagnosis of Griscelli syndrome and important to prevent death before stem cell transplantation. Received: 6 April 1999 / Accepted: 19 July 1999     

ͬ��������Ѫ��ϸ����ֲ���ƶ�ͯѪҺ��4������

目的观察同基因外周血造血干细胞移植治疗儿童再生障碍性贫血、白血病的植入情况及疗效。方法北京儿童医院于2004-08—2004-12,对4例分别患有慢性粒细胞性白血病(慢性期)、急性非淋巴细胞白血病(M2)、急性再生障碍性贫血、急性淋巴细胞白血病(ph1+)的患儿进行正规方案治疗,3例白血病患儿获得首次缓解,4例患儿接受不同预处理方案,进行同基因外周血干细胞移植。所有供者均为患儿的同卵双胎同胞,并经重组人粒细胞集落刺激因子(rhG-CSF)动员。结果4例患儿接受干细胞(MNC)平均数量为10·08×108/kg。白细胞及血小板平均植入时间分别为10·7d及12·3d,无明显移植并发症。病例4随诊5个月后复发,放弃治疗2个月后死亡,余病例均存活,可正常生活,随诊时间均在16个月以上。结论同基因外周血干细胞移植可以作为治疗包括白血病在内的多种血液病的有效方法,但其远期效果还有待进一步评估。     

Antibody response to vaccination after haematopoietic cell transplantation in children using a reduced dose schedule—A retrospective cohort study

Children receiving HCT loose protective immunity to vaccines received pre‐HCT. Therefore, revaccination post‐HCT is of major importance. In Denmark, a vaccination schedule with fewer doses post‐HCT has been used, including two doses for diphtheria, tetanus, polio, measles, mumps, and rubella, and one dose only for Haemophilus influenzae type B. The background for this was the presumption that post‐HCT immunization constituted booster vaccination of donor immunity. Our objective was to evaluate the proportion of children protected after the scheduled vaccination programme. A nationwide retrospective cohort study of all children who have received an HCT in Denmark during 1994‐2012. Antibody levels were analysed in blood samples drawn before and after vaccination, and the probability of achieving protection after the scheduled immunization programme was estimated. A total of 198 children were included. The protection post‐immunization was as follows: diphtheria 75.3%, tetanus 89.1%, polio 97.7%, and Haemophilus influenzae type B 94.8%. For diphtheria and tetanus, the probability of achieving protection increased to 93.8% and 97.3%, respectively, after a third dose. For measles, mumps, and rubella, the probability of achieving protection was 89.4%, 80.9%, and 94.2%, respectively. In conclusion, our findings support a more extensive vaccination schedule including three doses for diphtheria and tetanus which are in line with current international guidelines.     

Rehabilitative intervention during and after pediatric hematopoietic stem cell transplantation: An analysis of the existing literature

Hematopoietic stem cell transplantation is a therapeutic strategy for several oncohematological diseases. It increases survival rates but leads to a high incidence of related effects. The objective of this paper was to examine the existing literature on physical exercise interventions among pediatric HSCT recipients to explore the most often utilized rehabilitative assessment and treatment tools. Studies published from 2002 to April 1, 2015 were selected: 10 studies were included. A previous literary review has shown that rehabilitation programs have a positive impact on quality of life. Our analysis identified some significant outcome variables and shared intervention areas.