Diagnosis and Management of Acquired Aplastic Anemia: Consensus Statement of Indian Academy of Pediatrics

Justification: In India, there is a lack of uniformity of treatment strategies for aplastic anemia (AA), and many children are managed only with supportive care due to non-availability of hematopoietic stem cell transplantation (HSCT). Process: Eminent national faculty members were invited to participate in the process of forming a consensus statement in Hyderabad in July, 2016. Draft guidelines were circulated to all members, and comments received in a online meeting in October, 2020 were incorporated into the final draft. These were approved by all experts. Objective: To facilitate appropriate management of children with acquired aplastic anemia. Recommendations: Key recommendations are: i) A bone marrow biopsy is must to make a diagnosis of AA; ii) Rule out inherited bone marrow failure syndromes (IBMFS), connective tissue disorders, viral infections, paroxysmal nocturnal hemoglobinuria (PNH), drug or heavy metal induced marrow suppression in all cases of AA; iii) Conservative approach to transfusions should be followed, with a target to keep hemoglobin >6 g/dL in children with no co-morbidities; iv) HLA-matched sibling donor HSCT is the preferred choice of treatment for newly diagnosed very severe/ severe AA; v) In absence of HLA-matched family donor, a matched unrelated donor (MUD) transplant or immunosuppressive therapy (IST) should be considered as alternate choice based on physician expertise; vi) Fludarabine, cyclophosphamide and anti-thymocyte globulin (ATG) based conditioning with cyclosporine and methotrexate as graft versus host disease (GvHD) prophylaxis is the preferred regimen; vii) Horse ATG and cyclosporine are the recommended drugs for IST. One should wait for 3-6 months for the response assessment and consideration of next line therapy.

Infecciones respiratorias virales en episodios de fiebre en niños con trasplante de precursores hematopoyéticos / Respiratory viral infections during episodes of fever in children undergoing hematopoietic stem cell transplantation

Resumen Introducción: Los niños que reciben trasplante de precursores hematopoyéticos (TPH) pueden presentar infecciones respiratorias virales (IRV) durante episodios febriles. Los datos sobre su evolución clínica son escasos, así como la comparación de ellos con infecciones bacterianas (IB). Objetivo: Caracterizar la evolución clínica de pacientes con IRV, en comparación con IB en niños con TPH, cursando un episodio febril. Método: Estudio prospectivo en pacientes ≤ 18 años con cáncer y TPH ingresados por fiebre en el Hospital Luis Calvo Mackenna (2016-2019). Se realizó evaluación clínica y de laboratorio: hemocultivos, RPC para patógenos respiratorios (Filmarray®), cuantificación viral y medición de citoquinas en muestra nasal (Luminex®, 38 citoquinas). Se compararon los grupos IRV, IB y los de etiología no precisada (ENP) en relación con: infección respiratoria aguda (IRA), citoquinas nasales, ingreso a UCI, necesidad de ventilación mecánica, mortalidad y suspensión de antimicrobianos. Resultados: De 56 episodios febriles, 35 fueron IRV, 12 IB y 9 de ENP. Mediana de edad fue 8,5 años, 62% masculino. Un 94% de los casos IRV presentó IRA sintomática, versus 33% en los grupos IB y ENP (p < 0,001), con IRA baja en 69% de las IRV (p < 0,001). Rinovirus (54%) y coronavirus (15%) fueron las etiologías más frecuentemente detectadas. No hubo diferencias en citoquinas nasales entre los grupos IRV e IB. Ingreso a UCI: 11% del grupo IRV, 17% de IB y 11% de ENP (p = 0,88). Requirieron ventilación mecánica sólo 2 pacientes (p = 0,37) sin fallecimiento. Tras la detección viral respiratoria por RPC, se suspendió antimicrobianos en 26% de los casos con IRV (p = 0,04). Conclusión: Las IRV son frecuentes en niños con TPH y episodios febriles. La detección viral podría optimizar y racionalizar el uso de antimicrobianos en esta población.

Abstract Background: Children undergoing hematopoietic stem cell transplant (HSCT) can develop respiratory viral infections (RVI) during fever episodes. There are few data about clinical outcomes in RVI and compared to bacterial infections (BI) in this population. Aim: To determine clinical outcome of RVI, compared to BI in children with HSCT. Methods: Prospective study, patients ≤ 18 years with cancer and HSCT admitted with fever at a National Bone Marrow Transplant Center (Hospital Calvo Mackenna), Chile, (April-2016 to May-2019). Clinical assessment, laboratory tests, blood cultures, nasopharyngeal sample for multiplex-PCR (Filmarray®), viral loads by PCR and cytokine panel (Luminex®, 38 cytokines) were performed. The following outcomes were evaluated: upper/lower respiratory tract disease (RTD), admission to ICU, mechanical ventilation, mortality and antimicrobial withdrawal. Results: Of 56 febrile episodes, 35 (63%) were RVI, 12 (21%) BI and 9 (16%) with unknown etiology (UE). Median of age was 8.5 years, 62% male gender. Rhinovirus (54%) and coronavirus (15%) were the more frequent detected viruses. No significant differences in cytokine levels were observed between RVI and BI. 94% of RVI patients had symptomatic RTD, versus 33% in BI and 33% in UE group (p < 0.001), with lower-RTD in 69% of RVI group (p < 0,001). Admission to ICU was 11% in RVI, 17% in BI and 11% in UE group (p = 0.88); only 2 patients required mechanical ventilation (p = 0.37) and no mortality was reported. After an RVI was detected by PCR, antimicrobials were withdrawal in 26% of patients with RVI (p: 0.04). Conclusion: RVI are frequent etiologic agents in febrile episodes of patients with HSCT. Viral detection might help to rationalize the use of antimicrobials in this population.

Sobrecarga de cuidadores familiares de crianças e adolescentes em pós-transplante de células-tronco hematopoéticas imediato / Burden of family caregivers of children and adolescents in post-hematopoietic stem cell transplantation

Resumo: O objetivo deste trabalho foi avaliar a sobrecarga de cuidadores familiares de crianças e adolescentes no pós-transplante de células-tronco hematopoéticas imediato. Trata-se de um estudo de natureza quantitativa, do tipo analítico e transversal, vinculado ao projeto Construindo processos de cuidado na interface do cuidar em situações de enfermidade grave inserido na linha de pesquisa Processo de cuidar em saúde e enfermagem, realizado em duas instituições de saúde - um complexo hospitalar de ensino, de nível terciário, atendendo a casos de médio e grave risco, e um hospital geral de nível terciário, ambos de Curitiba, Paraná -, escolhidas nesta modalidade de tratamento. A amostra foi composta por 31 cuidadores de crianças e adolescentes no pós-transplante imediato e a coleta de dados foi realizada entre outubro de 2018 e junho de 2019. Foram caracterizados o perfil sociodemográfico dos cuidadores e o perfil clínico das crianças e adolescentes, por meio de questionários elaborados pela autora, e avaliada a sobrecarga do cuidador, pela caregiver burden scale. Para a análise dos dados, utilizaram-se a estatística descritiva, o teste não paramétrico de Mann-Whitney, o teste não paramétrico de Kruskal-Wallis e a correlação de Spearman. Os resultados evidenciaram a prevalência de cuidadores do sexo feminino (93,5%), mães (87,1%), casadas (41,9%), desempregadas (77,4%), recebendo benefícios sociais (51,6%) e residindo em casa de apoio (58,1%). As crianças e adolescentes eram do sexo masculino, idade variando de zero a 16 anos, com diagnóstico predominante de anemia de Fanconi e leucemia linfoide aguda. Os dados revelaram um escore global no valor de 2,4/4, sendo os domínios com maiores escores: tensão geral e decepção, ambos com 2,8/4. Na análise, houve correlação entre esses domínios, bem como entre a variável "ocupação" e o domínio "decepção". A sobrecarga subjetiva neste estudo relacionou-se com o significado de que o cuidar gera impacto positivo ou negativo no cuidado. Conclui-se que a sobrecarga do cuidado repercute nas diversas áreas da vida dos cuidadores, sendo o cuidar no domicílio um desafio para o familiar, um cuidar solitário e desgastante. A partir da avaliação da sobrecarga, será possível ter subsídios para a elaboração de ações em saúde que incluam o familiar no cuidado multidisciplinar.

Abstract: The objective of this research was to evaluate the overload of family caregivers of children and adolescents in immediate post-hematopoietic stem cell transplant. It is a quantitative study of analytical and traverse type, linked to the project Building care processes at the interface of care in situations of serious illness inserted in the research line Care process in health and nursing, accomplished in two health institutions (a teaching hospital compound of tertiary level assisting to cases of medium and serious risk, and a general hospital of tertiary level, both of Curitiba, Paraná), chosen in this treatment modality. The sample was composed by 31 caregivers of children and adolescents in the immediate post-transplant and the data collection was accomplished between October of 2018 and June of 2019. The caregivers social-demographic profile and the children and adolescents clinical profile were characterized through questionnaires elaborated by the author, and the caregivers overload was appraised using the caregiver burden scale. For the data analysis, the descriptive statistics, the Mann-Whitney U test, the Kruskal-Wallis test and the Spearman correlation were used. The results evidenced the prevalence of female caregivers (93.5%), mothers (87.1%), married (41.9%) and unemployed women (77.4%), receiving social benefits (51.6%), and living in support home (58.1%). The children and adolescents were male, with age varying from zero to 16 years old, and the predominant diagnosis was Fanconi anaemia and acute lymphoblastic leukemia. The data revealed a global score of 2.4/4, being the domains with larger scores: general tension and deception, both with 2.8/4. In the analysis, there was correlation among those domains, as well as among occupation and deception. The subjective overload in this study linked with the meaning that taking care generates positive or negative impact in care . In conclusion, the overload in care echoes in several areas of the caregivers' life, being the home taking care a lonely and stressful challenge for the relative. From the evaluation of the overload, it will be possible to have subsidies for the elaboration of actions in health that include the relative in the multidisciplinary care.

Hematopoietic stem cell transplantation in children with Griscelli Syndrome type 2: Experience and outcomes

Griscelli syndrome is a rare autosomal recessive inherited disorder characterized by hypopigmentation, silver colored hair, and associated immunological deficiency, which proves fatal in the absence of timely intervention. Our patients diagnosed with Griscelli syndrome-2 presented with fever, hepatosplenomegaly, and deranged hematological and biochemical parameters. Both cases underwent detailed investigations comprising of hair mount microscopic examination, degranulation assay, and mutational studies. Our cases showed defective degranulation activity by NK cells and gene mutation analysis revealed RAB27A mutation that causes defect of cytotoxic granule exocytosis from natural killer (NK) and T-cells, manifesting clinically as hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplantation in one of the patients resulted in stable chimerism; however, the second case relapsed within a month after SCT. Stem cell transplantation is the only curative therapeutic option for GS2; thus, improvement in posttransplantation management may reduce mortality and posttransplant complications. Hence, any child who presents with partial albinism and clinical features suggestive of HLH, a peripheral blood, hair shaft mount examination along with basic immunological NK and T-cell cytotoxicity assay by flow cytometry will help clinch the diagnosis early. It can subsequently be confirmed by molecular study. Timely therapeutic intervention can prevent relapses and severe infection and improve outcome in these cases.

Assessing the impact of ABO incompatibility on major allogeneic hematopoietic stem cell transplant outcomes: a prospective, single-center, cohort study

Abstract Background ABO blood group incompatibility between donor and recipient is associated with a number of immunohematological complications, but is not considered a major contraindication to allogeneic hematopoietic stem cell transplantation. However, available evidence from the literature seems to be conflicting as to the impact of incompatibility on overall survival, event-free survival, transplant-related mortality, graft-versus-host disease, and time to neutrophil and platelet engraftment. Methods This single-center, prospective, cohort study included patients with hematological malignancies who underwent a first allogeneic hematopoietic stem cell transplantation between 2008 and 2014. Patients receiving umbilical cord blood as the stem cell source were excluded from this analysis. The impact of ABO incompatibility was evaluated in respect to overall survival, event-free survival, transplant-related mortality, acute graft-versus-host disease and engraftment. Results A total of 130 patients were included of whom 78 (60%) were males. The median age at transplant was 36 (range: 2-65) years, 44 (33%) presented ABO incompatibility, 75 (58%) had acute leukemia, 111 (85%) had a related donor, 100 (77%) received peripheral blood hematopoietic stem cells as graft source and 99 (76%) underwent a myeloablative conditioning regimen. There was no statistically significant association between ABO incompatibility and overall survival, event-free survival, transplant-related mortality, grade II-IV acute graft-versus-host disease, neutrophil or platelet engraftment in multivariate analysis. Conclusion These results show that ABO incompatibility does not seem to influence these parameters in patients undergoing allogeneic hematopoietic stem cell transplantation.

Elementos constitutivos do cuidado às crianças, adolescentes e famílias no transplante de células-tronco hematopoiéticas: percepção da equipe de saúde / Constituent elements of care for children, adolescents and families in hematopoietic stem cell transplantation: perception of the health team

O cuidado corresponde a essência humana e envolve dialogicidade, afeto e inter-relação. O cuidado em saúde extrapola a visão biologicista e higienista, e nega as relações mecanizadas entre o ser que cuida e o ser cuidado. Desse modo, orienta-se pela ética e busca auxiliar o outro nos momentos de fragilidade a fim de que este se restabeleça a partir da sua singularidade. Neste sentido, esta pesquisa objetivou conhecer os elementos constitutivos do cuidado às crianças, adolescentes e famílias no processo de Transplante de Células-Tronco Hematopoéticas (TCTH) alogênico na percepção da equipe de saúde. Trata-se de uma Pesquisa Convergente Assistencial, de abordagem qualitativa. Participaram deste estudo 14 profissionais da saúde que cuidam de crianças e adolescentes durante o TCTH e que respeitavam os critérios de inclusão/exclusão. O cenário desta pesquisa foi a Unidade de Ambiente Protegido ­ Transplante de Medula Óssea de um hospital terciário do sul do país. As informações foram coletadas, nos meses de setembro a dezembro de 2018, por meio de entrevistas semi-estruturadas, as quais foram validadas pelos participantes. Os princípios éticos das pesquisas em ciências humanas e sociais foram respeitados segundo as resoluções nº466 de 2012 e nº510 de 07 de abril de 2016 e a pesquisa foi aprovada pela Comissão de Pesquisa da Escola de Enfermagem da UFRGS e pelo Comitê de Ética em Pesquisa da UFRGS via Plataforma Brasil. A análise das informações foi concomitante às coletas e emergiram três eixos principais intitulados: Construção do cuidado; Melhor interesse da criança e do adolescente; Reflexões dos profissionais sobre o cuidado da criança, adolescente e suas famílias submetidos ao TCTH - composto pelos subeixos: a visão do profissional sobre sua prática de cuidado; enfrentamento do profissional e a visão do profissional sobre o enfrentamento da criança, do adolescente e da família. A partir dos resultados foi possível identificar que o adoecimento da criança e do adolescente representa à família a possibilidade de morte do filho, bem como a perda dos projetos futuros, alterando, assim, sua trajetória de vida sonhada. Essa facticidade existencial soma-se a necessidade de realizar o TCTH, visto que este configura-se como um tratamento associado a altos índices de morbimortalidade. Neste cenário, os profissionais buscam articular seus conhecimentos a fim de estabelecer o melhor plano terapêutico e se sensibilizam diante das situações de vulnerabilidade vivenciadas pelas crianças/adolescentes e famílias. Destaca-se como contribuições para a saúde, em especial para a enfermagem, a visibilidade das percepções sobre o cuidado, evidenciando os aspectos existenciais envolvidos no TCTH. Identifica-se que a subjetividade permeia o processo do cuidado revelando a complexidade de estabelecer os limites terapêuticos e os cuidados paliativos pediátricos, bem como, aceitar a morte da criança e do adolescente como uma facticidade existencial. Esta visão pode ampliar as estratégias de cuidado nessa área.

Care corresponds to a human essence and involves dialogue, affection and interrelation. The health care goes beyond the biological and hygienist view and denies the mechanics relation between who cares and who been cared. It is guided by ethics and seeks to help other in the fragility moments to promove and restored uniqueness. In that way, this research aimed knows the constitutive elements of caring for children, adolescents and families in the process of allogenic hematopoietic stem cell transplant in the perception of health care team. A convergent care research method was adopted with a qualitative approach. Participated of this study a total of 14 health professionals who take care of children, adolescents and families and who respected inclusion/exclusion criteria. The scenario of this research was the Protected Environment Unity ­ TMO in a tertiary referral hospital of south region in Brazil. Informations were collected, during September to November 2018, through semi-structured interviews, which were validated by the participants. Ethical principles in humans and socials sciences research were respected according the resolutions nº 466 of 2012 and nº 510 of April 7th 2016, this survey was approved by the Research Committee of the UFRGS Nursing School and by the CEP of UFRGS via ´Plataforma Brazil´. Analysis information were concomitant with the assessment and showed tree principals axes named: Care construction; Better interest of children and adolescents axis; Professionals reflection about the caring of children, adolescents and their families submitted to HSCT ­ with sub-axes: professional´s perception about their care practice; professional´s coping strategies and their perception about coping strategies of children, adolescents and families. According the results was possible to identify that child and adolescent´s illness represents son´s death possibility for the family, as well as loosing future projects, thus altering their dream life trajectory. This existential facticity there is a need to perform the Hematopoietic Stem Cell Transplant (HSCT), since this is configured as a treatment associated with high rates of morbidity and mortality. In this scenario, professionals can be able to articulate their knowledge to establish the best therapeutic plan and in front of vulnerability situations touch their self by children, adolescents and families experience. As contribution for health, in special for nursing, stands out a visibility for perceptions about care, showing essential aspects involved in HSCT. It was identified that subjectivity permeates the process of care revealing a complexity in the establishment of therapeutic limits and pediatrics palliative care, as well as to accept child and adolescent death as a existential facticity. This vision can broaden strategies care in this area.

A resiliência na trajetória de clientes no pós-transplante de células-tronco hematopoiéticas / La resiliencia en la trayectoria de los clientes en post-trasplante de células madre hematopoyéticas / Resilience in the trajectory client post-transplantation hematopoietic stem cell

RESUMO Introdução: A resiliência apresenta-se como tema relevante de estudo no cotidiano do pós-transplante de células-tronco hematopoiéticas. Objetivo: identificar o nível de resiliência dos clientes no pós-transplante; e analisar os fatores de risco e de proteção, e expectativas presentes no cotidiano do pós-transplante. Metodos: Estudo qualitativo, realizado com 15 clientes no pós-transplante de células-tronco hematopoiéticas da Unidade de Transplante de Medula Óssea de um hospital universitário localizado no município do Rio de Janeiro, Brasil. Os dados foram coletados entre os meses de julho e agosto de 2011, por meio da Escala de Resiliência e da entrevista semiestruturada. Resultados: Os clientes apresentaram uma resiliência moderada, e da análise temática das entrevistas emergiram três subunidades: O tratamento que adoece e que faz perder a potência; Os suportes interno e externo: fortalecendo as estratégias de enfrentamento; e A superação como um processo. Conclusão: Os clientes se encontram em um processo de superação, uma vez que ainda vivenciam as dificuldades decorrentes do tratamento, requerendo estratégias adequadas de enfrentamento. Através dos pressupostos da resiliência, permitiu-se conhecer tais movimentos presentes neste universo, além de fomentar a necessidade de novas pesquisas dentro da temática(AU)

RESUMEN Introducción: La resiliencia presenta un tema relevante del estudio cotidiano post-trasplante de trasplante de células madre hematopoyéticas. Objetivo: Identificar el nivel de resiliencia de los clientes después del trasplante; y analizar el riesgo y los factores protectores presentes en el día a día post-trasplante. Métodos: estudio cualitativo realizado con 15 clientes en el post-trasplante de una unidad de trasplante de médula de un hospital universitario en la ciudad de Río de Janeiro, Brasil. Los datos fueron recolectados entre julio y agosto de 2011, por medio de la Escala de Resiliencia y entrevista semiestructurada. Resultados: Los clientes mostraron una resiliencia moderada, y el análisis temático de las entrevistas revelaron tres subunidades: tratamiento que hace enfermar y hace perder el poder; los soportes interno y externo: el fortalecimiento de las estrategias de supervivencia; y la superación como proceso. Conclusión: Los clientes estaban en un proceso de recuperación, ya que todavía experimentaban las dificultades resultantes del tratamiento, lo que requiere estrategias de afrontamiento adecuadas. A través de los supuestos de la capacidad de recuperación, se le permitió hacer frente a tales movimientos presentes en este universo, así como la promoción de la necesidad de nuevas investigaciones sobre el tema(AU)

ABSTRACT Introduction: Resilience is currently a topic worth studying in daily life for cases of hematopoietic stem cell transplantation. Objective: To identify the level of resilience of the clients after transplant and to analyze the risk and the protective factors present in the day-to-day post-transplant. Methods: Qualitative study conducted on 15 clients in the post-transplant of a bone marrow transplant unit of a university hospital in the city of Rio de Janeiro, Brazil. Data were collected between July and August 2011, through the Resilience Scale and a semi-structured interview. Results: Clients showed moderate resilience, and the thematic analysis of the interviews showed three subunits: treatment that makes people sick and lose power, internal and external supports (strengthening of survival strategies), and overcoming as a process. Conclusion: Clients were in a recovery process, as they still experienced the difficulties resulting from treatment, which requires adequate managing strategies. Through the assumptions of the capacity for recovery, they were allowed dealing with such movements present in this universe, as well as promoting the need for new research on the subject(AU)

Establishment of a animal model of allogeneic bone marrow transplantation plus thymic epithelial cells transplantation / 中华器官移植杂志

Objective To explore the establishment of animal model of allogeneic bone marrow transplantation plus thymic epithelial cells transplantation,and then examine the feasibility and effects of thymic epithelial cells transplantation applied in allogeneic bone marrow transplantation.Methods One day before transplantation the recipient BALB/C mice were given total-body irradiation,then transplanted with bone marrow cells from donor C57BL/6 mice and thymic epithelial cells from E14-16 embryonic thymus of donor C57BL/6 mice.In order to explore the appropriate irradiation dose,we set up three different dose groups:7 Gy;6.5 Gy;6 Gy.The recipient mice transplanted with BMT plus TCT served as experimental group,and those transplanted with BMT only served as control group (n =8 each).Then in vivo imaging in mammals was done to observe the thymic epithelial cells transplantation.Thymus index was measured.The thymus in each group was collected for histological examination and immunohistochemical staining of K5 and K8.Flow cytometry was used to examine the T cells subsets in peripheral blood of recipient mice 4 weeks after thymus transplantation.Results The recipient mice with 6.0 Gy TBI had long-term survival but implantation was done unsuccessfully,and those with 6.5 Gy had lower survival rate but implantation was done successfully.6.5 Gy was the minimum lethal dose and could be used as the appropriate irradiation does in this study.In vivo imaging in mammals detecting system showed the experimental group obvious fluorescent signals could be detected in the experimental group,but no fluorescence was found in the control group.Four weeks after transplantation,the thymus was bigger and thymus index was higher in the experimental group than in the control group.And the chiemra thymus of the experimental group also had normal cortex and medulla histological structure.Four weeks after transplantion,the percentages of CD4+ and CD8+ T cells of the peripheral blood in experimental group were significantly higher than in control group (P＜ 0.05).Conclusion Thymic epithelial cells can be transplanted in the thymus of the recipient mice with allogeneic bone marrow transplantation and promote the reconstitution of T lymphocytes of peripheral blood in the recipient mice.

Allogeneic hematopoietic stem cell transplantation in patients with advanced indolent lymphoproliferative disorders

BACKGROUND: The role of allogeneic hematopoietic stem cell transplantation for advanced indolent lymphoproliferative disorders remains to be established. OBJECTIVE: This paper aims to describe the results of allogeneic hematopoietic stem cell transplantation in patients with advanced indolent lymphoproliferative disorders. METHODS: This article reports on 29 adult patients submitted to allogeneic transplantations from 1997 to 2010. RESULTS: Most had follicular non-Hodgkin lymphoma (n = 14) or chronic lymphocytic leukemia (n = 12). The median age was 44 years (range: 24-53 years) and 65% of patients were male. Only 21% had had access to rituximab and 45% to fludarabine. All had advanced disease (stage IV) with partial response or stable disease. Most underwent myeloablative conditioning n = 17 - 59%). In this scenario, refractory disease was observed in seven (24%) patients, the 100-day mortality rate was 17% (n = 5) and relapse occurred in four patients (18%). The main cause of death throughout the follow up was refractory disease in six of the 12 patients who died. Moderate and severe chronic graft-versus-host disease was frequent; about 41% of 24 patients analyzed. The overall survival rates and disease free survival at 42 months were 56.7% and 45.4%, respectively. According to Kaplan-Meyer analysis, the median time from diagnosis to transplant predicted the overall survival; however age, gender and conditioning regimen did not predict the prognosis. It was impossible to reach other conclusions because of the small sample size in this study. CONCLUSIONS: The role of allogeneic transplantations should be re-evaluated in the era of targeted therapy.

Recent advances in the risk factors, diagnosis and management of Epstein-Barr virus post-transplant lymphoproliferative disease / Avances recientes en los factores de riesgo, diagnóstico y tratamiento de la enfermedad linfoproliferativa post trasplante con infección por virus de Epstein-Barr

Fifty years after the first reports of Epstein-Barr virus (EBV)-associated endemic Burkitt's lymphoma, EBV has emerged as the third most prevalent oncogenic virus worldwide. EBV infection is associated with various malignancies including Hodgkin and non-Hodgkin lymphoma, NK/T-cell lymphoma and nasopharyngeal carcinoma. Despite the highly specific immunologic control in the immunocompetent host, EBV can cause severe complications in the immunocompromised host (namely, post-transplant lymphoproliferative disease). This is particularly a problem in patients with delayed immune reconstitution post-hematopoietic stem cell transplant or solid organ transplant. Despite advances in diagnostic techniques and treatment algorithms allowing earlier identification and treatment of patients at highest risk, mortality rates remain as high as 90% if not treated early. The cornerstones of treatment include reduction in immunosuppression and in vivo B cell depletion with an anti-CD20 monoclonal antibody. However, these treatment modalities are not always feasible due to graft rejection, emergence of graft vs. host disease, and toxicity. Newer treatment modalities include the use of adoptive T cell therapy, which has shown promising results in various EBV-related malignancies. In this article we will review recent advances in risk factors, diagnosis and management of EBV-associated malignancies, particularly post-transplant lymphoproliferative disease. We will also discuss new and innovative treatment options including adoptive T cell therapy as well as management of special situations such as chronic active EBV and EBV-associated hemophagocytic lymphohistiocytosis.

A cincuenta años de los primeros reportes de asociación del linfoma de Burkitt con el virus de Epstein-Barr (VEB), el VEB ha emergido como el tercer virus de tipo oncogénico con mayor prevalencia a escala mundial. La infección por VEB se asocia con diversas neoplasias, incluyendo el linfoma de Hodgkin y el no Hodgkin, linfoma de células T/NK y carcinoma nasofaríngeo. A pesar del control inmunológico altamente específico en el huésped inmunocompetente, el VEB puede ocasionar complicaciones severas en el huésped inmunocomprometido (es decir, la enfermedad linfoproliferativa post-trasplante). Esto es un problema particularmente en pacientes en quienes se retrasa la reconstitución de la inmunidad después de un trasplante de células madre hematopoyéticas o un trasplante de órganos sólidos. A pesar de los avances en las técnicas de diagnóstico y los algoritmos de tratamiento que permiten la identificación temprana y el tratamiento de pacientes de alto riesgo, las tasas mortalidad siguen siendo muy altas (del 90%) si no se recibe tratamiento temprano. La piedra angular del tratamiento incluye la disminución de la inmunosupresión y la depleción de células B in vivo con un anticuerpo monoclonal anti-CD20. Sin embargo, estas modalidades de tratamiento no son siempre posibles debido al rechazo del injerto, la enfermedad de injerto contra huésped y la toxicidad. Nuevas modalidades de tratamiento incluyen el uso de la terapia adoptiva de células T, que ha mostrado resultados promisorios en diversas neoplasias relacionadas con el VEB. En este artículo se revisan los avances más recientes en cuanto a los factores de riesgo, diagnóstico y tratamiento de las neoplasias asociadas con VEB, particularmente la enfermedad linfoproliferativa post-trasplante. También se discuten los tratamientos más recientes e innovadores, que incluyen la terapia adoptiva de células T así como el manejo de situaciones especiales, como la infección crónica activa de VEB y la linfohistiocitosis hemafagocítica asociada con VEB.

Estudio retrospectivo de la aplicación de la amplificación génica cualitativa en muestras biológicas para el seguimiento de la toxoplasmosis en pacientes pediátricos receptores de trasplante de células progenitoras hematopoyéticas / Retrospective study of the implementation of the qualitative PCR technique in biological samples for monitoring toxoplasmosis in pediatric patients receiving hematopoietic stem cell transplantion

La toxoplasmosis es una infección oportunista causada por el parásito Toxoplasma gondii; su infección es grave y de difícil diagnóstico en pacientes que reciben un trasplante alogénico de células progenitoras hematopoyéticas (TCPH). En el Hospital de Pediatría S.A.M.I.C. "Profesor Dr. Juan P. Garrahan" se realizó la vigilancia postrasplante de 12 pacientes receptores de TCPH mediante la técnica de PCR cualitativa. La necesidad de seguimiento de estos pacientes fue definida por el antecedente de serología positiva para toxoplasmosis en el donante o receptor y ante la imposibilidad de iniciar el uso profiláctico de trimetoprima-sulfametoxazol a causa de la condición hematológica. Dos pacientes presentaron signos de enfermedad por T. gondii con resultado de PCR positivo y recibieron tratamiento con pirimetamina-clindamicina. En otros dos, la toxoplasmosis fue causa de muerte y hallazgo de autopsia, con resultado de PCR negativo. Cuatro pacientes recibieron tratamiento contra toxoplasmosis por la detección de una PCR positiva, sin manifestaciones clínicas. En los cuatro pacientes restantes no se detectaron signos de enfermedad por toxoplasmosis, con resultados de PCR negativos durante el seguimiento. La técnica de PCR cualitativa demostró ser útil para detectar la reactivación de la toxoplasmosis en receptores de TCPH, pero tiene limitaciones para el seguimiento y la toma de decisiones clínicas en pacientes con PCR positiva que persiste en el tiempo y manifestaciones de toxicidad por el tratamiento.

Toxoplasmosis is an opportunistic infection caused by the parasite Toxoplasma gondii. The infection is severe and difficult to diagnose in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Twelve patients receiving HSCT were monitored post-transplant, by qualitative PCR at the Children's Hospital S.A.M.I.C. "Prof. Dr. Juan P. Garrahan". The monitoring of these patients was defined by a history of positive serology for toxoplasmosis in the donor or recipient and because their hematologic condition did not allow the use of trimethoprim-sulfamethoxazole for prophylaxis. During the patients' monitoring, two of them with positive PCR results showed signs of illness by T. gondii and were treated with pyrimethamine-clindamycin. In two other patients, toxoplasmosis was the cause of death and an autopsy finding, showing negative PCR results. Four patients without clinical manifestations received treatment for toxoplasmosis because of positive PCR detection. In four patients there were no signs of toxoplasmosis disease and negative PCR results during follow-up. The qualitative PCR technique proved useful for the detection of toxoplasmosis reactivation in HSCT recipients, but has limitations in monitoring and making clinical decisions due to the persistence of positive PCR over time and manifestations of toxicity caused by the treatment.

Comparison of the direct fluorescence assay and real-time polymerase chain reaction for the detection of influenza virus A and B in immunocompromised patients

OBJECTIVE: This study evaluated the diagnostic performance of two methods for the detection of influenza virus in immunocompromised transplant patients. METHODS: A total of 475 respiratory samples, 236 from patients in a hematopoietic stem cell transplantation program and 239 from kidney transplant patients, were analyzed by a direct fluorescence assay and the Centers for Disease Control real-time polymerase chain reaction protocol for influenza A and B detection. RESULTS: Influenza detection using either method was 7.6% in the hematopoietic stem cell transplant group and 30.5% in the kidney transplant patient group. Influenza detection by real-time polymerase chain reaction yielded a higher positive rate compared with fluorescence than that reported by other studies, and this difference was more pronounced for influenza A. The fluorescence assay sensitivity, specificity, positive and negative predictive values, and kappa coefficient were 17.6%, 100%, 1, 0.83, and 0.256, respectively, and lower detection rates occurred in the kidney transplant patients. CONCLUSIONS: The real-time polymerase chain reaction performance and the associated turnaround time for a large number of samples support the choice of this method for use in different routine diagnostic settings and influenza surveillance in high-risk patients. .

Complicaciones infecciosas en el período inmediato precoz postrasplante de progenitores hematopoyéticos / Infectious complications in the immediate early post-transplantation of hematopoietic stem cells

Se realizó un estudio retrospectivo-descriptivo en el Servicio de Hematología del Hospital Clinicoquirúrgico Hermanos Ameijeiras desde enero de 1985 hasta diciembre de 2008, para determinar las complicaciones infecciosas en pacientes sometidos a trasplante de progenitores hematopoyéticos en el período precoz postrasplante (0-30 d). De los 179 trasplantes realizados, 127 fueron autólogos, 45 alogénicos y 7 mini-trasplantes. Las principales indicaciones fueron linfomas no Hodgkin, en 54 pacientes (30,2 por ciento), leucemias agudas no linfoblásticas, en 53 (29,6 por ciento) y linfomas de Hodgkin, en 26 (14, 5 por ciento). El esquema de acondicionamiento usado mayoritariamente fue ciclofosfamida, con etopósido o sin Úl, + irradiación corporal total. Se detectaron complicaciones infecciosas en 176 de los trasplantes realizados (98,3 por ciento), su aparición fue entre los días 4 y 7 después del trasplante y se relacionó con un conteo promedio de leucocitos menor de 500 x 10(9) /L y un conteo absoluto de neutrófilos menor de 100 x mm³. La forma clínica de presentación más frecuente fue la bacteriemia seguida de infecciones de piel y mucosas. Los gérmenes aislados con mayor frecuencia fueron el estafilococo coagulasa negativo, el género Candida y la Pseudomona aeruginosa. La antibioticoterapia empírica utilizada fue cefalosporina de tercera generación + aminoglucósido + vancomicina. La mortalidad general fue 8,9 por ciento (16/179), la sepsis fue la causa directa del fallecimiento en 7 casos (43,7 por ciento) con mayor incidencia en los trasplantes alogénicos, y las bacterias gramnegativas, las mayormente implicadas

A retrospective and descriptive study was carried out in the hematological service of Hermanos Ameijeiras clinical and surgical hospital from January 1985 to December 2008, in order to determine the infectious complications found in patients with hematopoietic stem cell transplants in the early post-transplantation period (0 to 30 days). Out of 179 transplants, 127 were autologous, 45 allogenic and 7 mini-transplants. The main indications for transplantation were non-Hodgking's lymphomas in 54 patients (30.2 percent), acute non-lymphoblastic leukemia in 53 (29.6 percent) and Hodgkin's lymphomas in 26 patients (14.5 percent). The mostly used conditioning schedule was cyclophosphamide with/without etoposide plus total body irradiation. One hundred seventy six transplants (98.3 percent) presented with infectious diseases; they occurred on the 4th through the 7th days after the transplantation and were related to average leukocyte count below 500 x 10(9)/L and absolute neutrophil count lower than 100 x mm³. The most frequent clinical presentation was bacteremia followed by skin and mucosal infections. The most commonly isolated germs were negative coagulase staphylococci, Candida genus and Pseudomona aeruginosa. The empirical antibiotic therapy was third generation cephalosporine plus aminoglucoside plus vancomycin. The general mortality rate was 8.9 percent (16 out of 179) and sepsis directly caused the death of 7 cases (43.7 percent), being the higher incidence in allogenic transplants, and the Gram negative bacteria were mostly involved

Osteopetrosis, calcificación más allá del sistema óseo. Reporte de un caso / Osteopetrosis - calcification beyond the skeletal system. A case report

Introducción. La osteopetrosis se presenta por una falla en la apoptosis de los osteoclastos, que producen un hueso altamente calcificado pero con mayor fragilidad. Al acumularse calcio en los espacios de los huesos largos destinados a la hematopoyesis, predomina la hematopoyesis secundaria. Con el tiempo se producen visceromegalias y pancitopenias. Es una enfermedad genética con baja incidencia y poca prevalencia en México. Caso clínico. Se trata de un paciente de sexo femenino de 12 años que inició con dolor en los huesos largos durante su niñez temprana de manera recurrente presentaba múltiples fracturas e infecciones; se mantenía en tratamiento con analgésicos y restricción de calcio. Se le considera como candidata para un trasplante de médula ósea, que no se ha realizado. Conclusiones. La osteopetrosis es una enfermedad poco común y compleja. Actualmente, no existe un tratamiento médico efectivo, por lo que es necesario un abordaje multidisciplinario. El trasplante de médula ósea constituye una alternativa viable para el tratamiento de algunos casos de osteopetrosis severa.

Background. Osteopetrosis represents a lack of apoptosis in osteoclastic activity, producing a highly calcified but fragile bone due to excess of calcium. Excess calcium deposited in the medullary compartment leads to bone expansion, producing a predominant secondary hematopoiesis accompanied by significant visceromegaly and pancytopenia. Osteopetrosis is a genetic disease with a low prevalence and incidence in Mexico. Case report. We report the case of a 12-year-old female who presented with bone pain in the lower extremities at an early age. A radiological diagnosis of ostepetrosis was made, and the condition was complicated by multiple fractures and infections. The patient was treated with dietary modifications and analgesics and was considered to be a candidate for hematopoietic stem-cell transplant. Conclusions. Osteopetrosis is a rare and complex disease without any current effective medical treatment, necessitating a multidisciplinary approach. Hematopoietic stem-cell transplantation offers a promising alternative treatment for certain cases of severe osteopetrosis.

Primary renal aspergillosis and renal stones in both kidneys associated with hematopoietic stem cell transplant / 대한혈액학회지

Invasive aspergillosis (IA) is a leading cause of infectious mortality in patients who have undergone a hematopoietic stem cell transplant (HSCT); the mortality due to IA ranges from 70% to 93% in HSCT patients. Early diagnosis and treatment are the cornerstones for the good prognosis of IA. Primary renal aspergillosis is an extremely rare presentation in patients who have undergone HSCT, and the risk factor for this uncommon presentation is not well known. We report a patient who developed primary renal aspergillosis and renal stones in both the kidneys after HSCT. Invasive renal aspergillosis was diagnosed after a nephrectomy, which was performed to treat massive renal hematoma.

Transplante de células-tronco hematopoéticas e a regeneração da hematopoese / Hematopoietic stem cell transplant and recovery of hematopoiesis

As células-tronco hematopoéticas periféricas (CTP) praticamente substituíram a medula óssea (MO) como fonte de células-tronco hematopoéticas nos transplantes autólogos e nos últimos anos é usada com maior frequência nos alogênicos, particularmente no tratamento de doenças avançadas. A recuperação hematopoética, utilizando esta fonte de células, é mais rápida após a utilização de CTP comparada com a MO. O sangue de cordão umbilical surgiu como uma outra fonte de células-tronco hematopoéticas para a realização de transplantes. O risco mínimo para o doador e a rápida disponibilidade estão entre as vantagens desta fonte de células. A recuperação mais lenta de neutrófilos e plaquetas é a maior preocupação do ponto de vista clínico. A biópsia de MO pode ser uma importante ferramenta para a obtenção de informações em relação à recuperação hematopoética após os transplantes de células-tronco hematopoéticas (TCTH). A histopatologia da reconstituição hematopoética da MO, após um transplante de sangue de cordão umbilical, demonstra um atraso quando comparada com os transplantes de MO. Entretanto, ocorre uma recuperação hematopoética gradual e, tardiamente, não são observadas diferenças entre os transplantes com MO e sangue de cordão umbilical. A histologia da MO, por sua vez, não esclarece a origem genotípica da hematopoese pós-transplante. Assim, a análise do quimerismo tornou-se um instrumento importante para o acompanhamento da enxertia e é a base da intervenção terapêutica para evitar a rejeição do enxerto, manter a enxertia e tratar uma recidiva clínica iminente através da imunoterapia. Esta revisão destacará a recuperação hematopoética após a realização de um TCTH.

Mobilized peripheral blood has replaced the use of bone marrow as a source of hematopoietic stem cells in most autologous transplants and is increasingly used in allogeneic transplants. The hematopoietic reconstitution after using mobilized peripheral blood is faster compared to bone marrow. Umbilical cord blood has emerged as another rich source of hematopoietic stem cells for transplantation. The minimal risk to the donor and the rapid availability are among the great advantages of this stem cell source. The slow recovery of neutrophil and platelet counts is the major clinical concern. Bone marrow biopsy is an important tool for obtaining information regarding the hematopoietic recovery after hematopoietic stem cell transplantation. The histopathological hematopoietic reconstitution of the bone marrow after umbilical cord blood transplantation is delayed compared to bone marrow transplantation. However, gradual hematopoietic recovery is seen, and afterwards no other differences comparing bone marrow and umbilical cord transplants are observed. Bone marrow histology does not elucidate the genotypic origin of post-transplant hematopoiesis. Hence, chimerism analysis has become an important instrument for engraftment surveillance, and is the basis for treatment intervention to avoid graft rejection, to maintain engraftment, and to treat clinical imminent relapse by immunotherapy. This review focuses on the hematopoietic recovery after hematopoietic stem cell transplantation.

Factors associated with bacteremia due to multidrug-resistant Gram-negative bacilli in hematopoietic stem cell transplant recipients

The epidemiology of bacteremia developing during neutropenia has changed in the past decade, with the re-emergence of Gram-negative (GN) bacteria and the development of multidrug resistance (MDR) among GN bacteria. We conducted a case-control study in order to identify factors associated with bacteremia due to multidrug-resistant Gram-negative (MDRGN) isolates in hematopoietic stem cell transplant recipients. Ten patients with MDRGN bacteremia were compared with 44 patients with GN bacteremia without MDR. Bacteremia due to Burkholderia or Stenotrophomonas sp was excluded from analysis (3 cases), because the possibility of intrinsical resistance. Infection due to MDRGN bacteria occurred in 2.9 percent of 342 hematopoietic stem cell transplant recipients. Klebsiella pneumoniae was the most frequent MDRGN (4 isolates), followed by Pseudomonas aeruginosa (3 isolates). Among non-MDRGN, P. aeruginosa was the most frequent agent (34 percent), followed by Escherichia coli (30 percent). The development of GN bacteremia during the empirical treatment of febrile neutropenia (breakthrough bacteremia) was associated with MDR (P < 0.001, odds ratio = 32, 95 percent confidence interval = 5_190) by multivariate analysis. Bacteremia due to MDRGN bacteria was associated with a higher death rate by univariate analysis (40 vs 9 percent; P = 0.03). We were unable to identify risk factors on admission or at the time of the first fever, but the occurrence of breakthrough bacteremia was strongly associated with MDRGN bacteria. An immediate change in the antibiotic regimen in such circumstances may improve the prognosis of these patients.

Chronic inflammatory demyelinating polyradiculoneuropathy in chronic graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: case report

The chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an unusual but important complication of hematopoietic stem cell transplantation (HSCT) rarely reported to date. We describe a 17-year-old woman with a diagnosis of acute myeloid leukemia due to Fanconi's anemia who was submitted to allogeneic HSCT and developed CIDP as part of graft-versus-host disease. Investigation showed high cerebrospinal fluid protein; electrophysiological studies revealed sensory-motor demyelinating polyradiculoneuropathy; muscle and nerve biopsy were compatible with CIDP.

A polirradiculoneuropatia desmielinizante inflamatória crônica (CIDP) é uma incomum, porém, importante complicação do transplante de células hematopoiéticas (HSCT) raramente relatada até a data. Nós descrevemos uma mulher de 17 anos com diagnóstico de leucemia mielóide aguda por anemia de Fanconi que foi submetida à HSCT e desenvolveu CIDP como parte da doença do enxerto contra o hospedeiro. A investigação mostrou elevação na proteína no líquor; estudo eletrofisiológico revelando polirradiculoneuropatia desmielinizante sensitivo-motora; e biópsia de músculo e nervo compatível com CIDP.

Monitoring Indexes of Plasma CsA Concentration in Patients Receiving Hematopoietic Stem Cell Transplantation / 中国药房

OBJECTIVE:To study the optimal monitoring indexes of plasma concentration of cyclosporine A(CsA) in patients receiving hematopoietic stem cell transplantation.METHODS:The lowest CsA concentration(C0) and the highest CsA concentration(C2) in 23 hematopoietic stem cell transplant recipients were detected by FPIA.All the data were analyzed statistically.RESULTS:Within 6 months after hematopoietic stem cell transplanttion,C0,C2,C0+C2 and C2/C0 in the recipients were(228.84?142.48) ?g?L-1,(741.50?294.42) ?g?L-1,(970.34?391.18) ?g?L-1 and(3.88?1.94) ?g?L-1,respectively.CONCLUSION:As reasonable monitoring indexes for the plasma concentration of CsA,C0+C2 and C2/C0 can comprehensively reflect the exposure of drug in body and monitor the toxicity of CsA in liver and kidney.