Experiencia de una década en niños sometidos a esplenectomía en el Hospital Nacional de Niños / Experience on children's splenectomy: a ten year single center retrospective study

Resumen Objetivo: describir las características clínicas y la evolución de los pacientes sometidos a esplenectomía en el Hospital Nacional de Niños, de enero de 1996 a diciembre del 2006. Métodos: este es un estudio descriptivo retrospectivo que analiza un periodo de 10 años, de pacientes sometidos a esplenectomías en el Hospital Nacional se Niños. Se realizó una revisión de 107 expedientes con el diagnóstico en cuestión. De estos expedientes se obtuvieron: datos clínicos, epidemiológicos, indicaciones para el procedimiento y su respectiva evolución, complicaciones y mortalidad asociada. Se analiza además el seguimiento de las recomendaciones con respecto a profilaxis antibiótica y vacunación. Resultados: se analizó una muestra total de 107 casos. Entre los resultados se encontró que la edad promedio de intervención fue de 6,4 años. Los diagnósticos más comunes fueron hemoglobinopatías (59,8 %), púrpura trombocitopénica idiopática (16,8 %) y osteopetrosis maligna (8,4 %). Entre las indicaciones para esplenectomías predominaron el tratamiento de enfermedad de base (39,9%), hiperesplenismo (26,2 %) y ausencia de respuesta al tratamiento médico (22,4 %). El procedimiento quirúrgico más común fue la laparotomía en el 87,9 % de los casos. La complicación quirúrgica inmediata más frecuente fue la hemorragia persistente (3,7 %), mientras que la complicación quirúrgica tardía más común fue la sepsis (16,8 %). La respuesta terapéutica en la mayoría de los pacientes fue completa (66,7 %). Hubo 5 pacientes fallecidos, de los cuales en dos se relacionó su mortalidad con sepsis. La edad promedio al momento de fallecimiento fue de 6,7 años. Conclusiones: la esplenectomía es una alternativa para el tratamiento de las enfermedades médicas, tras la cual se evidenció una respuesta satisfactoria en la mayoría de los casos del estudio.

Abstract Aim: to describe clinical characteristics and evolution of patients who underwent splenectomy in Costa Rica's National Children's Hospital during January 1996 through December 2006. Methods: This is a chart review study in a 10 year period including children who underwent splenectomy. A hundred and seven charts of children with ages between 0 and 18 years old were reviewed to obtain their clinical presentation, characteristics, indications for splenectomy, follow up, complications and mortality. Also the antibiotic prophylaxis and immunization schedule was analyzed based on international recommendations. Results: A total of 107 patients were included. Results showed that the mean age at which splenectomy was performed was 6.4 years. Most of the patients had their splenectomy due to hemoglobinophaties (59.8%), followed by immune thrombocytopenic purpura (16.8%) and malignant osteopetrosis (8.4%). The most common indications for splenectomy were treatment of the disease (39.9%), hyperesplenism (26.2%) and lack of responde to medical treatment (22.4%). Laparotomy was the most performed surgery (87.9%). Mainly sepsis and hemorrhage were found as complications due to procedure. Overall, complete response to surgical treatment was observed (66.7%). Five patients died during follow up. Conclusions: Splenectomy is an alternative for treating medical disease with predominantly good outcomes observed in our study.

Successful matched sibling donor marrow transplantation following reduced intensity conditioning in children with hemoglobinopathies.

Fifty-two children with symptomatic sickle cell disease sickle cell disease (SCD) (N = 43) or transfusion-dependent thalassemia (N = 9) received matched sibling donor marrow (46), marrow and cord product (5), or cord blood (1) allografts following reduced intensity conditioning (RIC) with alemtuzumab, fludarabine, and melphalan between March 2003 and May 2014*. The Kaplan-Meier probabilities of overall and event-free survival at a median of 3.42 (range, 0.75-11.83) years were 94.2% and 92.3% for the group, 93% and 90.7% for SCD, and 100% and 100% for thalassemia, respectively. Treatment-related mortality (all related to graft versus host disease, GVHD) was noted in three (5.7%) recipients, all 17-18 years of age. Acute and chronic GVHD was noted in 23% and 13%, respectively, with 81% of recipients off immunosuppression by 1 year. Graft rejection was limited to the single umbilical cord blood recipient who had prompt autologous hematopoietic recovery. Fourteen (27%) had mixed chimerism at 1 year and beyond; all had discontinued immunosuppression between 4 and 12 months from transplant with no subsequent consequence on GVHD or rejection. Infectious complications included predominantly bacteremia (48% were staphylococcus) and CMV reactivation (43%) necessitating preemptive therapy. Lymphocyte recovery beyond 6 months was associated with subsidence of infectious complications. All patients who engrafted were transfusion independent; no strokes or pulmonary complications of SCD were noted, and pain symptoms subsided within 6 months posttransplant. These findings support using RIC for patients with hemoglobinopathy undergoing matched sibling marrow transplantation (*www.Clinical Trials.gov: NCT00920972, NCT01050855, NCT02435901).

[Results of hematopoietic stem cell transplantation in hemoglobinopathies: thalassemia major and sickle cell disease]. / Resultados del trasplante de progenitores hematopoyéticos en hemoglobinopatías: talasemia maior y enfermedad drepanocítica.

BACKGROUND: The prevalence of hemoglobinopathies in Spain is increasing as a result of immigration. Thalassemia major presents with chronic hemolytic anemia that requires regular red blood cell transfusions within the first year of life. Patients with sickle cell disease suffer from chronic anemia, vasculopathy and progressive damage in almost any organ. There is decreased life expectancy in both conditions. Allogeneic hematopoietic stem cell transplantation represents the only potentially curative option. PATIENTS: Seventeen patients (fourteen thalassemia major, and three sickle cell disease) underwent allogeneic hematopoietic stem cell transplantations. RESULTS: In the thalassemia group, nine donors were HLA-geno-identical siblings, two were partially matched related donors (one HLA allele mismatch), and three unrelated donors. All three patients with sickle cell disease were transplanted from HLA-geno-identical siblings. The source of stem cells was bone marrow in sixteen cases. Median patient age at transplant was six years (range: 1-16) in the thalassemia group, and twelve years (range: 8-15) in the sickle cell disease group. The graft was successful in all patients. Secondary graft rejection was observed in two thalassemia patients rendering them dependent on blood transfusions. Complete chimerism was observed in thirteen patients and, although mixed chimerism occurred in two, with all of them showing normal hemoglobin levels after transplantation and not requiring further transfusion support. Patients affected by sickle cell disease did not present with new vaso-occlusive crises, and stabilization of pulmonary and neurological function was observed. Chronic graft-versus-host disease was detected in three patients affected by thalassemia, and hypogonadotrophic hypogonadism in five patients. CONCLUSIONS: We conclude that for thalassemia major and sickle cell disease, allogenic hematopoietic stem cell transplantation from HLA-geno-identical siblings offers a high probability of complication-free survival. Despite good results, morbidity and mortality associated with transplantation from unrelated donors is a risk that might be considered, in contrast to a non-curative medical treatment that offers a long term survival. For thalassemia major groups it could be an option, but not for sickle cell disease, which is still in the investigational phase.

Hematopoietic stem cell transplantation for hemoglobinopathies: current practice and emerging trends.

Despite improvements in the management of thalassemia major and sickle cell disease, treatment complications are frequent and life expectancy remains diminished for these patients. Hematopoietic stem cell transplantation (HSCT) is the only curative option currently available. Existing results for HSCT in patients with hemoglobinopathy are excellent and still improving. New conditioning regimens are being used to reduce treatment-related toxicity and new donor pools accessed to increase the number of patients who can undergo HSCT.

Glutathione S-transferase T1-null seems to be associated with graft failure in hematopoietic SCT.

Hematopoietic SCT (HSCT) from HLA-matched donors is sometimes complicated by GVHD or graft rejection, because of mismatched mHA. This study presents data suggesting the involvement of glutathione S-transferase theta-1 (GSTT1), a phase II detoxifying enzyme encoded by GSTT1, in Ab-mediated rejection of HSCT in children with congenital hemoglobinopathies (CHs). Mismatch of GSTT1, which often features a deletion polymorphism variant, can have major consequences in solid organ transplantation outcome. In liver transplantation, it has been shown to lead to de novo hepatitis, whereas in kidney transplantation, chronic allograft rejection has been documented. In this study on 18 children with CH who underwent HSCT, five cases of graft rejection occurred, all in GSTT1-null patients, four of which featured anti-GSTT1 antibodies. The data suggest that when GSTT1-null patients are transplanted with a GSTT1-positive graft, rejection due to an Ab-mediated immune response against GSTT1 displayed on transplanted stem cells may take place. Thus, it seems that detection of anti-GSTT1 antibodies in patients with a GSTT1-null genotype before transplantation may be predictive of graft rejection in the event of a GSTT1-positive donor.

High incidence of severe cyclosporine neurotoxicity in children affected by haemoglobinopaties undergoing myeloablative haematopoietic stem cell transplantation: early diagnosis and prompt intervention ameliorates neurological outcome.

BACKGROUND: Neurotoxicity is a recognized complication of cyclosporine A (CSA) treatment. The incidence of severe CSA-related neurological complications following hematopoietic stem cell transplantation (HSCT) is 4-11%. METHODS: We describe 6 cases of CSA related neurotoxicity out of 67 matched related HSCT performed in paediatric Middle East patients affected by haemoglobinopaties (5 beta thalassemia major, 1 sickle cell disease-SCD). Conditioning regimen consisted of iv busulphan, cyclophosphamide and graft-versus-host-disease (GvHD) prophylaxis with CSA, methylprednisolone, methotrexate and ATG. RESULTS: All 6 patients presented prodromes such as arterial hypertension, headache, visual disturbances and vomiting, one to two days before overt CSA neurotoxicity. CSA neurotoxicity consisted of generalized seizures, signs of endocranial hypertension and visual disturbances at a median day of onset of 11 days after HSCT (range +1 to +40). Brain magnetic resonance imaging (MRI) performed in all subjects showed reversible leukoencephalopathy predominantly in the posterior regions of the brain (PRES) in 5/6 patients. EEG performed in 5/6 patients was always abnormal. Neurotoxicity was not explainable by high CSA blood levels, as all patients had CSA in the therapeutic range with a median of 178 ng/ml (range 69-250). CSA was promptly stopped and switched to tacrolimus with disappearance of clinical and radiological findings. All patients are symptoms-free at a median follow up of 882 days (range 60-1065). CONCLUSIONS: Our experience suggests that paediatric patients with haemoglobinopaties have a high incidence of CSA related neurological events with no correlation between serum CSA levels and neurotoxicity. Prognosis is good following CSA removal. Specific prodromes such as arterial hypertension, headache or visual disturbances occurring in the early post-transplant period should be carefully evaluated with electrophysiological and MRI-based imaging in order to intervene promptly and avoid irreversible sequels.

Transplant outcomes in bone marrow failure syndromes and hemoglobinopathies.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potential cure for most bone marrow (BM) failure syndromes and hemoglobinopathies. Over the past decade, umbilical cord blood (UCB) has been used more frequently as a stem cell source in patients who lack a suitable BM donor. Although graft failure remains a significant problem, UCB transplantation (UCBT) using the optimal conditioning regimen can be a salvage treatment for patients without a suitable BM donor and warrants evaluation in further prospective studies.

Related cord blood banking for haematopoietic stem cell transplantation.

The aims of this single centre study were to assess the feasibility of related cord blood collecting, the appropriateness of storage and the final suitability for transplantation. Since September 1994, 63 families were enrolled in this study. Families were eligible if they were caring for a patient with a disorder treatable by haematopoietic stem cell transplantation and were experiencing a pregnancy. A total of 72 cord blood units were collected and stored for 64 patients (both siblings and parents). We focussed on human leucocyte antigen (HLA) compatibility and cell content as critical requirements to unit's suitability for transplantation. HLA-typing was carried out for 34 donor-recipient couples and most units (72%) mismatched with the related patients. About 60% of collections had a minimum cell dose considered acceptable for transplantation. Only 21% of units had both compatibility degree and cell content suitable for transplantation. When applicable, information on the compatibility degree between the foetus and the patient should be obtained during pregnancy. Appropriateness of related cord blood banking for parents should be further investigated and cost-effective guidelines policies should be provided. Finally, as banking of related cord blood units is an important resource then, this public service should be supported and enhanced.

Hematopoietic stem cell gene transfer for the treatment of hemoglobin disorders.

Hematopoietic stem cell (HSC)-targeted gene transfer is an attractive approach for the treatment of a number of hematopoietic disorders caused by single gene defects. Indeed, in a series of gene transfer trials for two different primary immunodeficiencies beginning early in this decade, outstanding success has been achieved. Despite generally low levels of engrafted, genetically modified HSCs, these trials were successful because of the marked selective advantage of gene-corrected lymphoid precursors that allowed reconstitution of the immune system. Unlike the immunodeficiencies, this robust level of in vivo selection is not available to hematopoietic repopulating cells or early progenitor cells following gene transfer of a therapeutic globin gene in the setting of beta-thalassemia and sickle cell disease. Both preclinical and clinical transplant studies involving bone marrow chimeras suggest that 20% or higher levels of engraftment of genetically modified HSCs will be needed for clinical success in the most severe of these disorders. Encouragingly, gene transfer levels in this range have recently been reported in a lentiviral vector gene transfer clinical trial for children with adrenoleukodystrophy. A clinical gene transfer trial for beta-thalassemia has begun in France, and one patient with transfusion-dependent HbE/beta-thalassemia has demonstrated a therapeutic effect after transplantation with autologous CD34(+) cells genetically modified with a beta-globin lentiviral vector. Here, the development and recent progress of gene therapy for the hemoglobin disorders is reviewed.

Umbilical cord blood transplantation: pros, cons and beyond.

Large body of clinical and scientific data has been generated since the first cord blood transplantation (CBT) was performed in 1989. Superior immune plasticity of CB grafts, that allows for less stringent HLA matching, is especially valuable in the face of a persistently growing need for unrelated donor (UD) transplants. Limited cell dose remains the main setback of CBT, particularly in adult population. New strategies, such as transplantation with two cord blood units or using non-myeloablative conditioning, have remarkably expanded the availability of CB transplants in adults with hematological malignancies. Clinical trials with in vitro expanded CB-derived stem cells are under way. Currently cord blood is considered a second best choice after matched bone marrow. However, results of recent international studies indicate that in particular clinical settings, such as in children with leukemia, CB may become a frontline hematopoietic stem cell (HSC) source for transplantation. Recent advances in understanding the unique biology of cord blood will further expand indications for its use in different settings, including those beyond hematopoietic stem cells transplantation (HSCT).

Reappraisal of in utero stem cell transplantation based on long-term results.

The therapeutic field of in utero transplantation of stem cells, into human fetuses, has developed since 1988 with the hope of improved probability of engraftment and tolerance, due to immune immaturity of the host. Fifteen years later, it is possible to evaluate the results that we and others have obtained in the treatment of several fetal diseases. Seven fetal patients have been treated in Lyon: In 2 cases, pregnancy termination was induced by the in utero injection; in the 5 other cases, engraftment was obtained and repeatedly documented with presence of donor HLA antigens and/or Y chromosome in recipients. In the 2 patients with combined immunodeficiency disease, a sustained reconstitution of immunity was obtained as a result of the transplant but other complications occurred thereafter. In patients with thalassemia major, Niemann-Pick disease or hemophilia, a very partial and very transitory benefit was only obtained. Approximately 33 other patients with immunodeficiencies, hemoglobinopathies or inborn errors of metabolism have been treated worldwide, over the last 13 years, with a comparable method, using parental or fetal stem cells transplanted in utero. Successful treatment has usually been recorded in immunodeficiencies, and insufficient results have been obtained in the other cases. This form of treatment can therefore be recommended after prenatal diagnosis of combined immunodeficiency but additional research is required to improve the degree of engraftment, the lack of resistance of the host and the 'space' available for hematopoiesis in the other conditions.

Stem cell therapy in utero.

In utero stem cell transplantation represents a new and still experimental therapeutic strategy for diseases related to the hematopoietic system, i.e. hemoglobinopathies, immunodeficiency diseases and metabolic disorders. To date, a total of 21 cases of transplantations using stem cells either of fetal liver or adult bone marrow origin have been reported in the literature. Success has been limited--with the exception of one case of beta-thalassemia--to four cases with immunodeficiency diseases. In this review the broad therapeutic implications as well as potentials and limitations of this technique are summarized. Furthermore, ethical considerations based on the use of fetal cells are pointed out and a prospective view concerning experimental and clinical future perspectives including the possibility for gene therapy is presented.

Neuroanestesia y Drepanocitosis: reporte de dos casos y revisión de la literatura / Neuroanesthesia and sickle cell disease: case report and literature review

Los autores describen dos casos de pacientes con anemia drepanocítica quienes presentaron hemorragia subaracnoidea por ruptura de aneurisma intracraneal, y fueron llevados a cirugía para su clipaje. Ambos tuvieron una evolución intra y postoperatoria satisfactoria. Se hizo una revisión bibliográfica acerca del manejo médico y anestésico perioperatorio a propósito de esta rara asociación de patologías. El control multidisciplinario de variables tales como hemoglobina, hemoglobina S, hidratación oxigenación, equilibrio ácido base y temperatura entre otras, garantizará la exitosa recuperación de estos pacientes

Fetal hematopoietic stem cell transplantation.

In utero hematopoietic stem cell transplantation (IUHSCTx) is a promising approach for the treatment of a potentially large number of fetuses affected by congenital hematologic disorders. With technical and molecular advances in prenatal diagnosis, the majority of these diseases can now be diagnosed early in gestation, allowing consideration of prenatal treatment. In addition, technical advances in fetal imaging and intervention make it possible to perform the transplants with relatively minimal risk. It, therefore, stands to reason that there is increasing interest in performing in utero hematopoietic stem cell transplantation at many fetal treatment centers. Although the approach remains experimentally promising, expansion of clinical application will depend on improved understanding of the biological barriers to engraftment in the fetus as well as the development of effective clinical strategies based on the hematopoietic biology of individual disorders. This article presents the current status of this emerging therapeutic approach.

[AS heterozygote hemoglobinopathy and coronary risk]. / Hémoglobinopathie hétérozygote AS et risque coronaire.

There have been several reports of vaso-occlusive events and sudden death in subjects with sickle cell trait. However, the precise mechanism underlying these episodes remains unclear. The clinical observations have been supported by in vitro studies in which haemoglobin AS (Hb AS) red cells showed abnormalities of their filterability, probably related to gelling or polymerisation of the Hb AS. These in vitro studies and reports in the literature of sickle-cell hearts led the authors to investigate the possible association between AS subject and coronary risk. The results of coronary angiography in 9 patients with Hb AS, paired with respect to the usual cardiovascular risk factors, were compared with those of 18 AA subjects. The number of patients who underwent coronary bypass surgery for three-vessel disease was much greater in the AS subjects. However, the difference was not statistically significant. This tendency of AS subjects to develop thrombosis and coronary artery disease requires further study with larger numbers of patients.

The spleen in children.

The spleen contributes importantly to the normal and pathologic removal of blood cells from the circulation and to defense against infection with encapsulated bacteria. Surgical splenectomy provides efficacious treatment for a number of pediatric disorders but is associated with perioperative morbidity and a life-long risk of overwhelming infection. Alternatives to conventional splenectomy include laparoscopic splenectomy, partial splenectomy, partial splenic embolization, and autologous splenic transplantation. Sickle cell disease is the most common cause of functional asplenia in children. Asplenia develops during infancy in many infants with sickle cell anemia, and prophylactic penicillin markedly reduces mortality from pneumococcal infection. In contrast, recent evidence suggests that children with sickle-hemoglobin C disease do not develop functional asplenia before 3 to 4 years of age and thus may not benefit from penicillin prophylaxis. Recommendations for the treatment of asplenic patients include pneumococcal, Haemophilus influenzae type b, and meningococcal immunizations, antimicrobial prophylaxis for selected patients, and prompt evaluation and aggressive treatment of acute febrile illness.

Bone marrow transplant for the haemoglobinopathies: past, present and future.

Bone marrow transplantation (BMT) is the only treatment currently available which can cure thalassaemia and sickle cell anaemia. However, it is not without risk and the complications of graft failure, GVHD, veno-occlusive disease, interstitial pneumonitis and infections, together with the toxicity of the conditioning therapy result in a transplant-related mortality in children of 10-20%. For the survivors, long-term sequelae include chronic GVHD, endocrinopathies and an increased incidence of secondary malignancies. The decision to offer BMT to a patient with a haemoglobinopathy must be based on a knowledge of the relative risks of transplant and conventional therapy. However, in sickle cell anaemia, a subset of patients with particularly severe disease can be identified at an early age when the risks associated with BMT are at their lowest. In thalassaemia, chelation therapy can delay the onset of organ damage due to hypertransfusion but is unlikely to prevent it entirely. The results of BMT in children without organ impairment are excellent and BMT must now be considered a real alternative to conventional treatment. Gene therapy is an exciting prospect for the future but recent progress in retroviral gene transfer has been hindered by poor infection efficiencies and expression levels in the target cells. The identification of the positive regulatory elements of both the alpha- and beta-globin genes may resolve some of these problems. Finally, alternative gene delivery systems are being investigated, but the introduction of gene therapy for the haemoglobinopathies into clinical practice may need to await successful gene targeting and replacement.

Bone marrow transplantation for thalassemia in Thailand.

We report our experience of bone marrow transplantation for thalassemia in Thailand. From July 1988 to September 1992, 10 thalassemic patients underwent allogeneic bone marrow transplantation. Two of them were homozygous beta-thalassemia and 8 were beta-thalassemia/Hb E disease. Seven were male and 3 female. The age ranged from 1.8-14 years. The conditioning regimen comprised busulfan 14 mg/kg and cyclophosphamide 200 mg/kg. For GVHD prophylaxis, either cyclosporine alone or in combination with short methotrexate was given. Five patients were alive and well 104-1534 days after transplantation. Three patients with severe manifestations at the time of transplant had partial engraftment, and lost their graft within 3 months. They survived with thalassemia 1041-1357 days after transplantation. One patient who received one antigen mismatched marrow from her brother had no engraftment and was alive with thalassemia 1429 days posttransplant. One patient died early on day 9 from CNS complication. No GVHD was observed in this series. These results indicate that bone marrow transplantation can cure thalassemia but there is still high autologous recovery rate in those with severe manifestations.