RESUMO
Diamond-Blackfan anemia (DBA) is a congenital anemia with erythroid cell aplasia. Most of the causative genes are ribosomal proteins. GATA1, a hematopoietic master transcription factor required for erythropoiesis, also causes DBA. GATA1 is located on Xp11.23; therefore, DBA develops only in males in an X-linked inheritance pattern. Here, we report a case of transient erythroblastopenia and moderate anemia in a female newborn infant with a de novo GATA1 variant. In this patient, increased methylation of the GATA1 wild-type allele was observed in erythroid cells. Skewed lyonization of GATA1 may cause mild transient erythroblastopenia in a female patient.
Assuntos
Anemia Aplástica , Anemia de Diamond-Blackfan , Anemia Hemolítica Congênita , Masculino , Lactente , Recém-Nascido , Humanos , Feminino , Proteínas Ribossômicas/genética , Anemia de Diamond-Blackfan/genética , Eritropoese , Fator de Transcrição GATA1/genéticaRESUMO
BACKGROUND: Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT). OBJECTIVES: This study sought to characterize HCT outcomes in APDS. METHODS: Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT. RESULTS: Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT. CONCLUSIONS: Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Doenças da Imunodeficiência Primária/terapia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Rejeição de Enxerto , Humanos , Estimativa de Kaplan-Meier , Inibidores de MTOR/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Doenças da Imunodeficiência Primária/mortalidade , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID). METHODS: We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID. RESULTS: The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival. CONCLUSIONS: RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are required to optimize the conditioning regimen for non-SCID PID.
Assuntos
Bussulfano/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Melfalan/uso terapêutico , Doenças da Imunodeficiência Primária/terapia , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Bussulfano/farmacocinética , Pré-Escolar , Combinação de Medicamentos , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Contagem de Leucócitos , Masculino , Doenças da Imunodeficiência Primária/imunologia , Doenças da Imunodeficiência Primária/mortalidade , Estudos Retrospectivos , Resultado do Tratamento , Vidarabina/uso terapêuticoAssuntos
Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/etiologia , Citomegalovirus , Laringite/diagnóstico , Laringite/etiologia , Imunodeficiência Combinada Severa/complicações , Adolescente , Antivirais/uso terapêutico , Biópsia , Criança , Classe Ia de Fosfatidilinositol 3-Quinase/genética , Infecções por Citomegalovirus/tratamento farmacológico , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Humanos , Lactente , Laringite/tratamento farmacológico , Masculino , Mutação , Imunodeficiência Combinada Severa/etiologia , Imunodeficiência Combinada Severa/imunologia , Avaliação de Sintomas , Resultado do TratamentoAssuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , DNA/genética , Dermatite/etiologia , Mutação , Síndromes Mielodisplásicas/genética , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Dermatite/diagnóstico , Dermatite/genética , Humanos , Masculino , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/metabolismo , Sequenciamento Completo do Genoma/métodosRESUMO
Human adenovirus infection (HAdV) may be fatal in patients undergoing allogeneic hematopoietic cell transplantation (HCT). Cidofovir is effective in only a part of the post-HCT HAdV infection. Therefore, posttransplant immune reconstitution is important for HAdV clearance. We describe the detailed immune reconstitution and response of adenovirus-specific T cells in a patient with inborn errors of immunity who had disseminated HAdV infection with hepatitis post-HCT and was treated with cidofovir. Though the patient received cidofovir for only 19 days starting from Day 72 after HCT because of renal dysfunction, we observed T-cell reconstitution, a decrease in HAdV copy number, and amelioration of the symptoms of HAdV infection after Day 90. We initially observed expanded NK and CD8+CD45RO+ memory subsets and later gradual increase of naïve T cells eveloped after cessation of cidofovir treatment. An increase in adenovirus-specific IFN-γ secretion from 2 to 4 months after HCT was confirmed by ELISpot assay. The progression of immune reconstitution and cidofovir treatment are considered to have contributed to survival in this patient. Optimization of transplantation methods, prompt appropriate antiviral medication, and virus-specific T-cell therapy would be necessary as the better strategy for systemic HAdV infection.
RESUMO
Background: Chronic granulomatous disease (CGD) is an inborn immune disorder in which the phagocytic system cannot eradicate pathogens, and autoinflammation occurs. Approximately half of the patients have associated gastrointestinal symptoms. Although most cases with CGD-associated colitis present nonspecific histology, colonoscopy in some cases shows brownish dots over a yellowish oedematous mucosa, which is termed a "leopard sign". However, the significance of these signs remains unclear. Methods: We collected data from patients with CGD whose colonoscopic findings showed the leopard sign. Results: Three patients with CGD and leopard signs were enrolled in this study. One patient underwent colonoscopy for frequent diarrhoea and weight gain failure, and another for anal fistula. The third patient was without gastrointestinal symptoms and underwent colonoscopy as a screening test before allogeneic haematopoietic cell transplantation (HCT). Endoscopic findings showed a mild leopard sign in the first case; however, non-contiguous and diffuse aphthae were observed throughout the colon. The other two cases were unremarkable except for the leopard sign. All the patients achieved remission with oral prednisolone or HCT. One patient underwent colonoscopy after HCT; results revealed improvements in endoscopy (including the leopard sign) and histological findings. However, another patient underwent colonoscopy after prednisolone treatment; this revealed no change in the leopard sign. Conclusion: The leopard sign in the colon may be a characteristic endoscopic finding of CGD, even in patients who do not develop severe gastrointestinal symptoms; however, it does not reflect the severity of CGD-associated colitis.
Assuntos
Colite , Gastroenteropatias , Doença Granulomatosa Crônica , Humanos , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/terapia , Colite/etiologia , Colite/complicações , Colonoscopia , Gastroenteropatias/complicações , PrednisolonaRESUMO
Severe combined immunodeficiency (SCID) is an inborn error of immunity that occurs in approximately 1 in 50,000 births, mainly due to impaired lymphocyte differentiation. Without curative treatment, such as hematopoietic cell transplantation (HCT) or gene therapy, severe infection in the first year of life could make this condition fatal. The results of HCT are poor when patients have active infections, thus requiring early diagnosis before onset of infection. In five cases of SCID diagnosed in Japan, the oral rotavirus vaccine had been administered before diagnosis. In this study, we demonstrated that the rotavirus from their stools was a vaccine-derived strain. In some cases, severe gastroenteritis triggered the diagnosis of SCID. However, newborn screening for SCID is available before the first rotavirus vaccination using assays for the detection of T-cell receptor excision circles (TRECs). Therefore, to improve the prognosis of patients with SCID in Japan, we should establish a screening system of TRECs for newborns throughout Japan.
Assuntos
Rotavirus , Imunodeficiência Combinada Severa , DNA , Humanos , Recém-Nascido , Japão , Triagem Neonatal/métodos , Rotavirus/genética , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia , Vacinação/efeitos adversosRESUMO
Idiopathic pneumonia syndrome (IPS) is an acute lung complication observed after the early posthematopoietic stem cell transplantation (HSCT) period. Ruxolitinib was effective for a patient with myelodysplastic syndrome who developed severe IPS after second HSCT. No severe adverse effects were observed. Ruxolitinib may be an alternative choice for HSCT-related IPS.