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1.
Blood Adv ; 2(7): 777-786, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29618462

RESUMO

Patients with juvenile idiopathic arthritis (JIA) can experience a severe disease course, with progressive destructive polyarthritis refractory to conventional therapy with disease-modifying antirheumatic drugs including biologics, as well as life-threatening complications including macrophage activation syndrome (MAS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative immunomodulatory strategy for patients with such refractory disease. We treated 16 patients in 5 transplant centers between 2007 and 2016: 11 children with systemic JIA and 5 with rheumatoid factor-negative polyarticular JIA; all were either refractory to standard therapy, had developed secondary hemophagocytic lymphohistiocytosis/MAS poorly responsive to treatment, or had failed autologous HSCT. All children received reduced toxicity fludarabine-based conditioning regimens and serotherapy with alemtuzumab. Fourteen of 16 patients are alive with a median follow-up of 29 months (range, 2.8-96 months). All patients had hematological recovery. Three patients had grade II-IV acute graft-versus-host disease. The incidence of viral infections after HSCT was high, likely due to the use of alemtuzumab in already heavily immunosuppressed patients. All patients had significant improvement of arthritis, resolution of MAS, and improved quality of life early following allo-HSCT; most importantly, 11 children achieved complete drug-free remission at the last follow-up. Allo-HSCT using alemtuzumab and reduced toxicity conditioning is a promising therapeutic option for patients with JIA refractory to conventional therapy and/or complicated by MAS. Long-term follow-up is required to ascertain whether disease control following HSCT continues indefinitely.

2.
J Clin Immunol ; 37(1): 42-50, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27807805

RESUMO

PURPOSE: We aimed to achieve a retrospective molecular diagnosis by applying state-of-the-art genomic sequencing methods to past patients with T-B+NK+ severe combined immunodeficiency (SCID). We included identification of copy number variations (CNVs) by whole exome sequencing (WES) using the CNV calling method ExomeDepth to detect gene alterations for which routine Sanger sequencing analysis is not suitable, such as large heterozygous deletions. METHODS: Of a total of 12 undiagnosed patients with T-B+NK+ SCID, we analyzed eight probands by WES, using GATK to detect single nucleotide variants (SNVs) and small insertions and deletions (INDELs) and ExomeDepth to detect CNVs. RESULTS: We found heterozygous single- or multi-exon deletions in IL7R, a known disease gene for autosomal recessive T-B+NK+ SCID, in four families (seven patients). In three families (five patients), these deletions coexisted with a heterozygous splice site or nonsense mutation elsewhere in the same gene, consistent with compound heterozygosity. In our cohort, about a quarter of T-B+NK+ SCID patients (26%) had such compound heterozygous IL7R deletions. CONCLUSIONS: We show that heterozygous IL7R exon deletions are common in T-B+NK+ SCID and are detectable by WES. They should be considered if Sanger sequencing fails to detect homozygous or compound heterozygous IL7R SNVs or INDELs.


Assuntos
Éxons , Heterozigoto , Receptores de Interleucina-7/genética , Deleção de Sequência , Sequenciamento Completo do Exoma , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Feminino , Expressão Gênica , Humanos , Mutação INDEL , Ativação Linfocitária , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-7/metabolismo , Estudos Retrospectivos , Fator de Transcrição STAT5/metabolismo , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia , Fluxo de Trabalho
3.
Emerg Infect Dis ; 22(10): 1720-7, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27648582

RESUMO

Severe infections are emerging as major risk factors for death among children with juvenile idiopathic arthritis (JIA). In particular, children with refractory JIA treated with long-term, multiple, and often combined immunosuppressive and antiinflammatory agents, including the new biological disease-modifying antirheumatic drugs (DMARDs), are at increased risk for severe infections and death. We investigated 4 persons with JIA who died during 1994-2013, three of overwhelming central venous catheter-related bacterial sepsis caused by coagulase-negative Staphylococus or α-hemolytic Streptococcus infection and 1 of disseminated adenovirus and Epstein-Barr virus infection). All 4 had active JIA refractory to long-term therapy with multiple and combined conventional and biological DMARDs. Two died while receiving high-dose systemic corticosteroids, methotrexate, and after recent exposure to anti-tumor necrosis factor-α biological DMARDs, and 2 during hematopoietic stem cell transplantation procedure. Reporting all cases of severe infections and especially deaths in these children is of paramount importance for accurate surveillance.


Assuntos
Artrite Juvenil/complicações , Infecções Relacionadas a Cateter/etiologia , Cateteres Venosos Centrais/efeitos adversos , Sepse/etiologia , Infecções por Adenovirus Humanos/etiologia , Adolescente , Corticosteroides/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Artrite Juvenil/mortalidade , Bacteriemia/etiologia , Bacteriemia/mortalidade , Criança , Infecções por Vírus Epstein-Barr/etiologia , Evolução Fatal , Feminino , Humanos , Metotrexato/uso terapêutico , Insuficiência de Múltiplos Órgãos/etiologia , Infecções Estafilocócicas/etiologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Viremia/etiologia
6.
Br J Haematol ; 145(1): 73-83, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19222467

RESUMO

Chronic granulomatous disease (CGD) causes recurrent infection and inflammatory disease. Despite antimicrobial prophylaxis, patients experience frequent hospitalisations and 50% mortality by 30 years. Haematopoietic stem cell transplantation (HSCT) can cure CGD with resolution of infection and colitis. This study reports the survival and long-term outcome in 20 conditioned patients treated between 1998 and 2007, using 10 matched sibling (MSD) and 10 unrelated donors (URD). Age at HSCT, graft-versus-host disease (GvHD), growth, and outcome were analysed. Fourteen had > or = 1 invasive infection, 10 had colitis and seven had growth failure before HSCT. Median age at transplantation was 75 months (range 15 months-21 years). Eighteen (90%) were alive 4-117 months (median 61) after HSCT with normal neutrophil function. Two died from disseminated fungal infection. Two experienced significant chronic GvHD, with continuing sequelae in 1. Colitis resolved within 8 weeks of HSCT. Mean weight and height for age Z scores on recovery from HSCT rose significantly (P < 0.001). HSCT with MSD or URD gave excellent engraftment and survival, remission of colitis and catch-up growth, with low incidence of significant GvHD. Transplant-associated complications were restricted to those with pre-existing infection or inflammation, supporting the argument for early HSCT for more CGD patients with a well matched donor.


Assuntos
Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas , Irmãos , Adolescente , Adulto , Criança , Pré-Escolar , Seguimentos , Doença Enxerto-Hospedeiro/complicações , Doença Granulomatosa Crônica/imunologia , Doença Granulomatosa Crônica/fisiopatologia , Crescimento , Teste de Histocompatibilidade , Humanos , Lactente , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Doadores de Tecidos , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
7.
Mol Immunol ; 47(1): 46-51, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19203795

RESUMO

UNLABELLED: As part of collaborative multi-centre study started in 2000, 7 children in the UK fulfilled the inclusion criteria for treatment with autologous T cell depleted (TCD) haematopoietic stem cell transplantation (HSCT) for severe juvenile idiopathic arthritis (JIA). Here we report on the outcome and transplant-related complications. OUTCOME: The initial, often dramatic clinical response in all patients was followed in 4 with sustained benefit, including the withdrawal of immunosuppressive and anti-inflammatory treatment, significant catch-up growth and immense improvement of the quality of life during 5-8 years long follow-up. Two patients relapsed within 1-12 months, and one died 4 months post transplant. COMPLICATIONS: Adenovirus reactivation with dissemination was lethal in one patient, whilst Epstein-Barr (EBV) and cytomegalovirus (CMV) reactivation-driven haemophagocytic syndrome responded to antiviral and immunomodulatory treatment in 2 patients. Both the conditioning and the T cell depletion of the graft, leading to severe immunosuppression and prolonged immune system function reconstitution, are the main predisposing factors for potentially life-threatening transplant-related complications. CONCLUSIONS: Autologous TCD HSCT for children with severe JIA results in two-phase response. The initial remission seen in all patients is due to immunosuppressive conditioning. This is followed by sustained drug-free remission in over 50% of patients, which is due to 'immunomodulatory' effects of TCD HSCT. The procedure carries a significant morbidity and mortality risk. However, this risk should be balanced against the risks of life-threatening infections occurring in this very selective group of patients on long-term and combined immunosuppressive and anti-inflammatory therapies. How to correctly identify and appropriately assess the patients in need for autologous TCD HSCT, particularly in relation to optimizing the timing for the procedure in regards to the newly available therapies with different biologic response modifiers, are some of the most important questions awaiting answers from this on-going study.


Assuntos
Artrite Juvenil/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Depleção Linfocítica , Adolescente , Artrite Juvenil/complicações , Artrite Juvenil/mortalidade , Criança , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Imunossupressão/efeitos adversos , Masculino , Seleção de Pacientes , Medição de Risco , Fatores de Tempo , Transplante Autólogo , Resultado do Tratamento , Reino Unido , Ativação Viral
8.
J Allergy Clin Immunol ; 121(2): 361-7, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18086494

RESUMO

BACKGROUND: Results of treatment of severe T-lymphocyte immunodeficiencies by means of hematopoietic stem cell (HSC) transplantation have improved. T cell-depleted haploidentical transplantations are successful if there is no HLA-identical donor. Methods to remove T lymphocytes include addition of anti-CD52 antibodies and CD34(+) HSC selection. OBJECTIVE: Assessment of long-term immune function is important after these treatments. We looked at immune reconstitution in 36 survivors for more than 2 years after HSC transplantation for severe T-lymphocyte immunodeficiencies and compared engraftment quality between the 2 T-lymphocyte depletion methods. METHODS: Chimerism, T- and B-lymphocyte subsets, immunoglobulin levels, and specific antibody production at last follow-up were examined. The chi(2) (Fisher exact test) and Wilcoxon rank sum analyses were used to compare the groups. RESULTS: Nineteen patients received anti-CD52-treated and 19 anti-CD34-treated HSCs. More anti-CD52-treated patients had full donor myeloid chimerism (P = .025). All patients had full donor T-lymphocyte chimerism. There was no difference in donor B-lymphocyte chimerism, but significantly more anti-CD52-treated patients had class-switched memory B lymphocytes (P = .024), normal IgG levels, and normal responses to tetanus and Haemophilus influenzae type B vaccination. More anti-CD52-treated patients with common gamma chain or Janus-associated kinase 3 severe combined immunodeficiency had donor B lymphocytes. CONCLUSION: Long-term T-lymphocyte function is good with either treatment method, with a low incidence of graft-versus-host disease. The results imply more incomplete donor chimerism in anti-CD34-treated patients with less B-lymphocyte function.


Assuntos
Anticorpos/uso terapêutico , Antígenos CD34/imunologia , Antígenos CD/imunologia , Antígenos de Neoplasias/imunologia , Glicoproteínas/imunologia , Transplante de Células-Tronco Hematopoéticas , Sistema Imunitário/fisiopatologia , Síndromes de Imunodeficiência/terapia , Linfócitos T , Linfócitos B , Antígeno CD52 , Infecções por Haemophilus/prevenção & controle , Haemophilus influenzae tipo b , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/patologia , Imunoglobulina G/sangue , Síndromes de Imunodeficiência/fisiopatologia , Memória Imunológica , Lactente , Subunidade gama Comum de Receptores de Interleucina/deficiência , Janus Quinase 3/deficiência , Estudos Longitudinais , Estudos Retrospectivos , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/metabolismo , Imunodeficiência Combinada Severa/patologia , Índice de Gravidade de Doença , Toxoide Tetânico/uso terapêutico , Quimeras de Transplante , Vacinação
10.
Pediatr Infect Dis J ; 26(2): 129-33, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17259874

RESUMO

BACKGROUND: Patients with severe combined immunodeficiency and preexisting viral pneumonitis formally had a poor outcome from hematopoietic stem cell transplantation. With inhaled steroid and antitumor necrosis factor alpha antibody treatment, results improved. The poor outcome of patients with viral central nervous system infection prompted this retrospective single center review. RESULTS: Eight of 71 patients with severe combined immunodeficiency transplanted since 1987 were identified with viral central nervous system infection (adenovirus [1], cytomegalovirus [2], Epstein-Barr virus [2], parvovirus [1], varicella zoster virus [1], human herpesvirus 6 [1]). Nonspecific neurologic symptoms included drowsiness, irritability, head lag, fisting and floppiness. Later symptoms included unresponsiveness, apnea, posturing, hypotonia, hyperreflexia and seizures. All had neuroradiologic investigations. Only one had an initially normal computed tomography scan. Magnetic resonance image abnormalities included cerebral atrophy, basal ganglia changes, diffuse leukoencephalopathy, and multifocal mass lesions. Five patients had virus identified from cerebrospinal fluid by polymerase chain reaction and brain tissue examination from 3 patients identified human herpesvirus 6, adenovirus type 41 and varicella zoster virus. Three children remain alive, 2 received replete marrow and one remains untransplanted. Others who received T cell depleted marrow died of neurologic sequelae. CONCLUSION: Outcome of viral central nervous system infection after hematopoietic stem cell transplantation for severe combined immunodeficiency is poor, particularly associated with T cell depleted marrow.


Assuntos
Viroses do Sistema Nervoso Central/complicações , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/terapia , Viroses do Sistema Nervoso Central/patologia , Viroses do Sistema Nervoso Central/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do Tratamento
12.
J Clin Microbiol ; 43(3): 1462-4, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15750134

RESUMO

Adenovirus causes disseminated disease following bone marrow transplantation (BMT). We report a child who underwent T-cell-depleted BMT. Adenovirus subgenus F serotype 41 was detected antemortem by PCR in cerebrospinal fluid and postmortem in other tissues. Serotypes 40 and 41, associated with gastrointestinal disease, have not previously been implicated in disseminated disease.


Assuntos
Infecções por Adenovirus Humanos/etiologia , Adenovírus Humanos/classificação , Transplante de Medula Óssea/efeitos adversos , Imunodeficiência Combinada Severa/terapia , Adenovírus Humanos/isolamento & purificação , Feminino , Humanos , Lactente , Reação em Cadeia da Polimerase
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