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1.
Haematologica ; 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33440924

RESUMO

Pediatric-onset Evans syndrome (pES) is defined by both immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) before the age of 18 years. There have been no comprehensive long-term studies of this rare disease, which can be associated to various immunopathological manifestations (IMs). We report outcomes of the 151 patients with pES and more than 5 years of follow-up from the nationwide French prospective OBS'CEREVANCE cohort. Median age at final follow-up was 18.5 (6.8-50.0) years and the median follow-up period was 11.3 (5.1-38.0) years. At 10 years, ITP and AIHA were in sustained complete remission in 54.5% and 78.4% of patients, respectively. The frequency and number of clinical and biological IMs increased with age: at 20 years old, 74% had at least one clinical cIM. A wide range of cIMs occurred, mainly lymphoproliferation, dermatological, gastrointestinal/hepatic and pneumological IMs. The number of cIMs was associated with a subsequent increase in the number of second-line treatments received (other than steroids and immunoglobulins; hazard ratio, 1.4; 95% confidence interval, 1.15-1.60; p = 0.0002, Cox proportional hazards method). Survival at 15 years after diagnosis was 84%. Death occurred at a median age of 18 (1.7-31.5) years, and the most frequent cause was infection. The number of second-line treatments and severe/recurrent infections were independently associated with mortality. In conclusion, longterm outcomes of pES showed remission of cytopenias but frequent IMs linked to high secondline treatment burden. Mortality was associated to drugs and/or underlying immunodeficiencies, and adolescents-young adults are a high-risk subgroup.

3.
J Pediatr ; 2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33340549

RESUMO

OBJECTIVE: To describe 4 subgroups of pediatric patients treated with splenectomy, hydroxychloroquine, azathioprine, or rituximab as the first-option, second-line treatment for chronic immune thrombocytopenia. STUDY DESIGN: Selection of patients with chronic immune thrombocytopenia from the French national prospective cohort of pediatric autoimmune cytopenia OBS'CEREVANCE and VIGICAIRE study, treated by splenectomy, hydroxychloroquine, azathioprine, or rituximab as a first second-line treatment. RESULTS: For 137 patients, treated between 1989 and 2016, the median follow-up after diagnosis and after treatment initiation was 8.5 (2.8-26.4) years and 4.7 (1.1-25.1) years, respectively. Median age at diagnosis and at initiation of treatment were 9 (0.7; 16) and 12 (2; 18.1) years, respectively without significant difference between subgroups. For the whole cohort, 24-month event-free survival was 62% (95% CI 55; 71). It was 85% (95% CI 77; 95) for the 56 patients treated with splenectomy, 60% (95% CI 44; 84) for the 23 patients treated with rituximab, 46% (95% CI 30; 71) for the 24 patients treated with azathioprine, and 37% (95% CI 24; 59) for the 34 patients treated with hydroxychloroquine (log-rank P < .0001). For the splenectomy subgroup, being older than 10 years at splenectomy tended to improve event-free survival (P = .05). Female teenagers with antinuclear antibody positivity benefited from hydroxychloroquine therapy. CONCLUSIONS: This national study, limiting pitfalls in the analysis of the effects of second-line therapies, showed that splenectomy remains the treatment associated with the better response at 24 months.

5.
J Exp Med ; 217(11)2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-32812031

RESUMO

Epstein-Barr virus (EBV) preferentially infects epithelial cells and B lymphocytes and sometimes T and NK lymphocytes. Persistence of EBV-infected cells results in severe lymphoproliferative disorders (LPDs). Diagnosis of EBV-driven T or NK cell LPD and chronic active EBV diseases (CAEBV) is difficult, often requiring biopsies. Herein, we report a flow-FISH cytometry assay that detects cells expressing EBV-encoded small RNAs (EBERs), allowing rapid identification of EBV-infected cells among PBMCs. EBV-infected B, T, and/or NK cells were detectable in various LPD conditions. Diagnosis of CAEBV in 22 patients of Caucasian and African origins was established. All exhibited circulating EBV-infected T and/or NK cells, highlighting that CAEBV is not restricted to native American and Asian populations. Proportions of EBV-infected cells correlated with blood EBV loads. We showed that EBV-infected T cells had an effector memory activated phenotype, whereas EBV-infected B cells expressed plasma cell differentiation markers. Thus, this method achieves accurate and unambiguous diagnoses of different forms of EBV-driven LPD and represents a powerful tool to study their pathophysiological mechanisms.

10.
Leukemia ; 34(6): 1658-1668, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31776464

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a rare aggressive myelodysplastic/myeloproliferative neoplasm of early childhood, initiated by RAS-activating mutations. Genomic analyses have recently described JMML mutational landscape; however, the nature of JMML-propagating cells (JMML-PCs) and the clonal architecture of the disease remained until now elusive. Combining genomic (exome, RNA-seq), Colony forming assay and xenograft studies, we detect the presence of JMML-PCs that faithfully reproduce JMML features including the complex/nonlinear organization of dominant/minor clones, both at diagnosis and relapse. Further integrated analysis also reveals that although the mutations are acquired in hematopoietic stem cells, JMML-PCs are not always restricted to this compartment, highlighting the heterogeneity of the disease during the initiation steps. We show that the hematopoietic stem/progenitor cell phenotype is globally maintained in JMML despite overexpression of CD90/THY-1 in a subset of patients. This study shed new lights into the ontogeny of JMML, and the identity of JMML-PCs, and provides robust models to monitor the disease and test novel therapeutic approaches.


Assuntos
Células-Tronco Hematopoéticas/patologia , Leucemia Mielomonocítica Juvenil/patologia , Células-Tronco Neoplásicas/patologia , Adolescente , Animais , Criança , Pré-Escolar , Feminino , Xenoenxertos , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/genética , Masculino , Camundongos , Mutação
11.
Pediatr Infect Dis J ; 39(3): 258-259, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31876612

RESUMO

We are reporting a case of Bacillus Calmette-Guérin vaccine-disseminated infection in a 19-month-old HIV-negative girl diagnosed with severe combined immunodeficiency. While standard culture protocols failed to isolate and culture the Mycobacterium bovis Bacillus Calmette-Guérin strain, it was isolated from skin and mesenteric lymph node biopsies using the shell-vial assay, allowing whole-genome sequencing and in silico drug susceptibility testing.


Assuntos
Testes de Sensibilidade Microbiana/métodos , Mycobacterium bovis , Imunodeficiência Combinada Severa/complicações , Tuberculose/diagnóstico , Tuberculose/etiologia , Antituberculosos/uso terapêutico , Biópsia , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/métodos , Quimioterapia Combinada , Feminino , Humanos , Lactente , Linfonodos/microbiologia , Linfonodos/patologia , Mycobacterium bovis/efeitos dos fármacos , Mycobacterium bovis/genética , Mycobacterium bovis/imunologia , Imunodeficiência Combinada Severa/terapia , Úlcera Cutânea/etiologia , Úlcera Cutânea/patologia , Resultado do Tratamento , Tuberculose/tratamento farmacológico
12.
J Clin Immunol ; 39(7): 702-712, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31401750

RESUMO

PURPOSE: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles. METHODS: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included. RESULTS: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04). CONCLUSION: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.


Assuntos
Serviços Médicos de Emergência , Hospitalização , Doenças da Imunodeficiência Primária/epidemiologia , Adulto , Criança , Controle de Doenças Transmissíveis , Doenças Transmissíveis/etiologia , Gerenciamento Clínico , França/epidemiologia , Humanos , Incidência , Profilaxia Pré-Exposição , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/etiologia , Doenças da Imunodeficiência Primária/terapia , Vigilância em Saúde Pública , Resultado do Tratamento
14.
Blood ; 134(1): 9-21, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-30940614

RESUMO

Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M- group). The M+ group displayed more severe disease than the M- group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.


Assuntos
Anemia Hemolítica Autoimune/genética , Anemia Hemolítica Autoimune/imunologia , Trombocitopenia/genética , Trombocitopenia/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Mutação , Adulto Jovem
15.
J Clin Immunol ; 39(2): 200-206, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30900095

RESUMO

PURPOSE: Neonatal immune neutropenia is observed in rare cases in newborns from mothers with idiopathic or autoimmune neutropenia, secondary to passive transfer of maternal granulocyte auto-antibodies. METHODS: We performed a literature review and report four supplementary cases from the French registry of neutropenia. RESULTS: Only 14 cases (11 mothers, 14 newborns) have been reported. Granulocyte aggregation (GAT) and granulocyte indirect immunofluorescence test (GIFT) are the recommended laboratory procedures for antibody detection. Monoclonal antibody-specific immobilization of granulocyte antigens (MAIGA)-confirmed antibody specificity. Antibody detection in newborns is not generally possible owing to extreme neutropenia. In half of the cases autoantibodies against neutrophils (AAN) were positive in maternal sera (7 out of 11). In some newborns tested, IgG+ AAN were also positive, with disappearance in parallel of spontaneous neutrophil count improvement. No correlation between maternal type of AAN and titer and neonatal neutropenia can be established. Neutropenia resolved spontaneously between 2 weeks and 4 months. Infections in newborns were observed in 43% of cases, with no deaths reported. Granulocyte colony-stimulating factor (G-CSF) was administered to some newborns (5 out of 14) in the case of infections. Low-dose G-CSF administered to childbearing women during pregnancy could be proposed to prevent neutropenia in newborns. CONCLUSIONS: From the few cases reported so far it is impossible to draw any conclusions regarding frequency, risk factors, and outcome, but the overall prognosis for newborns seems good. Because it can be associated with potentially severe neonatal infections, autoimmune neutropenia in childbearing mothers should be closely monitored in collaboration with gynecologists and pediatricians.


Assuntos
Neutropenia , Complicações Hematológicas na Gravidez , Adulto , Autoanticorpos/sangue , Feminino , França , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Granulócitos/imunologia , Humanos , Recém-Nascido , Infecções/tratamento farmacológico , Infecções/etiologia , Contagem de Leucócitos , Masculino , Mães , Neutropenia/sangue , Neutropenia/complicações , Neutropenia/imunologia , Gravidez , Complicações Hematológicas na Gravidez/sangue , Complicações Hematológicas na Gravidez/imunologia
16.
J Allergy Clin Immunol Pract ; 7(6): 1958-1969.e9, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30825606

RESUMO

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) germline mutations have been recently described. A comprehensive overview of this early-onset multiorgan autoimmune and lymphoproliferative disease has not yet been compiled. OBJECTIVE: We have conducted a systematic review of published STAT3 GOF cases to describe clinical, diagnostic, and therapeutic aspects of the disease. METHODS: A systematic review including articles published before October 10, 2018, in PubMed, Web of Science, and Cochrane Central Register of Controlled Trials databases was performed. We described cases of patients with STAT3 GOF germline mutations with genetic analysis and a concordant phenotype if functional analyses were not performed for the mutation. RESULTS: The search identified 18 publications describing 42 unique patients. Twenty-eight different mutations were described. Onset of disease was very early with an average age of 3 (0.5-5) years. The most frequent manifestations were autoimmune cytopenias (28 of 42), lymphoproliferation (27 of 42), enteropathy (24 of 42), interstitial lung disease (15 of 42), thyroiditis (13 of 42), diabetes (10 of 42), and postnatal growth failure (15 of 21). Immunodeficiency was not always a predominant feature. Most patients required significant immunosuppressive therapy. Five patients received hematopoietic stem cell transplantation, and 4 died from complications. Improvement of symptoms was observed for 8 of 9 patients who received targeted biotherapies. CONCLUSIONS: STAT3 GOF syndrome is a new clinical entity to consider when confronted with a patient with early-onset polyautoimmunity, lymphoproliferation, and growth failure. At this time, precise therapeutic guidelines are lacking, but use of anti-IL-6 receptor and JAK inhibitor biologics is an attractive possibility.


Assuntos
Fator de Transcrição STAT3/genética , Doenças do Sistema Endócrino/genética , Mutação com Ganho de Função , Gastroenteropatias/genética , Mutação em Linhagem Germinativa , Doenças Hematológicas/genética , Humanos , Doenças do Sistema Imunitário/genética , Pneumopatias/genética
17.
J Allergy Clin Immunol ; 143(6): 2238-2253, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30660643

RESUMO

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.


Assuntos
Ligante de CD40/deficiência , Transplante de Células-Tronco Hematopoéticas , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Resultado do Tratamento , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/mortalidade
18.
J Allergy Clin Immunol Pract ; 7(3): 848-855, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30391550

RESUMO

BACKGROUND: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8-deficient patients. RESULTS: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent lymphoma (1). Survival after matched related (n = 40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive. CONCLUSIONS: HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced-toxicity regimen may offer the best chance for survival.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/deficiência , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro , Humanos , Síndromes de Imunodeficiência/mortalidade , Lactente , Estimativa de Kaplan-Meier , Masculino , Adulto Jovem
19.
Proc Natl Acad Sci U S A ; 115(34): E8007-E8016, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30072435

RESUMO

Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5'-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5'-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.


Assuntos
Éxons , Síndromes de Imunodeficiência/genética , Mutação , Penetrância , Biossíntese de Proteínas/genética , Processamento de RNA/genética , Receptores de Laminina/genética , Proteínas Ribossômicas/genética , Baço/anormalidades , Regiões 5' não Traduzidas , Feminino , Efeito Fundador , Heterozigoto , Humanos , Síndromes de Imunodeficiência/metabolismo , Masculino , Doenças da Imunodeficiência Primária , Receptores de Laminina/biossíntese , Proteínas Ribossômicas/biossíntese , Baço/metabolismo
20.
Front Immunol ; 9: 1036, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29868001

RESUMO

The syndromic diarrhea/trichohepatoenteric syndrome (SD/THE) is a rare and multi-system genetic disorder caused by mutation in SKIV2L or in TTC37, two genes encoding subunits of the putative human SKI complex involved in RNA degradation. The main features are intractable diarrhea of infancy, hair abnormalities, facial dysmorphism, and intrauterine growth restriction. Immunologically this syndrome is associated with a hypogammaglobulinemia leading to an immunoglobulin supplementation. Our immune evaluation of a large French cohort of SD/THE patient revealed several immunological defects. First, switched memory B lymphocytes count is very low. Second, IFN-γ production by T and NK cells is impaired and associated with a reduced degranulation of NK cells. Third, T cell proliferation was abnormal in 3/6 TTC37-mutated patients. These three patients present with severe EBV infection and a transient hemophagocytosis which may be related to these immunological defects. Moreover, an immunological screening of patients with clinical features of SD/THE could facilitate both diagnosis and therapeutic management of these patients.


Assuntos
Linfócitos B/imunologia , Diarreia Infantil/complicações , Doenças do Cabelo/complicações , Síndromes de Imunodeficiência/etiologia , Células Matadoras Naturais/imunologia , Proteínas de Transporte/genética , Estudos de Coortes , DNA Helicases/genética , Diarreia Infantil/imunologia , Facies , Retardo do Crescimento Fetal/imunologia , Doenças do Cabelo/imunologia , Humanos , Síndromes de Imunodeficiência/genética , Memória Imunológica , Lactente , Recém-Nascido , Interferon gama/imunologia , Células Matadoras Naturais/patologia , Contagem de Linfócitos , Mutação , Linfócitos T/imunologia
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